REVIEW | doi:10.20944/preprints202002.0015.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cholangiocarcinoma; autophagy inhibition; autophagy inhibition; chemoresistance
Online: 3 February 2020 (05:20:36 CET)
Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multi-step nature of the process offers multiple regulation points prone to be deregulated and cause different human disease, but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within tumor microenvironment, but also to increase invasiveness and resistance to anti-cancer drugs such as chemotherapy. This review collects all clinical evidences of autophagy deregulation during cholangiocarcinogenesis together with all pre-clinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggests an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Pre-clinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer
COMMUNICATION | doi:10.20944/preprints202311.1331.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: medicinal plants; tyrosinase inhibition; melanin inhibition; hypermelanosis; cosmetics; skin lightening
Online: 22 November 2023 (07:31:58 CET)
There is a growing demand and use of herbal cosmetics for skin purposes due to their perceived safety when applied to the skin. Three Cassipourea species commonly known as “ummemezi” are used interchangeable by women in rural areas of Eastern Cape and KwaZulu-Natal provinces to treat hypermelanosis as well as sun protection. We conducted a phytochemical comparison of three Cassipourea species; C. flanaganii, C. gummiflua and C. malosana by LC-MS/MS analysis in negative mode. The results obtained from the LC-MS/MS yielded a total number of twenty-four compounds of different chemical classes, including fatty acids, steroids, di- and tri-terpenoids, flavonoids, phenolic acids were detected, and eighteen among them were tentatively identified. Despite the recent popularity of modern cosmetic products, it is clear that plants continue to play an important role in the local cosmetics industry in South Africa's Eastern Cape and KwaZulu-Natal community provinces. The findings of this study suggest that an alternative treatment for hyper-melanosis disorders should be developed further. The residual wild plant stocks are insufficient to meet commercial needs, thus, encouraging their sustainable use is a means of harnessing the conservation of these plants. Indigenous communities should be supported in the commercialization which could be linked to the rural economic development.
ARTICLE | doi:10.20944/preprints202102.0267.v2
Subject: Social Sciences, Psychology Keywords: response inhibition; behavioral inhibition; psychopathy traits; Go/NoGo task; smokers
Online: 11 February 2021 (13:32:51 CET)
Aims: Adolescence is a critical period because the brain is involved in the process of maturation that entails cognitive functions. On the way of maturation, an individual’s inhibitory control undergoes many changes and becomes vulnerable to different thrill-seeking like smoking, drinking, and so on. Smoking is highly prevalent among teenagers that are trying to take control of their behaviors in order to join society. They experience antisocial behavior too which is a trait that can lead adolescents to addiction. This trait is an inevitable part of psychopathy. Inhibitory deficits and psychopathy have been widely reported in addiction studies. The current study tried to investigate the relationship between psychopathic traits and behavioral inhibition between male smokers and non-smoker teenage students.Materials & Methods: Statistical sample of this research is 62 teenage students aged 17 years that are divided into smoker and non-smoker groups. The participants have been chosen through random sampling from the population of 10 high schools. The data have been gathered in Kordkoy and Gorgan in Golestan province. Behavioral bias has been measured by Go/NoGo task and psychopathic traits through youth psychopathic traits inventory. Also, the short form of Wechsler Adult Intelligence Scale test has been executed and used as a control variable.Findings: A meaningful difference has been found between the performance of smoker and non-smoker groups in Go/No Go task and psychopathic traits that are smokers performed weaker in comparison with non-smokers and psychopathic traits of smokers were meaningfully higher than non-smokers. On the other hand, there was no significant difference between these two groups in their Wechsler Adult Intelligence Scale scores.Conclusion: The results have shown that smokers have higher psychopathic traits and lower behavioral inhibition when compared with their non-smoker peers. According to the results of current research, smoking can decline the cognitive functions.
ARTICLE | doi:10.20944/preprints202308.1001.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: Brass; Corrosion; Inhibition efficiency; ESBB
Online: 14 August 2023 (09:39:15 CEST)
The Voltammetric and polarographic methods are proposed to determine the short time corro-sion rates of brass in 1N HCl solution. It should be noted that it is also possible to determine the corrosion rates of each species present in the solution, simultaneously like Cu (II) and Zn (II) in brass. Samples extracted from bark of Babul (ESBB) is used as corrosion inhibitors. The corrosion inhibition efficiency is 96% at 24h after the test started. These results are compared with the av-erage corrosion rates obtained by using gravimetric (PIT) and some electrochemical methods i.e. galvanostatic and potentiodynamic polarization measurements.
ARTICLE | doi:10.20944/preprints202305.2053.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: cancer; inhibition; resonant; frequency; formant
Online: 30 May 2023 (05:23:20 CEST)
Pulsed electric fields of specific frequencies emitted by a glass plasma antenna tube have been shown to slow the growth of Acute Lymphoblastic Leukemia cells by as much as 43% when exposed to a series of frequencies between 156kHz and 162kHz. This narrow band of frequencies is termed a “Destructive Cancer Resonant Frequency Formant” (DCRFF).
ARTICLE | doi:10.20944/preprints202108.0468.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Neisseria mucosa; Neisseria gonorrhoeae; inhibition
Online: 24 August 2021 (13:57:51 CEST)
We used agar overlay assays to assess if 24 circulating and historical isolates of Neisseria mucosa could inhibit the growth of 28 circulating and historical isolates of N. gonorrhoeae. We found no evidence of inhibition by N. mucosa (n=24). Positive controls Streptococcus pneumoniae and Escherichia coli demonstrated a strong inhibitory effect against the growth of N. gonorrhoeae.
ARTICLE | doi:10.20944/preprints202002.0018.v1
Online: 3 February 2020 (05:45:33 CET)
The amyloid fibril formation by $\alpha$-synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson's disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient aggregation inhibitor of numerous proteins, among them $\alpha$-synuclein. Here we show that this applies only to a small region of relevant parameter space and that under some conditions, EGCG can even accelerate α-synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that contrary to previous reports, EGCG is not able to re-model α-synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α-synuclein, but the inhibitory action is not robust against various relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterise promising amyloid inhibitors.
ARTICLE | doi:10.20944/preprints202309.1919.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: influenza; vaccines; antibodies; neuraminidase-inhibition; persistence.
Online: 28 September 2023 (17:59:45 CEST)
Neuraminidase (NA)-based immunity could reduce the harmful impact of novel antigenic variants of influenza viruses. Detection of neuraminidase-inhibiting (NI) antibodies in parallel with anti-hemagglutinin (HA) antibodies may enhance research of immunogenicity and duration of antibody response to influenza vaccines. To assess anti-NA antibodies after vaccination with seasonal inactivated influenza vaccines, we used the enzyme-linked lectin assay, and anti-HA antibodies were detected in hemagglutination inhibition assay. The dynamics of anti-NA antibody response differed depending on the virus subtype: antibodies to A/H3N2 virus neuraminidase increased later than antibodies to A/H1N1pdm09 subtype neuraminidase, and persisted longer. In contrast to HA antibodies, the fold increase in antibody titers to NA after vaccination poorly depended on the preexisting level. At the same time, NA antibody level after vaccination directly correlated with titers before vaccination. Difference was found in response to NA antigen between split and subunit adjuvanted vaccines and in NA functional activity in the vaccine formulations.
ARTICLE | doi:10.20944/preprints201705.0174.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: steroid; metabolism; anti-inflammatory drug; inhibition
Online: 24 May 2017 (08:25:26 CEST)
In vitro studies show that diclofenac inhibits enzymatic steroid glucuronidation. This study was designed to investigate the influence of diclofenac on the excretion of stanozolol and 3'-hydroxystanozolol via analyses in hair, blood and urine in vivo in a rat study. Brown Norway rats were administered with stanozolol (weeks 1-3) and diclofenac (weeks 1-6). Weekly assessment of steroid levels in hair was complemented with spot urine and serum tests. Levels of both stanozolol and 3'-hydroxystanozolol steadily increased in hair during stanozolol treatment and decreased post-treatment, but remained readily detectable for 6 weeks. In contrast, compared to control rats, diclofenac significantly reduced urinary excretion of 3’-hydroxystanozolol which was undetectable in most samples. This is the first report of diclofenac altering steroid metabolism in vivo, detrimentally affecting detection in urine, but not in hair which holds considerable advantages over urinalysis for anti-doping tests.
REVIEW | doi:10.20944/preprints202306.1180.v3
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: PCa; AR; ADT; TLK1 signaling; pathway inhibition
Online: 25 June 2023 (03:56:10 CEST)
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas’ associated with poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas’ still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained under-represented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
ARTICLE | doi:10.20944/preprints202306.0062.v1
Subject: Biology And Life Sciences, Food Science And Technology Keywords: inhibition; dairy products; cheese; essential oil; pathogens.
Online: 1 June 2023 (08:12:53 CEST)
“Minas Frescal” cheese is a high moisture product, subject to the proliferation of several microorganisms. Essential oils are natural antimicrobial alternatives that can increase the quality of dairy products. This study aimed to analyze the antimicrobial action of oregano (Origanum vulgare) and rosemary (Rosmarinus officinalis) essential oils against Escherichia coli and Staphylococcus aureus. An antimicrobial test by diffusion and microdilution was performed to calculate the MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration). The behavior of E. coli in “Minas Frescal” cheese added with oregano oil was evaluated. The MIC of oregano oil was 0.25% against E. coli and 1% against S. aureus. For rosemary essential oil, the MIC was 8% of against E. coli. There was no activity of rosemary oil against S. aureus. The MBC observed for oregano essential oil was 1% and 0.25% respectively for S. aureus and E. coli. Bacterial analysis during cheese storage with E. coli indicated inhibition of microorganisms by oregano essential oil at a concentration of 0.25%. No alterations were observed regards to physical-chemical attributes. The use of essential oil as an antimicrobial agent has potential for industrial use, and type of microorganism, oil and sensory reflexes in the product must be observed.
ARTICLE | doi:10.20944/preprints202306.0014.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: SGLT2 inhibition; empagliflozin; heart failure; interleukin 6
Online: 1 June 2023 (03:33:38 CEST)
Background: Inhibition of sodium-glucose co-transporter 2 (SGLT-2) has been shown to be beneficial in the treatment of diabetic and non-diabetic patients with heart failure with reduced ejection fraction (HFrEF). The underlying mechanisms are incompletely understood. The present prospective study investigates for the first time the effect of empagliflozin on various soluble markers of inflammation in HFrEF. Methods: We included 50 inpatients with HFrEF and diabetes mellitus type 2. Half of the patients received a therapy with the SGLT-2-inhibitor empagliflozin in addition to standard medication, the other half of the patients did not receive empagliflozin and were considered as control group. Quality of life, functional status and soluble immunological parameters in serum were assessed at baseline and after 3 months. Results: Baseline characteristics of both groups revealed no significant differences. Patients on empagliflozin demonstrated a significant improvement in the Minnesota living with heart failure questionnaire (baseline 44.2 ± 20.2 vs. 24 ± 17.7; p<0.001), in distance in the 6-minute walk test (baseline 343 ± 145 m vs. 450 ± 115 m; p<0.001) and in soluble interleukin-6 level (baseline 21.7 ± 21.8 pg/ml vs. 13.7 ± 15.8 pg/ml; p=0.008). There was no significant change of these or other parameters in the control group (p>0.05 each). Conclusions: The empagliflozin-induced improvement of quality of life and functional capacity in patients with HFrEF and type 2 diabetes mellitus is accompanied by a substantial reduction of interleukin-6 levels. Thus, antiinflammatory effects may contribute to the benefits of SGLT2-inhibitors in heart failure.
ARTICLE | doi:10.20944/preprints202305.1276.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: Paeonia suffruticosa; benzofuranones; cytotoxicity; NO production inhibition
Online: 18 May 2023 (05:26:34 CEST)
The Paeonia suffruticosa, called as 'Feng Dan', has been used for thousands of years in traditional Chinese medicine. In our chemical investigation on the root bark of the plant, five new phenolic dimers, namely paeobenzofuranone A‒E (1‒5), have been characterized. Their structures were determined by spectroscopic analysis including 1D and 2D NMR, HRESIMS, UV, and IR, as well as ECD calculations. Compounds 2, 4, and 5 showed cytotoxicity against three human cancer cell lines with IC50 values ranging from 6.7 to 25.1 μM. Compounds 1 and 2 showed certain inhibitory activity on NO production. To the best of our knowledge, the benzofuranone dimers and their cytotoxicity of P. suffruticosa are reported for the first time.
COMMUNICATION | doi:10.20944/preprints202212.0429.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: onion; PCR inhibition; pollenkitt; wetted pollen; pollination
Online: 22 December 2022 (12:58:49 CET)
There is little information on the use of pollen in molecular research, despite the increased interest to genome editing by pollen mediated transformation. PCR is useful tool as an express-method to evaluate editing results before pollination. A direct PCR protocol for pollen suspension has been adapted without the need for DNA pre-extraction. We showed that pollenkitt is a limiting factor for successful PCR on pollen. A simple pre-washing step of pollen suspension was able to eliminate the pollenkitt and enormously affect the PCR results. All currently existing methods of delivery of the editing system to pollen are carried out in a wet medium. Our pollenkitt study helped us develop a simple and effective pollination method using wetted onion pollen grains.
ARTICLE | doi:10.20944/preprints202209.0010.v1
Subject: Social Sciences, Behavior Sciences Keywords: neuromodulation; baroreflex sensitivity; dmNTS; pain inhibition; fibromyalgia
Online: 1 September 2022 (07:32:51 CEST)
The study presents a novel approach of programing pain inhibition in chronic pain patients based on the hypothesis that pain perception is modulated by dysfunctional dorsal medial nucleus tractus solitarii (dmNTS) reflex arcs that produce diminished baroreflex sensitivity (BRS) resulting from a conditioned response. This study tested whether administration of noxious and non-noxious electrical stimuli synchronized with the cardiac cycle resets BRS, reestablishing pain inhibition. 30 pain-free normotensives controls (NC) and 32 normotensives fibromyalgia (FM) patients received two, ≈8 minute-epochs of cardiac-gated, peripheral electrical stimuli. Non-painful and painful electrical stimuli were synchronized to the cardiac cycle as the neuromodulation experimental protocol (EP) with 2 control conditions (CC1, CC2). BRS, heart-rate-variability (HRV), pain threshold and tolerance, and clinical pain intensity were assessed.Reduced BRS in FM at baseline increased by 41% during two, ≈8 minute-epochs of stimulation. Thresholds in FM increased significantly during the experimental protocol (all Ps<0.001) as did HRV. FM levels of clinical pain significantly decreased by 35.52% during the experimental protocol but not during control stimulations (P<0.001). Baroreceptor training may reduce FM pain by BRS-mediated effects on intrinsic pain regulatory systems and autonomic pain modulation. These processes seem to be linked by classical and operant conditioning.
ARTICLE | doi:10.20944/preprints202108.0001.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Antitumoral drug; Choline kinase inhibition; Choline uptake
Online: 2 August 2021 (08:42:22 CEST)
Choline kinase inhibitors are an important class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here we present the characterization and the structure activity relationship of a series of non-symmetrical choline kinase inhibitors characterized by a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and for their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the best inhibitory results were those connected to the linker by the N-atom (4a-h) and these results are supported by docking studies. The compounds with the best antiproliferative results were those connected to the linker by the O-atom (3a-h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is greater the shorter the length of the linker, while in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with a low toxicity in non-tumoral cells (e.g human peripheral lymphocytes) respect to cancer cells. These compounds were also able to induce to induce apoptosis in Jurkat leukemic cells without causing significative variations of cell cycle. It is worth to mention that these derivatives, beside their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.
ARTICLE | doi:10.20944/preprints202011.0597.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Arylsulfatase; β-glucuronidase; Hydrogen peroxide; Hypochlorite; Inhibition
Online: 23 November 2020 (19:22:12 CET)
Arylsulfatase and β-glucuronidase are two important enzymes in human, which play important role on dynamic equilibrium of steroidal estrogens. This work probably for the first time reported that hydrogen peroxide (H2O2), hypochlorite and peracetic acid (PAA) could effectively inhibit the activities of arylsulfatase and/or β-glucuronidase. The 50 percent of inhibitions (IC50) of H2O2, and PAA on arylsulfatase were found to be 142.90±9.00, 91.83±10.01, and 43.46±2.92 μM, respectively. The corresponding respective IC50 of hypochlorite and PAA on β-glucuronidase were 704.90±41.40 and 23.26±0.82 μM, while H2O2 showed no inhibition on β-glucuronidase. It was further revealed that the inhibition of hypochlorite on both arylsulfatase and β-glucuronidase was irreversible. On the contrary, the inhibition by H2O2 and PAA was reversible. Moreover, it was found that the inhibitions of arylsulfatase and/or β-glucuronidase by these three chemicals were pH-dependent, among which the inhibition by H2O2 was competitive and non-competitive for PAA. In general, H2O2 and hypochlorite can be endogenously produced in human, which suggested that the two compounds are potential endocrine disruption compounds (EDCs) as they can cause endocrine disruption via inhibition of arylsulfatase and β-glucuronidase. This work further indicated that any agent that can induce production of H2O2 or hypochlorite in human is potential EDC, which explains why some EDCs with very weak or no estrogenic potency can cause endocrine disruption that confirmed in epidemiological studies.
ARTICLE | doi:10.20944/preprints201810.0355.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: assay; diarrhea; isolate; hydrolysis; proteins; inhibition zone
Online: 16 October 2018 (11:26:59 CEST)
The study compared antibacterial potential of hydrolysates of casein and alpha-lactalbumin from cow and goat milk on diarrhea-causing Escherichia coli and Staphylococcus aureus. Milk samples were aseptically obtained from lactating cows and goats. The samples were skimmed; casein was isolated using acetic acid and alpha-lactalbumin by filtrate thermoprecipitation at 75 °C. 50% of each isolate was reconstituted in a buffer and hydrolyzed with papain at 55 °C for 2 hours. The hydrolysates were heated to 75 °C to inactivate papain, cooled and their antibacterial activity determined by disc diffusion method. Results showed alpha-lactalbumins had higher degrees of hydrolysis and antibacterial activity than caseins; goat alpha-lactalbumin had the highest antibacterial activity with mean inhibition zones of 19.60 mm and 19.50 mm on E. coli and S. aureus. Cow alpha-lactalbumin inhibited E. coli more than S. aureus with inhibition zones of 16.80 mm and 12.50 mm. Cow and goat milk casein hydrolysates inhibited E. coli with mean inhibition zones of 8.00 mm and 10.90 mm and inhibited S. aureus with inhibition zones of 4.13 mm and 1.90 mm respectively. The research showed that the milk hydrolysates can be a source of antibiotics for diarrhea treatment. Research should be done to establish the peptide fractions associated with the observed bioactivity.
ARTICLE | doi:10.20944/preprints202303.0458.v1
Subject: Biology And Life Sciences, Food Science And Technology Keywords: acetic acid bacteria; alcohol tolerance; antioxidant activity; angiotensin-converting enzyme inhibition; α-glucosidase inhibition; Acetobacter cerevisiae; Acetobacter pasteurianus.
Online: 27 March 2023 (10:33:16 CEST)
Acetic acid bacteria (AAB) form a bacterial film on the surface of alcoholic solutions and ferment ethanol to acetic acid while also producing bioactive compounds. To discover functional AAB for industrial use, we isolated and selected strains from farm-produced vinegars using a CaCO3-containing medium. The seven strains belonged to Acetobacter cerevisiae and A. pasteurianus. Physiological properties were determined, including ethanol tolerance at up to 12% (v/v). Acidification at a growth temperature of 40 ℃ was seen for GHA 7, GYA 23, JGB 21-17, and GHA 20 strains, which may be useful in vinegar production where thermotolerant AAB are required. The seven AAB isolates had strong antibacterial activity against Staphylococcus aureus. Antioxidant activity was 2- and 4-fold higher, respectively, for A cerevisiae and A. pasteurianus than for the control, 1% acetic acid. We also observed 91.3% inhibition of angiotensin-converting enzyme activity for the KSO 5 strain, higher than that for the positive control, 0.1% captopril (76.9%). All strains showed complete inhibition of α-glucosidase, except JGB 21-17 and GHA 7 with 98.3% inhibition. Our work suggests usefulness of the strains selected as seed strains for highly efficient production of functional vinegar and illustrates identification of useful functional characteristics on a scientific basis.
ARTICLE | doi:10.20944/preprints202311.1294.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: inhibition; monoamine oxidase; MAO; thiazole; sulfonamide; SAR; synthesis
Online: 21 November 2023 (10:47:16 CET)
We have recently reported that a series of 1,3,4-oxadiazol-2-ylbenzenesulfonamides acts as potent and specific monoamine oxidase B (MAO-B) inhibitors with some compounds possessing potencies in the nanomolar range. While sulfonamide compounds (e.g., zonisamide) have been reported to inhibit the MAO enzymes, nanomolar MAO inhibition potencies for this class are not frequently observed. The present study expanded on these findings by replacing the 1,3,4-oxazole moiety with a 1,3-thiazole heterocycle. A series of 23 primary sulfonamides were synthesized by reaction of an α-haloketone with a substituted carbothioamide. The results of the MAO inhibition studies showed that the 1,3-thiazolylbenzenesulfonamides were specific inhibitors of human MAO-B. The most potent MAO-B inhibitor exhibited an in vitro IC50 value of 0.103 µM (3j). The derivatives were, however, weaker inhibitors of human MAO-A with the most potent compound exhibiting an IC50 value of 11.9 µM (3a). Examination of the structure-activity relationships (SARs) showed that the most potent MAO-B inhibition was obtained with substitution of the sulfonamide on the meta position of the phenyl rather than the para position. This study concludes that 1,3-thiazolylbenzenesulfonamides represent a class of potent and specific MAO-B inhibitors, which may serve as leads for the development of new treatments for disease states such as Parkinson’s disease.
REVIEW | doi:10.20944/preprints202308.0651.v1
Subject: Biology And Life Sciences, Other Keywords: cancer; adhesion; metastasis; inhibition; therapeutic approaches; targeted therapies
Online: 9 August 2023 (02:48:16 CEST)
This comprehensive review delves into cancer's complexity, focusing on adhesion, metastasis, and inhibition. It explores the pivotal role of these factors in disease progression and therapeutic strategies. This review covers cancer cell migration, invasion, and colonization of distant organs, emphasizing the significance of cell adhesion and the intricate metastasis process. Inhibition approaches targeting adhesion molecules, such as integrins and cadherins, are discussed. Overall, this review contributes significantly to advancing cancer research and developing targeted therapies, holding promise for improving patient outcomes worldwide. Exploring different inhibition strategies revealed promising therapeutic targets to alleviate adhesion and metastasis of cancer cells. The effectiveness of integrin-blocking antibodies, small molecule inhibitors targeting FAK and the TGF-β pathway, and combination therapies underscores their potential to disrupt focal adhesions and control epithelial-mesenchymal transition processes. The identification of as FAK, Src, β-catenin and SMAD4 offers valuable starting points for further research and the development of targeted therapies. The complex interrelationships between adhesion and metastatic signaling networks will be relevant to the development of new treatment approaches.
REVIEW | doi:10.20944/preprints202307.2141.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Hydatid cyst fluid; Antigen; Cancer inhibition; Apoptosis; Metastasis
Online: 1 August 2023 (02:54:51 CEST)
Hydatid cyst fluid is a complex biological substance consisting primarily of water, proteins, lipids, carbohydrates, salts, enzymes, hormones, growth factors, immune modulators, and other bioactive molecules. Antigens, including antigen B (AgB) and antigen 5 family members (Ag5), have been identified in hydatid cyst fluid and have been shown to have the ability to inhibit cancer progression. The exact mechanisms by which these components exert inhibitory effects on cancer progression are not fully understood, but it is believed that they may influence multiple signaling pathways involved in cell proliferation, survival, angiogenesis, and metastasis. In vitro studies have demonstrated that treatment with hydatid cyst fluid or specific antigens can inhibit cell growth, induce apoptosis, and suppress the migration of cancer cells. Animal model studies have also demonstrated significant inhibition of tumor growth, reduction in angiogenesis, and suppression of metastasis. Limited clinical studies have shown promising outcomes, including improved overall survival and reduced recurrence rates among breast cancer patients receiving AgB immunotherapy alongside standard treatment.
ARTICLE | doi:10.20944/preprints202305.0615.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Croton; yeast; inhibition; chemical composition and action mechanisms
Online: 9 May 2023 (08:46:49 CEST)
Multiresistant pathogens pose a serious threat to human health. The genus candida is one class of human pathogenic yeasts responsible for infections affecting healthy and immunocompromised patients. In this context, plant essential oils emerged as a future natural alternative to control the diseases caused by these pathogens. Here, it highlighted antimicrobial activity and the mechanisms of action of the essential oil extracted from Croton pluriglandulosus Carn.-Torres & Riina (CpEO) leaves on human pathogenic microorganisms in planktonic and biofilm lifestyles. In addition, for the first time, the oil composition was revealed by GC-MS analysis and the toxicity to human red blood cells (HRBC). Twenty-six chemical compounds were identified in EOCp, Elemicin, Bicyclogermacrene, caryophyllene, brevifolin and 2,4,6-trimethoxy-styrene. Through hemolytic assay, it was shown that CpEO has no toxicity to human RBCs. At the concentration of 50 μg mL-1, CpEO did not show great antibacterial potential. However, promising data were found for C. krusei and C. parapsilosis inhibiting by 89.3% and 80.7% of planktonic cell growth and 83.5% and 77.9% the biofilm formation, respectively. Furthermore, the mechanisms of action CpEO were elucidated by fluorescence. Scanning electron microscopy revealed damage to the cell membrane and pore formation, ROS overproduction, and Induction of apoptosis in candida cells. Our results reinforce the potential of CpEO as an effective alternative molecule of pharmaceutical interest.
ARTICLE | doi:10.20944/preprints202304.0561.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Bilirubin; 7α- and 7β-hydroxysteroid dehydrogenases; Activity; Inhibition
Online: 19 April 2023 (07:35:44 CEST)
7α- and 7β-hydroxysteroid dehydrogenases (HSDH) are a pair of enzymes that can catalyze the isomerization of hydroxyl group at site 7 of bile acids. In previous study, we found that the activities of 7α- and 7β-HSDH can be inhibited by bilirubin. In order to clarify the impact, the effects of bilirubin on enzymes were studied by kinetics, spectrum and docking analysis. Relative activity of 7α-HSDH remained less than 40 % under 1 mM bilirubin, for 7β-HSDH, only 18 % activity left at the same condition. Using taurochenodeoxycholic acid (TCDCA) as substrate, the Km of 7α-HSDH was up to 0.63 mM from 0.24 mM after binding with bilirubin, the Km of 7β-HSDH rose from 1.14 mM to 1.87 mM for the catalysis of tauroursodeoxycholic acid (TUDCA). The affinity of 7α- and 7β-HSDH to substrate decreased with the effect of bilirubin. The binding of bilirubin with 7α- or 7β-HSDH were analyzed by UV–Vis spectra, Fluorescence spectra and Circular dichroism (CD) spectra. The results reflected that bilirubin caused a slight change in the secondary structure of 7α- or 7β-HSDH, and the changes were correlated with the ratio of bilirubin to enzyme. 10 candidate molecular docking results were presented to reflect the binding of bilirubin with 7α- or 7β-HSDH and to explore the inhibition mechanism. This research not only provides the more in-depth understanding of 7α- and 7β-HSDH, but also reminds us to avoid the inhibition of bilirubin on hydroxysteroid dehydrogenases.
REVIEW | doi:10.20944/preprints202208.0236.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Archaea; transcription inhibition; RNA polymerase; viruses; evolution; antibiotics
Online: 12 August 2022 (11:25:05 CEST)
Multisubunit RNA polymerases (RNAP) carry out transcription in all domains of life; during vi-rus infection, RNAPs are targeted by transcription factors encoded by either the cell or the virus, resulting in the global repression of transcription with distinct outcomes for different host-virus combinations. These repressors serve as versatile molecular probes to study RNAP mechanisms, as well as they aid the exploration of druggable sites for the development of new antibiotics. Here, we review the mechanisms and structural basis of RNAP inhibition by the viral repressor RIP and the crenarchaeal negative regulator TFS4, which follow distinct strategies. RIP operates by occluding the DNA-binding channel and mimicking the initiation factor TFB/TFIIB. RIP binds tightly to the clamp and locks it into one fixed position, thereby preventing conformational oscil-lations that are critical for RNAP function as it progresses through the transcription cycle. TFS4 engages with RNAP in a similar manner to transcript cleavage factors such as TFS/TFIIS through the NTP-entry channel; TFS4 interferes with the trigger loop and bridge helix within the active site by occlusion and allosteric mechanisms, respectively. The conformational changes of RNAP described above are universally conserved and are also seen in inactive dimers of eukaryotic RNAPI and several inhibited RNAP complexes of both bacterial and eukaryotic RNA polymer-ases, including inactive states that precede transcription termination. A comparison of target sites and inhibitory mechanisms reveals that proteinaceous repressors and RNAP-specific antibiotics use surprisingly common ways to inhibit RNAP function.
ARTICLE | doi:10.20944/preprints202205.0156.v1
Subject: Biology And Life Sciences, Agricultural Science And Agronomy Keywords: Antimycin A; wheat blast; inhibition; biopesticide; biological control
Online: 12 May 2022 (04:02:42 CEST)
Application of chemical pesticides to protect agricultural crops from pests and diseases is discouraged due to their harmful effects on human and environment. Therefore, alternative approaches for crop pro-tection through microbial or microbe originated pesticides have been gaining momentum. Wheat blast is a destructive fungal disease caused by Magnaporthe oryzae Triticum (MoT) pathotype, which poses a seri-ous threat to global food security. Screening of secondary metabolites against MoT revealed that antimy-cin A isolated from a marine Streptomyces sp. had significant inhibitory effect on mycelial growth in vitro. This study aimed to investigate the inhibitory effects of antimycin A on some critical life stages of MoT and evaluate the efficacy of wheat blast disease control by this natural product. Bioassay indicated that antimycin A suppressed mycelial growth, conidiogenesis, germination of conidia and formation of ap-pressoria in germinated conidia of MoT in a dose-dependent manner with minimum inhibitory concen-tration 0.005 μg/disk. If germinated, antimycin A induced abnormal germ tubes (4.8%) and suppressed the formation of appressoria. Interestingly, application of antimycin A significantly suppressed wheat blast disease in both seedling and heading stages of wheat supporting the results from invitro study. This is the first report on inhibition of mycelial growth, conidiogenesis, conidia germination, detrimental morphological alterations in germinated conidia, and suppression of wheat blast disease caused by a Triticum pathotype of M. Oryzae. Further study is required to unravel the precise mode of action of this promising natural compound for considering it as a biopesticide to combat wheat blast.
COMMUNICATION | doi:10.20944/preprints202004.0220.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: alphaherpesvirus; EHV-1; phosphatidylserine; inhibition; pathogen host interaction
Online: 14 April 2020 (08:54:01 CEST)
Exposure of phosphatidylserine (PS) in the outer leaflet of the plasma membrane is induced by infection with several members of the Alphaherpesvirinae subfamily. There is evidence that PS is used by the equine herpesvirus type 1 (EHV-1) during entry, but the exact role of PS and other phospholipids in the entry process remains unknown. Here, we investigated the interaction of differently charged phospholipids with virus particles and determined their influence on infection. Our data show that liposomes containing negatively charged PS or positively charged DOTAP [N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium)] inhibited EHV-1 infection, while neutral phosphatidylcholine (PC) had no effect. Inhibition of infection with PS was transient, decreased with time, and was dose dependent. Our findings indicate that both cationic and anionic phospholipids can interact with the virus and reduce infectivity, while acting through different mechanisms. Charged phospholipids were found to have antiviral effects and can may be used to inhibit EHV-1 infection.
ARTICLE | doi:10.20944/preprints201901.0086.v1
Subject: Business, Economics And Management, Finance Keywords: Quinoxaline Analogs, Synthesis, Thymidine phosphorylase inhibition, Molecular docking
Online: 9 January 2019 (13:23:49 CET)
We have synthesized quinoxaline analogs (1-25), characterized by 1HNMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent analog among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure- activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.
ARTICLE | doi:10.20944/preprints201807.0472.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: chitosan; quorum sensing; antibacterial activity; quorum sensing inhibition
Online: 25 July 2018 (08:32:31 CEST)
New approaches to deal with drug-resistant pathogenic bacteria are urgent. We studied the antibacterial effect of chitosans against an E. coli quorum sensing biosensor reporter strain, and selected a non-toxic chitosan to evaluate its QS inhibition activity and its effect on bacterial aggregation. To this end, chitosans of varying DA (12 to 69%) and Mw (29 to 288 KDa) were studied. Only chitosans of low DA (~12%) inhibited the bacterial growth, regardless of the Mw. Chitosan MDP DA30 (DA 42% and Mw 115 kDa) was selected for further QS inhibition and SEM imaging studies. MDP DA30 chitosan exhibited QS inhibition activity in an inverse dose-dependent manner (≤12.5 µg/mL). SEM images revealed that this chitosan, when added at low concentration (≤30.6 µg/mL), induced substantial bacterial aggregation, whereas at high concentration (234.3 µg/mL), it did not. Aggregation explains the QS inhibition activity as the consequence of retardation of the diffusion of AHL.
ARTICLE | doi:10.20944/preprints201803.0116.v1
Subject: Chemistry And Materials Science, Chemical Engineering Keywords: oxazole-triazole; inhibition corrosion; mild steel; EIS; DFT
Online: 15 March 2018 (05:10:29 CET)
1-[(4-ethyl-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl)methyl]-4-phenyl-1H-1,2,3-triazole (Ph4) and1-[(4-ethyl-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl)methyl]-5-phenyl-1H-1,2,3-triazole (Ph5) are new isomers of the triazole derivative family, were synthesized and tested on the corrosion of mild steel in molar hydrochloric acid molar media using weight loss, electrochemical polarization and impedance spectroscopy. Then the experimental results were confirmed by quantum chemical calculations using DFT at B3LYP /6-31G (d,p). The compound Ph4 is the best inhibitor and its inhibitory efficiency increased with increasing concentration and reaching 95% at 10−3 M. Polarization curves studies show that both compounds tested are mixed-type inhibitors. Nyquist curves presented a single capacitive loop, their diameter increases progressively with both inhibitors concentration. The change of the substitution phenyl from position 5 to position 4 in the triazole ring increases the inhibitory effect of the triazole compounds. The effect of temperature on the corrosion behavior of iron indicates that the inhibitory efficiency of the two inhibitors decreases with increasing temperature in the range of 308 to 338K. DFT study is in good correlationwith the experimental results.
ARTICLE | doi:10.20944/preprints202309.2142.v1
Subject: Biology And Life Sciences, Virology Keywords: phage therapy; phage inhibition; complement system; Pseudomonas aeruginosa; myophages
Online: 30 September 2023 (07:42:38 CEST)
Therapeutic phages are primarily chosen based on their in vitro bacteriolytic activity. Although anti-phage antibodies are known to inhibit phage infection, the influence of other immune system components is less well known. An important anti-bacterial and anti-viral innate immune system that may interact with phages is the complement system, a cascade of proteases that recognizes and targets invading microorganisms. In this study, we aimed to study the effects of serum components such as complement on the infectivity of different phages targeting Pseudomonas aeruginosa. We used a fluorescence-based assay to monitor the killing of P. aeruginosa by phages of different morphotypes in presence of human serum. Our results reveal that several myophages are inhibited by serum in a concentration-dependent way, while the activity of four podophages and one siphophage tested in this study is not affected by serum. By using specific nanobodies blocking different components of the complement cascade, we show that activation of the classical complement pathway is a driver of phage inhibition. To determine the mechanism of inhibition, we produced bioorthogonally labeled fluorescent phages to study their binding by means of microscopy and flow cytometry. We show that phage adsorption is hampered in presence of active complement. Our results indicate that interactions with complement may affect in vivo activity of therapeutically administered phages. A better understanding of this phenomenon is essential to optimize the design and application of therapeutic phage cocktails.
ARTICLE | doi:10.20944/preprints202206.0274.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Cyclea peltata; Diabetes Mellitus; Docking; Schrodinger; Alpha amylase; Inhibition
Online: 20 June 2022 (14:33:11 CEST)
The primary goal of this research is to examine the α-amylase inhibitory effect of phytoconstituents found in the roots of the Cyclea peltata plant. The extract will also be used to investigate the effect of root extract on α-amylase inhibition assay. The roots were gathered, processed, and extracted in petroleum ether before being kept at 4ºC. The extract was exposed to a preliminary phytochemical examination. The extract was employed in the α-amylase inhibition experiment at concentrations of 50, 100, 200, 400, 600, 800, and 1000 µg/ml with acarbose as a control. Molecular docking analysis was performed on the phytoconstituents cycleapeltine, cycleadrine, cycleacurine, cycleanorine, cycleahomine chloride, and acarbose on human pancreatic alpha-amylase 1B2Y. A preliminary phytochemical study revealed the presence of alkaloids, saponins, and terpenoids. The tests came back negative for flavonoids, steroids, and tannin. The root extract inhibited α-amylase at 69.42 ± 0.74 % at 1000 µg/ml and acarbose at 94.63 ± 0.57 %. The IC50 value was calculated and found to be 484.08 µg/ml for the extract and 42.47 µg/ml. The docking studies, revealed that cycleacurine (-4.751 Kcal/mol) has a comparable anti-diabetic effect to Acarbose (-6.713 Kcal/mol). Furthermore, the function groups –OH and –NH found in phytoconstituents interacted with the active site of 1B2Y similarly to acarbose. This provides evidence that the function groups –OH and –NH present in the phytoconstituents might inhibit alpha amylase.
ARTICLE | doi:10.20944/preprints202111.0348.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Agar over assay; bacterial inhibition; Neisseria gonorrhoeae; Neisseria mucosa
Online: 19 November 2021 (12:23:16 CET)
Antibiotic-sparing treatments are required to prevent the further emergence of anti-microbial resistance in Neisseria gonorrhoeae. Commensal Neisseria species have previously been found to inhibit the growth of pathogenic Neisseria species. For example, a previous study found that 3 out of 5 historical isolates of Neisseria mucosa could inhibit the growth of N. gonorrhoeae. In this study, we used agar overlay assays to assess if 24 circulating and historical isolates of Neisseria mucosa could inhibit the growth of 28 circulating and historical isolates of N. gonorrhoeae. Although pitting around each colony of N. mucosa created an optical illusion of decreased growth of N. gonorrhoeae, we found no evidence of inhibition (n=24). In contrast, positive controls of Streptococcus pneumoniae and Escherichia coli demonstrated a strong inhibitory effect against the growth of N. gonorrhoeae.
REVIEW | doi:10.20944/preprints201908.0112.v1
Subject: Social Sciences, Behavior Sciences Keywords: active sensing; navigation; neural circuits; inhibition; C. elegans; invertebrate
Online: 8 August 2019 (17:24:40 CEST)
From single-cell organisms to complex neural networks, all evolved to provide control solutions to generate context and goal-specific actions. Neural circuits performing sensorimotor computation to drive navigation employ inhibitory control as a gating mechanism, as they hierarchically transform (multi)sensory information into motor actions. Here, we focus on this literature to critically discuss the proposition that prominent inhibitory projections form sensorimotor circuits. After reviewing the neural circuits of navigation across various invertebrate species, we argue that with increased neural circuit complexity and the emergence of parallel computations inhibitory circuits acquire new functions. The contribution of inhibitory neurotransmission for navigation goes beyond shaping the communication that drives motor neurons, instead, include encoding of emergent sensorimotor representations. A mechanistic understanding of the neural circuits performing sensorimotor computations in invertebrates will unravel the minimum circuit requirements driving adaptive navigation.
REVIEW | doi:10.20944/preprints201811.0631.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: adipogenesis; bioactive compounds; fat accumulation; hibiscus sabdariffa; lipase inhibition
Online: 30 November 2018 (10:33:47 CET)
Obesity is a condition associated with the accumulation of excess fat in the body, energy imbalance, lipogenesis etc. which increases adipose tissue mass through adipogenesis and probes a health risk. Its prevalence has become a large burden on the world at large. One of the solutions to tackling obesity is with the use of bioactive compounds. We critically examined the effectiveness of hibiscus sabdariffa (HS) on various parameters associated with development of obesity such as; effect of HSE on body weight and energy expenditure, effect of HSE on fat accumulation, effect of HSE on lipase inhibition, effect of HSE on adipocyte differentiation/adipogenesis. This review has gathered reports on the various anti-obesity effects of HS bioactives in cell and animal models, as well as in humans. Reports have shown that hibiscus sabdariffa derived bioactives are potent in the treatment of obesity with evident reduction in body weight, inhibition of lipid accumulation and suppression of adipogenesis through PPARγ pathway and other transcriptional factors.
REVIEW | doi:10.20944/preprints201805.0145.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: carbonic anhydrase, enzyme inhibition, metalloenzymes, amino acid, glaucoma, tumors
Online: 9 May 2018 (13:55:15 CEST)
Carbonic Anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life kingdoms, classified into seven genetically different families (α-θ). These enzymes catalyse the reversible hydration of carbonic anhydride (CO2), generating bicarbonate (HCO3-) and protons (H+). Fifteen isoforms of human CA (hCA I-XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or the progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) are used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.
COMMUNICATION | doi:10.20944/preprints201705.0050.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: ABCC transporter; lateral roots; Triticum aestivum; auxin; transport inhibition
Online: 8 May 2017 (07:48:20 CEST)
TaABCC13 is member of wheat ABCC subclass of transporters. The RNAi mediated silencing of this transporter in wheat results in lowering of seed phytic acid level and other developmental defects. In addition to that, wheat ABCC13 was involved in cadmium detoxification as evident by the complementation assays in yeast. The appearance of early lateral roots in these transgenic seedlings speculated the possibility for studying the role of localized auxin-mediated effects. In the current study, firstly, the expression of auxin related genes was studied in the transgenic roots. Enhanced expression of genes pertaining to either auxin biosynthesis or its transport was observed in transgenic wheat seedling roots suggesting the direct effect of the hormone. Further, the early emergence of lateral roots in transgenic wheat seedlings was affected due to the presence of auxin-transport inhibitor suggesting the direct effect of hormones in root development. In conclusion, herein we provide the novel evidence for the auxin mediated regulation of lateral root emergence in TaABCC13:RNAi seedlings.
ARTICLE | doi:10.20944/preprints202312.0482.v1
Subject: Food Science And Technology, Biology And Life Sciences Keywords: Durvillaea incurvata; aging; enzymes inhibition; Alzheimer's, diabetes; hypertension
Online: 7 December 2023 (07:12:27 CET)
World population is in a demographic transition, with an increase in number of older adults and prevalence of diseases related to aging. This study evaluated in vitro the potential of an ultrasound-assisted extract from Durvillaea incurvata to inhibit key enzymes associated with development of age-related diseases. Results show that an ultrasound-assisted extract as well as conventional extract from Durvillaea incurvata presented anti-diabetes potential by exhibiting inhibitory activity against α-glucosidase enzymes (91.8 ± 1.0 % and 93.8 ± 0.3 % respectively, at 500 µg/mL) and α-amylase (42.2 ± 1.4 % and 61.9 ± 0.9 % respectively, at 1500 µg/mL), related to starch digestion and postprandial glycemic response. Also, extracts presented inhibitory activity on the enzyme acetylcholinesterase (51.5% and 50.8% respectively, at 500 µg/mL) and butyrylcholinesterase (32.8% and 34.4% respectively, at 0.5 mg /mL), biomarkers associated with Alzheimer's disease, and showed inhibitory activity against angiotensin-I converting enzyme (98.7 ± 7.4% and 93.0 ± 3.4% respectively, at 2.0 mg /mL), key in the regulation of vascular tone and blood pressure, which helps to prevent the development of hypertension. In conclusion, the ultrasound-assisted extract of Durvillaea incurvata has the potential to prevent the development of age-related pathologies, such as diabetes, Alzheimer's disease, and hypertension.
ARTICLE | doi:10.20944/preprints202310.1689.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: marine yeast; microbial phylogenetics; bioactivity; antioxidant; biological control; tyrosinase inhibition
Online: 26 October 2023 (11:10:54 CEST)
Marine yeasts have versatile applications in industrial, medical and environmental fields, but have received little attention compared to terrestrial yeasts and filamentous fungi. In this study, a phylogenetic analysis of 11 marine-derived yeasts was conducted using internal transcribed spacers and nuclear large subunit rDNA, and their bioactivities, such as antioxidant, antibacterial, and tyrosinase inhibition activities, were investigated. The 11 marine-derived yeasts were identified to belong to seven species including Geotrichum candidum, Metschnikowia bicuspidata, Papiliotrema fonsecae, Rhodotorula mucilaginosa, Vishniacozyma carnescens, Yamadazyma olivae, and Yarrowia lipolytica, and three strains of these were candidates for new species of the genera Aureobasidium, Rhodotorula, and Vishniacozyma. Most extracts showed antioxidant activity, whereas seven strains exhibited antibacterial activities against Bacillus subtilis. Only Aureobasidium sp. US-Sd3 among the 11 isolates showed tyrosinase inhibition. Metschnikowia bicuspidata BP-Up1 and Yamadazyma olivae K2-6 showed notable radical-scavenging activity, which has not been reported previously. Among the isolates, Aureobasidium sp. US-Sd3 exhibited the highest antibacterial and tyrosinase inhibitory activities. Overall, our results demonstrate the potential of marine-derived yeasts as a source of bioactive compounds for improving industrial applications.
ARTICLE | doi:10.20944/preprints202310.1083.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: Stellera chamaejasme L; stellerterpenoids A–C; ECD calculation; NO inhibition
Online: 17 October 2023 (15:08:18 CEST)
An undescribed diterpene, stellerterpenoid A (1) and two undescribed sesquiterpenoids, stellerterpenoids B and C (2-3), together with six known compounds, were isolated from the roots of Stellera chamaejasme L. Their structures were elucidated by extensive spectroscopic data (1D, 2D NMR, IR, UV and HR-ESI-MS). The absolute configuration of 1-3 were elucidated based on ECD calculation. Among of them, stellerterpenoid A was a rare 13, 14 - seco nortigliane diterpenoid and stellerterpenoid B was a guaiacane type sesquiterpenoid with an unusual 1, 2-diketone moiety. The known stelleraguaianone B (5) exhibited moderate activity to suppress NO production in LPS - simulated macrophages with an IC50 value of 24.76 ± 0.4 μM. None of the compounds showed inhibitory influenza virus and tumor activity.
ARTICLE | doi:10.20944/preprints202310.0179.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Acetate; Gene dosage effect; Acetoacetyl-CoA synthase; Compartmentalization; Substrate inhibition
Online: 4 October 2023 (12:25:12 CEST)
High production cost is one of the major factors that limit the market growth of polyhydroxyalkanoates (PHAs) as a biopolymer. Improving PHA synthesis performance and utilizing low grade feedstock are two logical strategies for reducing the cost. As an oleaginous yeast, Y. lipolytica has a high carbon flux through acetyl-CoA (main PHB precursor) which makes it a desired cell factory for PHB biosynthesis. Two different metabolic pathways introduced into Y. lipolytica PO1f in this study for enhancing PHB biosynthesis, along with glucose and acetate as co-substrates. Results showed that NBC pathway led to more than 11% PHB accumulation, while there was non-detectable PHB accumulations using ABC pathway. Further modifications were done using peroxisomal compartmentalization and gene-dose overexpression. Final strain showed up to 41% PHB of CDW with a growth rate of 0.227 h-1. Low growth rate was observed using acetate or glucose as sole carbon and energy source. The co-substrate strategy showed compensatory effect on overcoming inhibitory and toxic effects of both substrates at high concentrations. Cultivating the engineered strain in optimal co-substrate condition predicted by RSM led to 83.4 g/L biomass concentration and 31.7 g/L PHB.
ARTICLE | doi:10.20944/preprints202305.0448.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: acoustic startle response (ASR); prepulse inhibition (PPI); attention; Spike2 script
Online: 8 May 2023 (04:58:10 CEST)
This article presents a low-cost and flexible solution for acoustic startle response (ASR) tests that can be used in any laboratory with CED Power1401 or a similar Spike2-based interface. ASR is a reflexive response to an unexpected, loud acoustic stimulus, and prepulse inhibition (PPI) is a phenomenon in which the startle response is reduced when preceded by a weak prestimulus of the same modality. Measuring PPI is important because changes in PPI have been observed in patients with various psychiatric and neurological disorders. Commercial ASR testing systems are expensive, and their closed source code affects their transparency and result reproducibility. The proposed setup is easy to install and use, and simultaneous recording of ASR and brain activity (electrocorticogram or intracerebral local field potential) is possible. The Spike2 script is customizable and supports a wide range of PPI protocols. The article presents data obtained in female rats, both wild-type (WT) and dopamine transporter knockout (DAT-KO), showing the same tendency as the data obtained in males, with ASR on single pulse higher than ASR on prepulse+pulse, and PPI reduced in DAT-KO rats compared to WT.
TECHNICAL NOTE | doi:10.20944/preprints202304.0352.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: hiPSC; Differentiation; Neurons; Disease Modeling; dual SMAD inhibition; NGN2 overexpression
Online: 14 April 2023 (05:02:28 CEST)
Human induced pluripotent stem cells (hiPSCs) have two characteristic abilities 1) self-renewal and 2) differentiation into all cell types in the human body. It is this ability of iPSCs to differentiate into any desired cell type that makes them amenable to disease modeling. iPSCs can further be engineered to carry a disease-specific mutation or be derived from patients to phenocopy the disease. To model neurodegenerative/neurodevelopmental disorders iPSCs are differentiated into neurons. This chapter describes protocols for two different approaches to generate neurons from iPSCs, first using dual SMAD inhibition to generate neural progenitor cells which are then differentiated into neurons, and second using single transcription factor (NGN2) over-expression to drive differentiation of iPSCs directly into neurons.
ARTICLE | doi:10.20944/preprints202301.0540.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: β -Lapachone; Bactericidal; Biofilms; Resistant; Zone of inhibition; Antimicrobial activity
Online: 30 January 2023 (06:10:49 CET)
Background: Bacterial infections constantly have a large impact on public health, because of increased rates of resistance and reduced frequency of development of novel antibiotics. The utility of conventional antibiotics for treating bacterial infections has become increasingly challenging. The aim of the study was to assess the antibacterial effect of β -Lapachone, a novel synthetic compound. Methods: The antibacterial activity of the β -Lapachone compound was examined against laboratory strains by agar well diffusion method, minimal inhibitory concentration (MICs), and minimal bactericidal concentration (MBCs). Growth kinetics inhibition in presence of β -Lapachone on Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa (ATCC 27853) was assessed by MABA. Crystal violet blue assay was used for biofilm inhibition assays, biofilm eradication assay and for molecular modeling PyMOL was used. Results: β -Lapachone exhibited potent antimicrobial activity against laboratory strains of bacteria with MIC of 0.2 mM for S. saprophyticus and Staphylococcus aureus, and 0.04 mM for Staphylococcus epidermidis and Pseudomonas aeruginosa ATCC 27853. The inhibition of catalase enzyme was found to be the cause for its antibacterial activity. Molecular modeling predicted the binding of β -Lap at active site and heme binding site of catalase, KatA. The activity of some commercial antibiotics was enhanced in association with β -Lap. In addition, β -Lap inhibited the biofilm formation and eradicated the already formed and ultra-mature biofilms of aforesaid bacterial strains.
REVIEW | doi:10.20944/preprints202207.0024.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: post-translation modifications; CK2; Huntington’s Disease; Kinase Inhibition; HTT phosphorylation
Online: 1 July 2022 (17:47:10 CEST)
Huntington’s Disease (HD) is a devastating neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, for which no disease modifying therapies are currently available. Much of the recent research has focused on developing therapies to directly lower HTT expression, and while promising, these therapies have presented several challenges regarding administration and efficacy. Another promising therapeutic approach is the modulation of HTT post-translational modifications (PTMs) that are dysregulated in disease and have shown to play a key role in HTT toxicity. Among all PTMs, modulation of HTT phosphorylation has been proposed as an attractive therapeutic option due to the possibility of orally administering specific kinase effectors. One of the kinases described to participate in HTT phosphorylation is Protein Kinase CK2. CK2 has recently emerged as a target for the treatment of several neurological and psychiatric disorders, although its role in HD remains controversial. While pharmacological studies in vitro inhibiting CK2 resulted in reduced HTT phosphorylation and increased toxicity, genetic approaches in mouse models of HD have provided beneficial effects. In this review we discuss potential therapeutic approaches related to the manipulation of HTT-PTMs with special emphasis on the role of CK2 as a therapeutic target in HD.
REVIEW | doi:10.20944/preprints202201.0314.v1
Subject: Social Sciences, Behavior Sciences Keywords: executive functions; executive control; birds; inhibition; working memory; shifting; flexibility
Online: 20 January 2022 (20:52:34 CET)
Executive functions comprise top-down cognitive processes that exert control over information processing, from acquiring information to issuing a behavioural response. These cognitive processes of inhibition, working memory and shifting underpin complex cognitive skills, such as episodic memory and planning, which have been repeatedly investigated in several bird species in recent decades. Until recently, avian executive functions were studied in relatively few bird species, but have gained traction in comparative cognitive research following MacLean and colleagues’ large-scale study (2014). Therefore, in this review paper, relevant previous findings are collected and organized to facilitate further investigations of these core cognitive processes in birds. This review can assist in integrating findings from avian and mammalian cognitive research and further current understanding of executive functions’ significance and evolution.
ARTICLE | doi:10.20944/preprints202104.0670.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Mayaro; MAPKs; p38, SB203580; PROTACs; NR-7h; Losmapimod; replication; inhibition
Online: 26 April 2021 (13:17:06 CEST)
Mayaro virus (MAYV) hijacks the host´s cell machinery to effectively replicate. The mitogen-activated protein kinases (MAPKs) p38, JNK and ERK1/2 have emerged as crucial cellular factors implicated in different stages of the viral cycle. However, whether MAYV uses these MAPKs to competently replicate has not yet been determined. The aim of this study was to evaluate the impact of MAPKs inhibition on MAYV replication using primary human dermal fibroblasts (HDFs) and HeLa cells. Viral yields in supernatants from MAYV-infected cells treated or untreated with inhibitors SB203580, SP600125, U0126 or Losmapimod were quantified using plaque assay. Also, viral protein expression was analyzed using immunoblot and immunofluorescence. Knockdown of p38⍺/p38β isoforms was performed in HDFs using the PROTACs molecule NR-7h. Our data demonstrated that HDFs are highly susceptible to MAYV infection. SB203580, a p38 inhibitor, reduced MAYV replication in a dose-dependent manner in both HDFs and HeLa cells. Additionally, SB203580 significantly decreased viral E1 protein expression. Similarly, knockdown or inhibition of p38⍺/p38β isoforms with NR-7h or Losmapimod, respectively, affected MAYV replication in a dose-dependent manner. Collectively, these findings suggest that p38 could play an important role in MAYV replication and could serve as a therapeutic target to control MAYV infection.
ARTICLE | doi:10.20944/preprints202103.0541.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: α-Amylase inhibition; Tannic acid; Mixing order; Binding interactions; Adsorption
Online: 22 March 2021 (15:35:35 CET)
The effects of mixing orders of tannic acid (TA), starch and α-amylase on the enzyme inhibition of TA were studied, including mixing TA with α-amylase before starch addition (order 1), mixing TA with pre-gelatinized starch before α-amylase addition (order 2) and co-gelatinizing TA with starch before α-amylase addition (order 3). It was found that the enzyme inhibition was always highest for order 1 because TA could bind with the enzyme active site thoroughly before digestion occurred. Both order 2 and 3 reduced α-amylase inhibition through decreasing binding of TA with the enzyme, which resulted from the non-covalent physical adsorption of TA with gelatinized starch. Interestingly, at low TA concentration, α-amylase inhibition for order 2 was higher than order 3, while at high TA concentration, the inhibition was shown with opposite trend, which arose from the difference in the adsorption property between the pre-gelatinized and co-gelatinized starch at the corresponding TA concentrations. Besides, both the crystalline structures and apparent morphology of starch were not significantly altered by TA addition for order 2 and 3. Conclusively, although a polyphenol may have an acceptable inhibitory activity in vitro, the actual effect may not reach the expected one when taking processing procedures into account.
Subject: Environmental And Earth Sciences, Atmospheric Science And Meteorology Keywords: environmental risk assessment; polycyclic musk compounds; acute toxicity; growth inhibition; larvae development
Online: 11 February 2021 (13:23:39 CET)
The current research investigated the environmental risk of the polycyclic musk compounds, Galaxolide® (HHCB) and Tonalide® (AHTN), in the marine environments. These substances are lipophilic, bioaccumulated and potentially biomagnified in aquatic organisms. To understand the toxicity of HHCB and AHTN, we performed acute toxicity tests by exposing marine microalgae (Phaeodactylum tricornutum, Tretraselmis chuii and Isochrysis galbana), crustaceans (Artemia franciscana), echinoderms (Paracentrotus lividus), bivalves (Mytilus galloprovincialis), fish (Sparus aurata) and a candidate freshwater microalga (Raphidocelis subcapitata) to environmentally relevant concentrations (0.005 - 5 µg/L) following standardized protocols. The effects of both substances on microalgae growth were incipient and only I. galbana was sensitive to HHCB and AHTN, with IC10 values of 5.22 µg/L and 0.328 µg/L, respectively. Significant (p < 0.01) concentration dependent responses were measured in P. lividus and M. galloprovincialis larvae developments as well as S. aurata mortality tested with HHCB. The effect of HHCB on P. lividus larvae development was the most sensitive endpoint recorded, producing an EC50 value of 4.07 µg/L. Our results show that HHCB represents a high risk to P. lividus larvae development for early life stages in marine environments.
ARTICLE | doi:10.20944/preprints202102.0016.v1
Subject: Social Sciences, Psychology Keywords: development; adolescents; perceptual inhibition; joint visual search task; executive function
Online: 1 February 2021 (11:38:03 CET)
Recent studies suggest that the developmental curves in adolescence, related to the development of executive functions, could be fitted to a non-linear trajectory of development with progressions and retrogressions. Therefore, the present study proposes to analyze the pattern of development in Perceptual Inhibition (PI), considering all stages of adolescence (early, middle, and late) in intervals of one year. To this aim, we worked with a sample of 275 participants between 10 and 25 years, who performed a joint visual and search task (to measure PI). We have fitted exGaussian functions to the probability distributions of the mean response time across the sample and performed a covariance analysis (ANCOVA). The results showed that the 10- to 13-year-old groups performed similarly in the task and differ from the 14- to 19-year-old participants. We found significant differences between the older group and all the rest of the groups. We discuss the important changes that can be observed in relation to the nonlinear trajectory of development that would show the PI during adolescence.
ARTICLE | doi:10.20944/preprints202003.0360.v2
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: SARS-CoV-2; transcriptional inhibition; COVID-19; drug repurposing; TMPRSS2
Online: 28 April 2020 (09:39:02 CEST)
There is an urgent need to identify effective therapies for COVID-19. The SARS-CoV-2 host factor protease TMPRSS2 is required for viral entry and thus an attractive target for therapeutic intervention. In mouse, knockout of tmprss2 led to protection against SARS-CoV-1 with no deleterious phenotypes, and in human populations genetic loss of TMPRSS2 does not appear to be selected against. Here, we mined publicly available gene expression data to identify several compounds that down-regulate TMPRSS2. Recognizing the need for immediately available treatment options, we focused on FDA-approved drugs. We found 20 independent studies that implicate estrogenic and androgenic compounds as transcriptional modulators of TMPRSS2, suggesting these classes of drugs may be promising therapeutic candidates for clinical testing and observational studies of COVID-19. We also note that expression of TMPRSS2 is highly variable and skewed in humans, with a minority of individuals having extremely high expression. Combined with literature showing that inhibition of TMPRSS2 protease activity reduces SARS-CoV-2 viral entry in human cells, our results raise the hypothesis that modulation of TMPRSS2 expression is a promising therapeutic avenue for COVID-19.
ARTICLE | doi:10.20944/preprints202002.0297.v1
Subject: Chemistry And Materials Science, Electrochemistry Keywords: light alloys; magnesium; corrosion; vanadate; phosphate; fluoride; inhibition; conversion coating
Online: 21 February 2020 (02:21:19 CET)
The anodic polarization response of magnesium alloy AZ31 was characterized during exposure to aerated 0.1M NaCl solutions with millimolar additions of NaVO3, Na3PO4, Na2HPO4, NaF and various pairings to assess their ability to inhibit corrosion kinetics and retard localized corrosion. Each of the candidate inhibitors reduced the corrosion rate of the alloy to some degree. A Na3PO4 - NaVO3 pair produced a powerful inhibiting response decreasing the corrosion rate to about 10-7 A/cm2, which was two orders of magnitude lower than the uninhibited control case. A Bliss Independence assessment indicated that this inhibitor pair acted synergistically. A Na2HPO4 - NaVO3 pair reduced the corrosion rate to 10-6 A/cm2 but was not assessed to be acting synergistically. The NaVO3 - NaF pair did not reduce the corrosion rate significantly compared to the control case and was an antagonistic pairing. SEM imaging showed film formation due to exposure, which appears to be the origins of the observed inhibition. The resistance to localized corrosion was assessed as the difference in the breakdown potential and the corrosion potential with larger values indicating a lower probability of localized corrosion during free corrosion exposures. Effects of the inhibitors on this characteristic were mixed, but each of the inhibitor pairs yielded potential differences in excess of 100mV. A conceptual conversion coating process based on a mixture of vanadate and phosphate compounds were demonstrated. A fluoride-bearing formulation produced coatings whose total impedance was increased by a factor or 2 compared to an uncoated control. A fluoride-free formulation produced coatings whose corrosion resistance was increased by more than a factor of 3.
COMMUNICATION | doi:10.20944/preprints201906.0278.v1
Subject: Biology And Life Sciences, Biophysics Keywords: photosystem II; redox potential; electron transfer; charge separation; photo-inhibition
Online: 27 June 2019 (05:54:13 CEST)
Structural perturbations in the Mn4CaO5 cluster site, an oxygen-evolving complex of photosystem II, such as those induced by Ca2+/Sr2+ exchanges or Ca/Mn-removal have been known to induce long-range positive shifts (+30 mV to +150 mV) in the redox potential of the primary quinone electron acceptor plastoquinone A (QA) located 40 Å distant from the OEC. Here, we reanalyzed the crystal structure of Sr-PSII solved at 2.1 Å and compare it with the native Ca-PSII of 1.9 Å with focus on the acceptor site and report on the possible long-range interactions between the donor, Mn4Ca(Sr)O5 cluster, and acceptor sites.
ARTICLE | doi:10.20944/preprints202212.0127.v1
Subject: Environmental And Earth Sciences, Environmental Science Keywords: ecotoxicology; post-coagulation sludge; phytotoxicity; inhibition test; germination inhibition test; particle size distribution; pressure sand filter; circular economy; toxicity classification; gravitational properties of sludge
Online: 7 December 2022 (10:22:15 CET)
Swimming pools are examples of water-intensive facilities, where solutions for reducing economic and environmental costs are increasingly frequently searched. One of the solutions is the recovery of water from wastewater, including from washings obtained through the process of rinsing filter bed. The study objective was the qualitative and quantitative assessment of post-coagulation sludges, the main pollutant found in the washings. During the analyses, assessment of the sedimentation capabilities of the sludges was performed (gravitationally), particle size distribution was assessed (particle size distribution analyzer) and assessment of phytotoxicity with the use of plant indicators in short-term tests was performed (Lemna minor, Lepidium sativum, Sinapis alba, Raphanus sativus). The samples were collected from two independent circulations, which differed in terms of capacity and type of coagulant used. The tested post-coagulation sludges were characterized by high content of total suspended solids: in samples from Circulation 1 from 251 to 128 mg/l, in Circulation 2 from 489 to 228 mg/l. However, the sedimentation processes enabled significant separation of sludges. The hydrolyzed coagulant contributed to the improvement of sedimentation capabilities of sludges. Despite the fact that in many samples low sludge concentrations favored stimulation of plant growth, the post-coagulation sludges can constitute a hazard to plant growth, particularly in the long-term perspective.
ARTICLE | doi:10.20944/preprints202310.0789.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: sodium sulfobutyl ether-β-cyclodextrin; ranitidine; apparent permeability coefficient; permeability; inhibition
Online: 12 October 2023 (20:13:47 CEST)
Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-β-cyclodextrin (SBE-β-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-β-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, the apparent permeability coefficient of ranitidine decreased to 4.62×10-5 , 4.5×10-5 , 3.61×10-5 and 1.08×10-5 in Caco-2 cells, respectively. The same results were obtained from oral pharmacokinetic study in rats; Further studies indicated that SBE-β-CD significantly increased the zeta potential of ranitidine. SBE-β-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-β-CD should be chosen with caution for drugs with poor permeability.
ARTICLE | doi:10.20944/preprints202306.1076.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Thymoquinone; SBE-β-CD; Leukemia; Drug delivery system; Telomerase inhibition; Apoptosis
Online: 15 June 2023 (05:37:50 CEST)
Leukemia, characterized by abnormal blood cell proliferation, remains a significant challenge in cancer treatment. Thymoquinone (TQ), a bioactive compound derived from black seed, has demonstrated anticancer properties, including telomerase inhibition and induction of apoptosis. However, TQ's poor solubility and limited bioavailability hinder its clinical application. This study explores the use of SBE-β-CD, a cyclodextrin derivative, to enhance the solubility and stability of TQ for leukemia treatment. SBE-β-CD offers low hemolytic activity and has been successfully employed in controlled drug release systems. The study investigates the formation of inclusion complexes between TQ and SBE-β-CD and assesses their effects on leukemia cell growth. Results indicate that the TQ/SBE-β-CD complex exhibits improved solubility and enhanced cytotoxic effects compared to TQ alone, suggesting the potential of SBE-β-CD as a drug delivery system for TQ. Annexin V-FITC tests demonstrate increased apoptosis and reduced telomerase activity in leukemia cells treated with TQ/SBE-β-CD, supporting its anti-leukemic potential. Molecular docking analysis reveals a strong binding affinity between TQ and telomerase. However, further research is needed to optimize the apoptotic effects and minimize necrosis induction. In conclusion, TQ/SBE-β-CD shows promise as a novel strategy for leukemia treatment by targeting telomerase and enhancing the cytotoxic effects of TQ, offering a potential solution to overcome the limitations of TQ's poor solubility and bioavailability.
ARTICLE | doi:10.20944/preprints202305.1006.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Melanoma; drug discovery; spliceosomal inhibition; BRAF; cell line xenograft; organ histopathology
Online: 15 May 2023 (09:19:54 CEST)
Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported melanoma actives that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2. In a separate study, we reported that these compounds were non-toxic to Balb/C mice at 50 mg/kg suggesting their utility in in vivo studies. In the present study, we aimed to determine the therapeutic potential of these compounds by testing them in A375 cell-line derived xenograft in nu/nu mice. Animals were randomized into four groups (n=12/group) to receive subcutaneous administration of vehicle, 10 mg/kg vemurafenib, and 25 mg/kg 2155-14 and 2155-18 three times per week for 15 days along with a control group. The results revealed that both 2155-14 and 2155-18 significantly decreased the growth of A375 tumors, which was comparable to vemurafenib. These results were confirmed by tumor volume, weight, and histopathological examination. In conclusion, these results suggest a therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2.
BRIEF REPORT | doi:10.20944/preprints202211.0063.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: melanoma; drug discovery; spliceosomal inhibition; acute toxicity; blood chemistry; organ histopathology
Online: 3 November 2022 (01:43:05 CET)
Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported melanoma actives that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2 (Palrasu et al., 2019). Given lack of knowledge about side effects of using spliceosomal binders in humans, an acute toxicity study was conducted to evaluate these compounds in mice. Male and female mice were treated with compounds 2155-14 and 2155-18 at 50mg/kg/day via subcutaneous injections and the clinical signs of distress were monitored for 21 days and compared with control mice. Additionally, effect of the leads on blood chemistry, blood cell counts, and organs was evaluated. No significant changes were observed in the mice body weight, blood cell count, blood chemistry, or organs following the compound treatment. The results show that our compounds 2155-14 and 2155-18 are not toxic for the study period of three weeks.
ARTICLE | doi:10.20944/preprints202209.0287.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Coffea arabica; antioxidant; acetylcholinesterase inhibition; catalepsy; unilateral 6-hydroxydopamine lesion; caffeine
Online: 20 September 2022 (03:22:27 CEST)
Epidemiologic studies suggest an inverse correlation between coffee consumption and the occurrence of neurodegenerative diseases, but the role of caffeine and roasting degree are still matter of debate. The objective of this work was to evaluate the effects of caffeinated (light, medium, and dark roast) and decaffeinated instant coffee samples in acetylcholinesterase inhibition and antioxidant assays, as well as in animal models of Parkinson’s disease. Caffeinated coffees inhibited the acetylcholinesterase in much smaller concentrations than decaffeinated coffee. All coffee samples showed antioxidant capacity without relation with the caffeine content. Dopaminergic-like activity in the haloperidol-induced catalepsy test was observed with caffeinated coffee, but not in the decaffeinated sample. The medium roast coffee reduced the number of rotations of rats after methamphetamine administration on the 6-hydroxydopamine unilateral lesion of the medial forebrain bundle. However, the coffee treatment did not avoid the loss of dopaminergic neurons on substantia nigra pars compact and only the smallest dose of coffee was able to avoid the decrease of dopamine levels in the lesioned side of the striatum. Altogether, these results suggest that coffee exerts moderate pro-cholinergic and pro-dopaminergic effects and caffeine seems to be the main responsible for these effects.
Subject: Chemistry And Materials Science, Biomaterials Keywords: concrete; pore solution; silica; pozzolan; corrosion; cyclic voltammetry; silicate; corrosion inhibition
Online: 14 October 2020 (10:48:58 CEST)
Reinforcement corrosion due to chloride attack is of major economic significance for reinforced concrete structures. Pozzolans are known to inhibit corrosion initiation mainly by reducing concrete permeability. However, there is evidence in the literature that changes in the chemical environment in the concrete due to the pozzolans may be creating improved corrosion resistance, by themselves. In this study, the composition of a pore solution of mature hydrated cement paste containing silica-fume at different ratios was analyzed. The electrochemical behavior of reinforcing steel was studied in simulated pore solutions with silicate concentrations ranging from 0 to 35.6 mM, which are within the concentration range found by pore solution extraction to be up to 49 mM. Polished reinforcing steel specimens were used for cyclic voltammetry in simulated pore solutions with chloride concentrations of 10-20%. Better corrosion protection was found with increasing silicate concentration up to 3.56 mM. This was indicated by lower corrosion currents both in the passive state and after anodic activation. Anodic activation of steel in a 35.6 mM silicate solution with 20% NaCl yielded a higher potential than the anterior potential.
REVIEW | doi:10.20944/preprints202007.0275.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Transcranial magnetic stimulation; Corticospinal excitability; Cortical inhibition; Cortical facilitation; Eccentric cycling
Online: 4 August 2020 (07:57:25 CEST)
Corticospinal excitability and particularly the balance between cortical inhibitory and excitatory processes (assessed in a muscle using transcranial magnetic stimulation), are affected by neurodegenerative pathologies or following a stroke. Non-fatiguing conventional locomotor exercise, such as cycling or walking, decreases intracortical inhibition and/or increases intracortical facilitation. These modifications notably seem to be a consequence of neurotrophic factors (e.g., brain-derived neurotrophic factors) resulting from hemodynamic solicitation. Furthermore, it can be inferred from non-invasive brain and peripheral stimulation studies that repeated activation of neural networks can endogenously shape neuroplasticity. Such mechanisms could also occur following eccentric exercises (i.e., active lengthening of the muscle), during which motor-related cortical potential is of greater magnitude and lasts longer (assessed by electroencephalography) than during concentric exercises (i.e., muscle shortening). As single-joint eccentric exercise decreased short- and long-interval intracortical inhibition and increased intracortical facilitation (assessed by paired-pulse transcranial magnetic stimulation immediately after), locomotor eccentric exercise may be even more potent by adding hemodynamic-related neuroplastic processes to endogenous processes. Besides, eccentric exercise is especially useful to develop relatively high force levels at low cardiorespiratory and perceived intensity, which can be a training goal in addition to inducing neuroplastic changes. Further studies are required to understand how neuroplasticity is 1) acutely influenced by locomotor exercise characteristics (e.g., intensity, duration), 2) modulated by an exercise-based rehabilitation program, 3) related to functional cognitive and motor outcomes relevant to pathological population.
ARTICLE | doi:10.20944/preprints202006.0358.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: Enzyme inhibition; Secondary Metabolites; In-silico Analysis; Molecular docking; Drug candidates
Online: 30 June 2020 (08:11:28 CEST)
Metabolic enzymes are often targeted for drug development programs of metabolic diseases such as diabetes and its complications. Many secondary metabolites isolated from natural products have shown therapeutic action against these enzymes. However, some commercially available synthetic drugs have shown unfriendly impacts with various side effects. Thus, this research has focused on a comprehensive study of secondary metabolites showing better inhibitory activities towards metabolic enzymes such as α-amylase, α-glucosidase, aldose reductase, and lipase. Further receptor-based virtual screening was performed against the various secondary metabolites database designed in-silico. Using Gold combined with subsequent post-docking analyses, the score was obtained as methyl xestospongic ester (Gold score 65.83), 2,″4″-O-diacetylquercitrin (Gold score 65.15), kaempferol-3-O-neohesperidoside (Gold score 53.37) and isosalvianolic acid C methyl ester (Gold score 53.44) for lipase, aldol reductase, α-amylase, and α-glucosidase, respectively. Besides, vitexin and isovitexin for α-amylase; N-trans-Caffeoyl-tyramin for α-glucosidase; purpurolide F and schaftoside for lipase; acteoside and orientin for aldose reductase could be potential drugs for respective enzymes based on in-silico analyses, supported by experimental IC50 values reported. They could bind to the competitive sites of the various targets of metabolic enzymes, and finally, toxicity analysis using ProTox-II was also performed.
ARTICLE | doi:10.20944/preprints201908.0028.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: vegetable waste; phenolics; hyperglycemia-induced oxidative stress; antioxidant activity; AGE inhibition
Online: 2 August 2019 (10:36:17 CEST)
Pomegranate peel is a natural source of phenolics, claimed to possess healing properties, among which antioxidant and antidiabetic. In line with this evidence, the ethyl acetate PGE extract, obtained by Soxhlet from the peel of Dente di cavallo DC2 variety and characterized by a 4% amount of ellagic acid, has been studied for its hypoglycemic, antiglycation and antioxidative cytoprotective properties, in order to support a possible further nutraceutical interest. The α-amylase and α-glucosidase enzyme inhibition, interference with advanced glycation end-products (AGE) formation and metal chelating abilities were evaluated as hypoglycemic mechanisms. Also, considering that oxidative stress is associated with hyperglycemia complications, PGE antioxidant cytoprotective properties under hyperglycemic conditions were assayed. Phenolic profile was characterized by integrated chromatographic and spectrophotometric methods. Under our experimental conditions, PGE strongly inhibited the tested enzymes, especially α-glucosidase, and exerted chelating and antiglycation properties. Also, it reduced both ROS and GSH levels under hyperglycemic conditions, thus suggesting its ability to support cell functions by counteracting intracellular oxidative stress. Along with ellagic acid, rutin was the major identified flavonoid (about 4 %) of PGE. Present results suggest PGE to be a possible remedy for hyperglycemia management and encourage further studies to exploit its promising properties.
ARTICLE | doi:10.20944/preprints201802.0177.v1
Subject: Environmental And Earth Sciences, Environmental Science Keywords: shortcut nitrification; constructed rapid infiltration system; potassium chlorate inhibition; domestic sewage
Online: 27 February 2018 (08:50:13 CET)
Constructed rapid infiltration system (CRI) is a new type of sewage biofilm treatment technology, but due to its anaerobic zone lacks of the carbon sources and the condition for nitrate retention, its nitrogen removal perfomance is very poor; However, shortcut nitrification-denitrification process presents distinctive advantages, as it saves oxygen, requires less organic matter and needs less time for denitrification compared to conventional nitrogen removal method. Thus, if the shortcut nitrification-denitrification process could be applied to CRI system properly, the simpler, more economic and efficient nitrogen removal method will be obtained. But, as its reaction process shows that the first and the most important step of achieving shortcut nitrification-denitrification is to achieve shortcut nitrification. Thus, in this study, we explored the feasibility to achieve shortcut nitrification, which produces nitrite as the dominant nitrogen species in effluent, by addition of potassium chlorate (KClO3) to the influent. In an experimental CRI model system, the effects on nitrogen removal, nitrate inhibition and nitrite accumulation were studied, and the advantages of achieving shortcut nitrification-denitrification were also analysed. The results showed that shortcut nitrification was successfully achieved and maintained in a CRI system by adding 5 mM KClO3 to the influent at a constant pH of 8.4. Under these conditions nitrite accumulation rate was increased, while a lower concentration of 3 mM KClO3 had no obvious effect. The addition of 5 mM KClO3 in influent presumably allowed sufficient activity of ammonia-oxidizing bacteria (AOB) but inhibited nitrite-oxidizing bacteria (NOB) strongly enough to result in a maximum nitrite accumulation rate of up to over 80%. As a result, nitrite became the dominant nitrogen product in the effluent. Moreover, if the shortcut denitrification will be achieved in the subsequent research, it could save 60.27 mg carbon source (CH3OH) consumption when treatment of per liter sewage in CRI system compared with full denitrification process.
ARTICLE | doi:10.20944/preprints201708.0060.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Passiflora cincinnata Mast; redox activity; cell cytotoxicity; α-amylase inhibition; antihyperglycaemic
Online: 17 August 2017 (10:29:55 CEST)
Passiflora cincinnata Mast is a plant popularly used in traditional medicine in northeastern Brazil. The present study aimed to evaluate the anti-lipoperoxidative and anti-α-amylase properties, and cytotoxicity of an extract and fraction of passion fruit leaves (P. cincinnata Mast), as well as the antihyperglecemiant activity of the fraction rich in glycosylated flavonoids and showing low cytotoxicity in rats with a postprandial hyperglycaemia condition. The ethyl acetate fraction (F.ACT) of the P. cincinnata leaves presented the best anti-lipoperoxide properties with TBARs 81.49%, 95.48% and 75.62% lower than AAPH, FeSO4 and H2O2 induced controls, respectively, at 200 μg.mL-1. In addition, it presented an anti-α-amylase potential, with a better ability to inhibit the α-amylase enzyme in comparison to the acarbose control (IC50 6.49 ± 0.11 and 12.01 ± 0.4 μg.mL-1, respectively). The hydroalcoholic extract of P. cincinnata (ExEt) presented high content of total tannins, flavonoids and flavonols. However, F.ACT had the highest concentration of flavonoids among the fractions studied. HPLC analysis of this fraction revealed the presence of the flavonoids isovitexin, orientin and isoorientin. F.ACT showed low to no cytotoxicity below 150 μg.mL-1. Regarding the post-prandial antihyperglycaemic activity of F.ACT, it was observed at 50 and 100 mg.kg-1.
ARTICLE | doi:10.20944/preprints201609.0123.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: carbonic anhydrase; acetylcholinesterase; β-Lactam; 2-Azetidinone; enzyme inhibition; enzyme purification
Online: 30 September 2016 (05:38:45 CEST)
β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was also examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The Ki values of β-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0.25-1.13 nM against AChE. Our findings indicate that β-lactams (2a-k) inhibit both CA isoenzymes and AChE at low nanomolar concentrations.
CONCEPT PAPER | doi:10.20944/preprints202005.0182.v1
Subject: Biology And Life Sciences, Virology Keywords: Coronavirus Nsp proteins; ribosomal proteins homology; inhibition of ribosome turn over; rRNA methyltransferase; protein synthesis inhibition; low ATP formation; blood clotting; low blood pressure and coma
Online: 10 May 2020 (18:14:55 CEST)
Multi-Alignment method coupled with phylogenetic analysis we disclosed the Nsp9 and Nsp10 non-structural proteins of Corona Virus as rRNA RlmH/K methyltransferases with similarities with bin recombinase and int-core integrase fold. Further, Nsp9 has similarities to S8 ribosomal protein and Nap10 has similarity to S10 ribosomal protein. Previously, we showed Nsp13, Nsp14, Nsp15 and Nsp16 are also different types of rRNA RlmE/N and Cfr-like methyltransferases-ribonuclease with RNA helicase domains. Two domains of Nsp13 astonishingly have similarities to ribosomal proteins L6 and L9. Taken together, Nsp9/10 and Nsp13-16 proteins could mimic host ribosome assembly and also could methylate rRNA of mitobibosome preventing mitochondrial protein synthesis and oxidative phosphorylation. Low ATP synthesis causes lowering blood pressure following coma but very ATP concentration (1-10nM) surely induces platelets aggregation through vWA, collagen and GpIIb/IIIa proteins followed by fibrin formation and blood clotting as recently have seen in the lung of many Corona virus infected patients. We have also postulated that two polyproteins itself resemble like 28S and 38S mitoribosome subunits and compete with rRNAs inhibiting the ribosome turnover and new protein synthesis due to their similarities with many ribosomal proteins. Such finding may be valuable in computer-based novel drug design against Corona virus.
ARTICLE | doi:10.20944/preprints202310.1486.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: heparan sulfate; enoxaparin; coronavirus; SARS-CoV-2; ACE2, absorption inhibition; molecular docking
Online: 24 October 2023 (08:12:50 CEST)
SARS-CoV-2 attachment and entry inside mammalian cells is mainly mediated by human angiotensin-converting enzyme 2 (ACE2) and its interaction with spike protein. However, it is well known that spike protein also interacts with other molecules like glycosaminoglycans (GAG), e.g., heparan sulfate (HS) or Enoxaparin (EX), which are linear, anionically charged polysaccharides known for their biological activities. The mode of action of these two polysaccharides is to bind spike protein to block the interaction with ACE2 receptors. This study aimed to assess a model capable of confirming the activity of these GAGs in both the wild-type strain of SARS-CoV-2 and its variants, such as the highly variable BA.2.86. This was achieved by combining in silico modeling with in vitro determination using BacMam technology. The results showed the antiviral activity of HS and EX both in vitro and through the in-silico analysis, reconciling conflicting findings from recent studies on the cellular entry of SARS-CoV-2. In conclusion, it is possible to highlight the ability of these molecules to circumvent the high variability of SARS-CoV-2, providing valuable insights into intervention strategies targeting cell entry mechanisms and establishing a safe in vitro model.
ARTICLE | doi:10.20944/preprints202309.1869.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Enterocins; Enterococcus; breast-fed infants; bacterial infection; Listeria monocytogenes; selective inhibition; probiotic
Online: 27 September 2023 (09:17:31 CEST)
Enterocins are bacteriocins synthesized by Enterococcus strains that show an interesting antimi-crobial effectiveness against foodborne pathogens such as Listeria monocytogenes. The objectives of this study were identify and analyze the expression of enterocin genes of Enterococcus isolated from breast-fed infants and evaluate the ability to inhibit three human isolates of virulent Lis-teria monocytogenes, as well as some probiotic bacteria. The susceptibility of the strains of L. mon-ocytogenes to fifteen antibiotics was tested, detecting resistance to cefoxitin (constitutive-ly resistant), oxacillin and clindamycin. Production of enterocins A, B and P were observed in Enterococcus faecium isolates, and enterocin AS-48 in an Enterococcus faecalis isolate. AS-48 showed antilisterial activity by itself, while the joint action of enterocins A and B, or B and P was neces-sary for inhibiting L. monocytogenes, demonstrating a synergistic effect of those combinations. The presence of multiple enterocin genes does not assured the inhibition of L. monocytogenes strains. However, the expression of multiple enterocin genes showed a good correlation with the inhibition capacity of these strains. Furthermore the potential beneficial strains of lactobacil-li and bifidobacteria examined were not inhibited by any of the enterocins produced individu-ally or in combination, with the exception of Bifidobacterium longum BB536, which was inhibited by enterocin AS-48 and the joint production of enterocins A and B or B and P. The enterocins studied here could be candidates for developing alternative treatments against antibi-otic-resistant bacterial infections. Moreover, these selected enterocin-producing E. faecium strains isolated from breast-fed infants could be used as probiotic strains due to their antilisterial effect as well as the absence of virulence factors.
REVIEW | doi:10.20944/preprints202209.0057.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: enteric methane; ruminants; mitigation; rumen; adoption; cost effectiveness; methanogenesis inhibition; feed additives
Online: 5 September 2022 (10:29:25 CEST)
This paper analyzes the mitigation of enteric methane (CH4) emissions from ruminants with the use of feed additives inhibiting of rumen methanogenesis to limit global temperature increase to 1.5 °C. A mathematical simulation conducted herein predicted that pronounced inhibition of rumen methanogenesis with pure chemicals or bromoform-containing algae can contribute to limit global temperature increase by 2050 to 1.5 °C only if widely adopted at a global level and considering an efficacy higher than obtained in most studies. Currently, the most important limitations to the adoption of antimethanogenic feed additives are probably increased feeding cost without a consistent return in production efficiency, and achieving sustained delivery of inhibitors to the rumens of non-supplemented, extensively ranging animals. Economic incentives, and changes in rumen microbial metabolism caused by inhibiting methanogenesis, could potentially be used to make the methanogenesis inhibition intervention cost effective. Also, the composition of the methanogenic community, and rate of disappearance of inhibitors of methanogenesis in the rumen can influence the effective dose of the inhibitors, and hence the cost of their adoption. Possible means for sustained delivery of antimethanogenic compounds to extensively grazing animals are discussed. Limitations and knowledge gaps of these approaches, and future research directions, are examined.
ARTICLE | doi:10.20944/preprints202102.0195.v1
Subject: Social Sciences, Psychology Keywords: Executive functions; music education; cognitive development; planning; inhibition; decision making; working memory
Online: 8 February 2021 (11:44:19 CET)
In recent years, music education in Ibero-America has been losing ground within the school environment in favor of the development of curricular systems that benefit academic results in standardized tests. Despite this, several studies in the field of cognitive neurosciences have found evidence of great relevance and in which it can be observed how music education can favor cognitive development and performance in practically all stages of human development, with important results in language tasks, attention, and executive functions such as planning, inhibition, cognitive flexibility and working memory.
REVIEW | doi:10.20944/preprints202010.0234.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: myostatin inhibition; Duchenne Muscular Dystrophy; skeletal muscle; muscle development; clinical trials; translation
Online: 12 October 2020 (12:07:43 CEST)
Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcomes measures selected: the myostatin inhibition story thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models has failed to translate into clinical benefit to patients has been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.
ARTICLE | doi:10.20944/preprints202311.1460.v1
Subject: Biology And Life Sciences, Parasitology Keywords: Onchocerciasis; drug discovery; anthelmintics; O. gutturosa; motility and MTT inhibition; FDA approved drugs
Online: 23 November 2023 (09:31:11 CET)
Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study we have examined the anti-Onchocerca activity of a range of existing FDA approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against O. gutturosa adult male parasites using a concentration of 1.25 x 10-5 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50-99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate, rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti-Onchocerca drug candidates worthy of further investigation.
ARTICLE | doi:10.20944/preprints202305.0738.v1
Subject: Environmental And Earth Sciences, Pollution Keywords: carbon nanomaterials; graphene family materials; bioassay; nanotoxicology; ecotoxicology; flow cytometry; growth rate inhibition
Online: 10 May 2023 (10:36:24 CEST)
The growing production and application of carbon-based nanomaterials (CNMs) represent possible risks for aquatic systems. However, the variety of CNMs with different physical and chemical properties, and different morphology complicated the understanding of their potential toxicity. This paper aims to evaluate and compare the toxic impact of four most common CNMs, namely multiwalled carbon nanotubes (CNTs), fullerene (C60), graphene (Gr), and graphene oxide (GrO) in marine microalgae Porphyridium purpureum. The microalgae cells were exposed to the CNMs for 96 h and measured by flow cytometry. Based on the obtained results, we determined no observed effect level (NOEL), calculated EC10 and EC50 concentrations for growth rate inhibition, esterase activity, membrane potential, and reactive oxygen species (ROS) generation changes for each tested CNMs. According to the sensitivity (growth rate inhibition) of P. purpureum, the used CNMs can be listed in following order: CNTs > GrO > Gr > C60. The toxicity of CNTs was significantly higher than the toxic effect of the other used CNMs and only this sample caused increase of ROS generation in microalgae cells. This effect caused by trace metal residuals in CNTs and high affinity between particles and microalgae associated with the presence of exopolysaccharide coverage on P. purpureum cells.
REVIEW | doi:10.20944/preprints202301.0532.v2
Subject: Biology And Life Sciences, Plant Sciences Keywords: natural products; plant extracts; Myrtus communis; medicinal plants; antimicrobial; antioxidants; antiviral; biofilm inhibition
Online: 7 February 2023 (03:33:29 CET)
Myrtus communis L., commonly known as true myrtle, is a medicinal plant native to the Mediterranean area. Since ancient times inhabitants of this area have been using it for its cultural and medicinal properties. Due to the high content of essential oil in its flowers, leaves and fruits, M. communis is an important medicinal and aromatic species from Myrtaceae family. Because of the presence of vast diversity of biomolecules in its aerial parts, it exhibits several biological properties of antioxidant, antimicrobial and anticancer. There has been increasing scientific interest in the field to understand the pleotropic effects of its extracts or essential oils on various ailments and diseases. This purpose of this review is to summarizes the chemical composition, traditional uses, and biological activities of M. communis L. leaves documented in numerous recent studies.
ARTICLE | doi:10.20944/preprints202106.0528.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: ACE-inhibition; antioxidant potential; processed cheddar cheese; water soluble extract; ethanol soluble extract
Online: 22 June 2021 (07:45:25 CEST)
The purpose of this study was to develop an in-vitro digestion protocol to evaluate the antioxidant potential of the peptides found in processed cheddar cheese using digestion enzymes. We studied first antioxidant and angiotensin converting enzyme (ACE) inhibition and antioxidant activities of processed cheddar cheese with the addition of spices e.g. cumin, clove and black pepper made from buffalo milk and ripened for 9 months. Then we conducted an in vitro digestion of processed cheddar cheese by gastric and duodenal enzymes. Freeze dried water (WSE) and ethanol soluble fractions (ESE) of processed cheddar cheese were also monitored for their ACE inhibition activity and antioxidant activities. In our preliminary experiments, different levels of spices (cumin, clove and black pepper) were tested into cheese matrix and only one level 0.2g/100g (0.2%) on the basis of cheese weight was considered good concerning sensory evaluation. Significant increase in ACE-inhibition (%) of processed Cheddar cheese as well as its WSE and ESE was obtained. Lower IC50 values were found after duodenal phase digestion compared to oral phase digestion.
ARTICLE | doi:10.20944/preprints202103.0596.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: postharvest treatment; jasmonate; metabolite profiling; lipid metabolism; Solanum lycopersicum; ethylene inhibition; fruit quality
Online: 24 March 2021 (16:12:21 CET)
Application of exogenous jasmonate can stimulate the production of ethylene, carotenoids and aroma compounds, resulting in the acceleration of fruit ripening. These alterations improve fruit quality and make fruit desirable for human consumption, but overripening of a fruit results in large losses of fruit crops. In order to overcome this problem, 1-methylcyclopropene was ap-plied to the fruits due to its capacity to block the receptors of ethylene, resulting in the sup-pressed of fruit ripening. In this study, treatments only with 1-methylcyclopropene, and with both 1-methylcyclopropene and methyl jasmonate was conducted to observe if an exogenous methyl jasmonate can improve the levels of metabolites in their fruits with ethylene receptors blocked. Fruits were analyzed at 4, 10 and 21 day after harvest (DAH) and compared with the no treated fruits. The postharvest treatments affected primary metabolites (sugars, organic acids, amino acids and fatty acids) and secondary metabolites (carotenoids, tocopherols and phytoster-ols). However, the lipid metabolism of the tomato was the most impacted by the exogenous jasmonate. Fatty acids, carotenoids, tocopherols and phytosterols showed a delay in their pro-duction at 4 and 10 DAH. In contrast, at 21 DAH these non-polar metabolites exhibited an im-portant improvement in their accumulation.
ARTICLE | doi:10.20944/preprints202012.0289.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: remdesivir; perturbation of nucleotide pools; inhibition of RNA and DNA synthesis; CTP synthase
Online: 11 December 2020 (15:57:14 CET)
Remdesivir (RDV) has garnered much hope for its moderate anti-COVID-19 effects, but its limited amelioration of survival in hospitalized patient causes a huge controversy over the applicability of RDV to COVID-19 treatment. Developing strategies to improve its antivirus efficacy is urgently required. As anticipated, RDV exhibits similar behavior with other nucleotide analogs to disrupt the metabolism of natural endogenous ribonucleotides (RNs) and deoxyribonucleotides (dRNs). Alterations in endogenous RNs and dRNs play a critical role in virus replication as well as other key cellular functions. Thus elucidation of the disturbances of RDV on RNs and dRNs could help to understand its exact mechanism of action. Here, the metabolic profiling determined by liquid chromatography–mass spectrometry method showed a general increase in the abundance of nucleotides and a more than 2-fold increase for specific nucleotides. However, the variation of pyrimidine ribonucleotides was relative slight or even contrary, resulting in obvious imbalance between purine and pyrimidine ribonucleotides, which implied the obstacle of RDV to pyrimidine synthesis and could further block the transcription and replication of viral RNA. Additionally, the extreme disequilibrium between cytidine triphosphate (CTP) and cytidine monophosphate might result from the inhibition of CTP synthase and provide a metabolic target for the treatment of COVID-19 infection. Since nucleotides metabolism pathways are vulnerable to nucleotide analogues and are liable to be the regulation targets, it is promising to enhance the efficacy of RDV through co-administration with CTP synthase inhibitors or de novo pyrimidine synthesis inhibitors to exacerbate the imbalance of nucleotide pools.
ARTICLE | doi:10.20944/preprints202012.0032.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Colorectal cancer; Dehydrodiisoeugenol (DEH); Autophagy inhibition; Endoplasmic reticulum (ER) stress; anti-cancer agent
Online: 1 December 2020 (14:57:00 CET)
Dehydrodiisoeugenol (DEH), a novel lignan component extracted from the Nutmeg seeds, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anti-cancer activity in gastrointestinal cancer is still to be investigated. Here, the anti-cancer effect of DEH to human colorectal cancer and its underlying mechanism were evaluated. The DEH treatment arrests the cell cycle of colorectal cancer cells at G1/S phase, which leading to a significant cell growth inhibition. Moreover, it can induce strong cellular autophagy and the autophagy would be inhibited through autophagic inhibitors with reducing EDH-induced inhibition of cell growth in colorectal cancer cells. Further studies indicated that DEH can also induce endoplasmic reticulum (ER) stress, and could subsequently stimulating autophagy through activating PERK/eIF2α and IRE1α/XBP-1s/CHOP pathways. Knockdown of PERK or IRE1α can significantly decrease the DEH-induced autophagy and retrieve cell viability in cells treated with DEH. What’s more, DEH exhibits significant anti-cancer activities through CDX- and PDX-model as well. Taken together, our studies strongly suggest that DEH might be a potential anti-cancer agent against colorectal cancer via activating ER stress-induced autophagy inhibition.
ARTICLE | doi:10.20944/preprints202004.0161.v2
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: COVID-19; docking; drug repurposing; natural products; in silico drug design; viral replication inhibition
Online: 1 June 2020 (02:42:54 CEST)
We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the SARS-CoV-2 virus causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top- ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
ARTICLE | doi:10.20944/preprints201901.0062.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: small molecule; ligand; receptor; docking; molecular dynamics; DNA repair; inhibition; PCNA; ADME; toxicology
Online: 8 January 2019 (11:10:26 CET)
Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for Herg channel blockage and Ames carcinogenicity, there was considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.
ARTICLE | doi:10.20944/preprints201807.0351.v1
Subject: Chemistry And Materials Science, Materials Science And Technology Keywords: electrochemical sensor; inhibition bacteria sensor array; immobilization of bacteria; water pollution; pattern recognition
Online: 19 July 2018 (11:51:41 CEST)
The development of a novel and simple inhibition biosensor array for detection of water pollutants based on immobilized bacteria is the main goal of this work. A series of electrochemical measurements (i.e. cyclic voltammograms) were carried out on screen-printed gold electrodes with three types of bacteria, namely Escherichia coli, Shewanella oneidensis, and Methylococcus capsulatus, immobilized via poly L-lysine. For comparison purposes, similar measurements were carried out on bacteria samples in solutions,; also optical measurements (fluorescence microscopy, optical density, and flow cytometry) were performed on the same bacteria in both liquid and immobilized forms. The study of the effect of heavy metal ions (lead), pesticides (atrazine) and petrochemicals (hexane) on DC electrochemical characteristics of immobilized bacteria revealed a possibility of pattern recognition of the above inhibition agents in aquatic environment.
ARTICLE | doi:10.20944/preprints202308.1475.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: acetylcholinesterase inhibitory test; molecular docking; blood-brain barrier permeation; memory impairment; AChE inhibition kinetics
Online: 21 August 2023 (13:46:47 CEST)
The acetylcholinesterase-inhibitory potential of the oleanane-type triterpenes and their glycosides from the Terminalia arjuna (Combreatceae) bark, i.e. arjunic acid, arjunolic acid, arjungenin, arjunglucoside I, sericic acid, and arjunetin, is presented. The studies are based on the in silico pharmacokinetic and biomimetic studies, the acetylcholinesterase (AChE) inhibitory activity tests, and the molecular docking research. Based on the calculated pharmacokinetic parameters, arjunetin and arjunglucoside I are indicated as able to cross the blood-brain barrier. The compounds of interest exhibit marked acetylcholinesterase inhibitory potential, which was tested in the TLC bioautography test. The longest time to reach brain equilibrium is observed for both the arjunic and arjunolic acids and the shortest one for arjunetin. All compounds exhibit high and relatively similar magnitude of binding energies, varying from ca. -15 to -13 kcal/mol. The superposition of the most favorable positions of all ligands interacting with AChE is analyzed. The correlation between the experimentally determined IC50 values and the steric parameters of the molecules is investigated. The inhibition of the enzyme by the analyzed compounds shows their potential to be used as cognition enhancing agents. For the most potent compound (arjunglucoside I; ARG), the kinetics of AChE inhibition is tested. The Michaelis–Menten constant (Km) for the hydrolysis of the acetylthiocholine iodide substrate was calculated to be 0.011 mM.
ARTICLE | doi:10.20944/preprints202307.0569.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: Porphyromonas gingivalis; Symphytum Officinale; Panax Ginseng; Metronidazole; Biofilm Inhibition; Acylated Homoserine Lactones; Periodontal Diseases.
Online: 10 July 2023 (09:51:35 CEST)
Background: The important periodontal disease pathogen Porphyromonas gingivalis produces large biofilms that increase its pathogenicity. Finding natural antimicrobial agents is crucial because of the rise in antibiotic resistance. Objective: The purpose of this study was to determine if plant extracts such as Symphytum officinale (S) and Panax ginseng (G) were effective against P. gingivalis separately and in combination with a common antibiotic Metronidazole (F). Materials and Procedures: Six different dilutions were produced the plant extracts and antibiotic separately and in combination with G and F and S and F using two-fold serial dilution technique. To evaluate the effects of these substances biofilm inhibition experiments were conducted. Plaque samples were collected from periodontitis patients to isolate P. gingivalis and standard strain of P. gingivalis (ATCC 33277) were bought. Additionally, Acylated Homoserine Lactones (AHLs) detection was carried out to look for any activity that would interfere with quorum sensing. GraphPad prism was used for statistical analysis with p value < 0.05. Results: The combinations of Symphytum Officinale and Metronidazole (S+F) showed the maximum effectiveness in biofilm inhibition (98.7%), which was better than G+F (98.2%) with substantial variations in biofilm inhibition levels in different treatment regimes. Notably, the isolate from the patient was more active than the standard strain. Additionally, the plant extracts and their combinations at particular dilutions had notable inhibitory effects on the generation of AHL (p <0.05). Conclusion: The study highlights the possibility of Symphytum Officinale and Panax Ginseng as effective treatments for P. gingivalis biofilm and AHLs, both on their own and in combination with Metronidazole. These organic substances may open the door to cutting-edge methods of treating periodontal disorders.
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: hearing loss; aging; hyperactivity; excitability; loss of inhibition; neurophysiology; auditory perception; neural plasticity; speech processing
Online: 15 April 2021 (13:34:54 CEST)
Many aging adults experience some form of hearing problems that may arise from auditory peripheral damage. However, it has been increasingly acknowledged that hearing loss is not only a dysfunction of the auditory periphery but results from changes within the entire auditory system, from periphery to cortex. Damage to the auditory periphery is associated with an increase in neural activity at various stages throughout the auditory pathway. Here, we review neurophysiological evidence of hyperactivity, auditory perceptual difficulties that may result from hyperactivity, and outline open conceptual and methodological questions related to the study of hyperactivity. We suggest that hyperactivity alters all aspects of hearing – including spectral, temporal, spatial hearing – and, in turn, impairs speech comprehension when background sound is present. By focusing on the perceptual consequences of hyperactivity and the potential challenges of investigating hyperactivity in humans, we hope to bring animal and human electrophysiologists closer together to better understand hearing problems in older adulthood.
ARTICLE | doi:10.20944/preprints202304.0914.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Metformin; Quorum sensing; Quorum quenching; Pseudomonas aeruginosa; Virulence; Drug repurposing; Anti-virulence therapy; Biofilm inhibition
Online: 25 April 2023 (09:54:20 CEST)
Metformin (MeT) is an FDA-approved drug with a myriad of health benefits. Besides being used as an anti-diabetic drug, MeT is also effective against various cancers, liver-, cardiovascular-, and renal diseases. It has also been proven to demonstrate anti-ageing and neuroprotective effects. This study was undertaken to examine its unique potential as an anti-virulence drug against an opportunistic bacterial pathogen, Pseudomonas aeruginosa. Due to the menace of multidrug resistance in pathogenic microorganisms, many novel or repurposed drugs with anti-virulence prospects are emerging as next-generation therapies with the aim to overshadow the application of existing antimicrobial regimens. The quorum sensing (QS) mechanisms of P. aeruginosa are an attractive drug target for attenuating bacterial virulence. In this context, the anti-QS potential of MeT was scrutinized using biosensor assays. MeT was comprehensively evaluated for its effects on different motility phenotypes, virulence factor production (phenotypic and genotypic expression) along with biofilm development in P. aeruginosa in vitro. At sub-lethal concentrations, MeT displayed prolific quorum quenching (QQ) ability and remarkably inhibited AHL biosynthesis in P. aeruginosa. Moreover, MeT (1/8 MIC) effectively downregulated the expression levels of various QS- and virulence genes in P. aeruginosa, which coincided with a notable reduction in the levels of alginate, hemolysin, pyocyanin, pyochelin, elastase, and protease production. In silico analysis through molecular docking also predicted strong associations between the QS receptors of P. aeruginosa and MeT. MeT also compromised the motility phenotypes and successfully abrogated biofilm formation by inhibiting EPS production in P. aeruginosa. Hence, the QQ, anti-virulence, and anti-fouling potential of MeT was elucidated for the first time against P. aeruginosa.
ARTICLE | doi:10.20944/preprints202303.0539.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: Antibiotic resistance; metallo-β-lactamases; metal-dependent enzymes; broad-spectrum inhibitors; inhibition assays; enzyme kinetics
Online: 31 March 2023 (03:35:02 CEST)
Metallo-β-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since β-lactam antibiotics, which are inactivated by MBLs, constitute ~65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against representatives of each of the three subgroups of MBLs (B1, B2, B3). Several compounds are potent inhibitors of each MBL tested, making them excellent candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL subfamilies, with Ki values in the low µM range. Furthermore, this compound also dis-plays synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents one of the most promising compounds developed yet to combat MBLs.
ARTICLE | doi:10.20944/preprints201911.0039.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: heart failure; Sacubitril/valsartan; Neprilysin inhibition; reduced ejection fraction; echocardiography; Nt-Pro-BNP; hemodynamic; remodeling
Online: 4 November 2019 (11:20:22 CET)
Background: Sacubitril/valsartan has been shown to be superior to enalapril in reducing the risks of death and hospitalization for heart failure (HF). However the effect on cardiac performance remains unknown. We sought to evaluate the effects of sacubitril/valsartan on clinical, bioumoral and echocardiographic parameters in patients with HFrEF. Methods: Sacubitril/valsartan was administered to 205 HFrEF patients. Results: Among 230 patients (mean age 59 ± 10 years, 46% with ischemic heart disease) 205 (89%) completed the study. After a follow–up of 10.49 (2.93±18.44) months, the percentage of patients in NYHA class III changed from 40% to 17% (p<0.001). Median N–Type natriuretic peptide (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205 pg/mL, (p=0.01). Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p=0.047). Ejection fraction (from 27± 5.9% to 30 ± 7.7% (p<0.001) and E/A ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p=0.002)) improved. Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p=0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/sec to 2.64 ± 0.59 m/sec (p<0.014). CONCLUSIONS: Sacubitril/valsartan induce “hemodynamic reverse remodeling” and in association with Nt-proBNP concentrations lowering improve NYHA class despite a diuretic dose reduction.
ARTICLE | doi:10.20944/preprints201711.0196.v1
Subject: Biology And Life Sciences, Agricultural Science And Agronomy Keywords: carbohydrate starvation; non-structural carbohydrate; photosynthesis; photosynthesis inhibition; respiration; relative growth rate; structure; diurnal variation
Online: 30 November 2017 (08:48:58 CET)
Predicting the growth response of seedlings from the environmental responses of photosynthesis and metabolism may be improved by considering the dynamics of non-structural carbohydrate, NSC, over a diurnal cycle. Attenuation of growth metabolism when NSC content is low could explain why some NSC is conserved through the night. A dynamic model, incorporating diurnal variation in NSC, was developed to simulate growth of seedlings hour-by-hour. I compared predictions of this model to published growth and NSC data for seedlings that varied according to temperature, light, day length, or CO2. Prolonged-darkness experiments showed a temperature dependent upper limit on the respiration capacity. Respiration was attenuated as NSC was depleted. Furthermore, when NSC was high at dawn, inhibition of photosynthesis could attenuate the accumulation of NSC under low temperature, or high light, or high CO2. These concepts were used to simulate plant metabolism and growth rates and diurnal variation of NSC in tomato seedlings under two light levels and various temperatures. Comparison of other results using the same model parameters showed the dynamic model could predict results for starch and starch-less plants, and when growth was affected by CO2 enrichment and day length.
ARTICLE | doi:10.20944/preprints202310.0589.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Daptomycin; PMMA cement; mechanical properties; elution; antimicrobial effectiveness; inhibition zone test; Vancomycin-resistant germs; PMMA spacer
Online: 10 October 2023 (07:17:42 CEST)
Background: Number of joint infections caused by Vancomycin-resistant pathogens is emerging. Currently no PMMA cement is commercially available to cover VRE. Daptomycin shows promising results in infection treatment, offers a good safety profile and reduced risk for resistance development. Purpose of this in vitro study is to investigate the mechanical stability, handling properties, elution behavior and antimicrobial effectiveness of PMMA cement loaded with three different Daptomycin concentrations in comparison to commercially available ALBC; Methods: Mechanical properties and handling characteristics (ISO 5833, DIN 53435), HPLC elution, antimicrobial effectiveness with proliferation assay (DIN 17025) and inhibition zone testing were investigated; Results: All tested Daptomycin concentrations fulfilled ISO and DIN mechanical strength. Dosage of 0.5. g added Daptomycin did not show any antimicrobial effectiveness in contrast to 1.0 g and1.5 g. Cement with 1.5 g Daptomycin was best in elution and effectiveness, showed good mechanical ISO strength, ISO doughing was a little longer sticky and setting was faster as Vancomycin containing reference cement; Conclusion: PMMA cement containing 0.5 g Gentamicin and 1.5 g Daptomycin could be a good alternative to the already established COPAL® G+V for PJI treatment of VRE.
REVIEW | doi:10.20944/preprints202308.1824.v1
Subject: Biology And Life Sciences, Life Sciences Keywords: antifungal peptides; enzyme-like activity; growth inhibition; antifungal activity; fungal metabolites; quorum response molecules; combined antifungals
Online: 28 August 2023 (09:44:34 CEST)
Biomimetics, which are similar to natural compounds that play an important role in the metabolism, manifestation of functional activity and reproduction of various fungi, have a pronounced attrac-tion in the current search for new effective antifungals. Actual trends in the development of this area of research indicate that unnatural amino acids can be used as such biomimetics, including those containing halogen atoms; compounds similar to nitrogenous bases embedded in the nucleic acids synthesized by fungi; peptides imitating fungal analogues; molecules similar to natural sub-strates of numerous fungal enzymes and Quorum Sensing signaling molecules of fungi and yeast; etc. Most part of the review is devoted to the analysis of semi-synthetic and synthetic antifungal peptides and their targets of action. This review is aimed at combining and systematizing the cur-rent scientific information accumulating in this area of research, developing various antifungals with an assessment of the effectiveness of the created biomimetics and the possibility of combining them with other antimicrobial substances to reduce cell resistance and improve antifungal effects.
ARTICLE | doi:10.20944/preprints202305.0769.v1
Subject: Environmental And Earth Sciences, Pollution Keywords: carbon nanotubes; graphene; fullerene; nanotoxicology; bioassay; growth rate inhibition; flow cytometry; nanoparticles; oxidative stress; environmental fate
Online: 10 May 2023 (14:49:02 CEST)
This work is related to the environmental toxicology risk assessment and evaluation of possible transformation of carbon-based nanomaterials (CNMs) after the contact with marine microalgae. The materials used in the study represent common and widely applied multiwalled carbon nanotubes (CNTs), fullerene (C60), graphene (Gr), and graphene oxide (GrO). The toxicity was evaluated as growth rate inhibition, esterase activity, membrane potential, and reactive oxygen species generation changes. The measurement was performed with flow cytometry after 3, 24, 96 h, and 7 days. Biotransformation of nanomaterials were evaluated after 7 days of microalgae cultivation with CNMs by FTIR and Raman spectroscopy. The calculated toxic level (EC50 in mg/L, 96 h) of ued CNMs reduced in the following order: CNTs (18.98) > GrO (76.77) > Gr (159.40) > C60 (414.0). Oxidative stress and membrane depolarization was the main toxic action of CNTs and GrO. At the same time, Gr and C60 decreased the toxic action with time and had no negative impact on microalgae even at concentration of 125 mg/L. Moreover, C60 and Gr after seven days of the contact with microalgae cells obtained structural deformations.
ARTICLE | doi:10.20944/preprints202111.0184.v2
Subject: Biology And Life Sciences, Virology Keywords: baloxavir marboxil; H5N1 highly pathogenic avian influenza virus; viral replication; inhibition; lung inflammation; combination therapy; oseltamivir
Online: 12 January 2022 (13:18:58 CET)
Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-hour delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.
ARTICLE | doi:10.20944/preprints201906.0301.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: tumor blood vessel; Tumor Angiogenic Inhibition Triggered Necrosis (TAITN); CXCR4 antagonist; oral squamous cell carcinoma; hypoxia
Online: 28 June 2019 (15:18:43 CEST)
CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis thereby supports tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To ask the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic area with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.
ARTICLE | doi:10.20944/preprints202308.1845.v1
Subject: Engineering, Metallurgy And Metallurgical Engineering Keywords: Localised corrosion and inhibition; wire beam electrode (WBE); scanning vibrating electrode technique (SVET); scanning electrochemical microscopy (SECM)
Online: 28 August 2023 (09:54:49 CEST)
The inhibition of localised corrosion is known to involve multiple processes taking place over a range of time and length scales that are difficult to study by conventional electrochemical methods. This work demonstrates an approach to probing complex localised electrochemical processes by combining an electrochemically integrated multi-electrode array (also known as wire beam electrode (WBE)), scanning vibrating electrode technique, scanning electrochemical microscopy and surface analytical techniques. Each technique reveals certain aspects of the dynamically changing, multi-scale, inhibitor-microstructure interactions and local chemistry over a heterogeneous AA2024-T3 alloy surface in the presence of an environmentally friendly inhibitor; cerium diphenyl phosphate (Ce(dpp)3).
ARTICLE | doi:10.20944/preprints201811.0330.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: hyperpigmentation; tyrosinase inhibitors; 3-(2,4-dihydroxyphenyl)propionic acid; structure-activity relationship study; B16-F10 cellular melanogenesis inhibition
Online: 14 November 2018 (09:59:45 CET)
Compounds with tyrosinase inhibitory efficacy could be effective as depigmenting agents. Although a large number of natural and synthetic tyrosinase inhibitors have been reported, few of them are used as skin-whitening agents due to poor activity and safety concerns. 3-(2,4-Dihydroxyphenyl)propionic acid (DPPA), a naturally occurring compound isolated from Ficus carica, was previously discovered as a moderate tyrosinase inhibitor. In this study, the structure-activity relationship study of DPPA was conducted. Compound 3g, with the 2,4-resorcinol subunit and terminal hydrophobic di-butylamino group, was identified with low nanomolar enzymatic IC50 value. Additionally, compound 3g could effectively reduce melanin levels in B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH) without affecting cell viability and proliferation. All these results indicated that compound 3g could be considered as a promising candidate for the treatment of diseases associated with hyperpigmentation.
REVIEW | doi:10.20944/preprints201802.0070.v1
Subject: Environmental And Earth Sciences, Environmental Science Keywords: microbial sulphide oxidation, corrosion, mine waste and water remediation, biofilm development, inhibition of Acid mine and rock draiange
Online: 8 February 2018 (15:35:56 CET)
Abstract: Measures to counteract AMD generation need to start at the mineral surface, inhibiting mineral-oxidizing, acidophilic microbes. Laboratory and long-term field tests with pyrite-containing mining wastes, where Carbonaceous Phosphate Mining Waste (CPMW) was added, resulted in low acidity, and near neutral drainage. The effect was reproducible, nd confirmed by several independent research groups. This was shown to involve an organic coating, likely a biofilm. The biofilm formation was confirmed when CPMW was added to lignite coal waste with an initial pH of 1. Forty five days after the addition, the coal waste was dominated by heterotrophic microorganisms in biofilms. A review of the scientific literature supports that CPMW has physical and chemical characteristics which are capable of inducing a strong inhibitory effect on sulphide oxidation by forming an organic coating over the mineral surface. CPMW characteristics appear to provide the cornerstone of a new technology for the reduction of sulphide oxidation in mine wastes. An hypothesis for testing this technology is presented which could result in an economical and sustainable approach to mine waste and water management.
REVIEW | doi:10.20944/preprints202306.0051.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: green synthesis; MOFs; amyloid proteins; prionase; mycotoxins; growth inhibition; quorum sensing; quorum quenching; lactamases; biofilms; chitinases; lactonases; His6-OPH
Online: 1 June 2023 (07:31:58 CEST)
Active research of metal-containing compounds and enzymes as effective antifungal agents is currently noted. The interest in metals is due to the wide variety of ligands that can be used for metals, including chemically synthesized and naturally obtained variants as a result of the so-called "green synthesis". The main mechanism of antifungal action of metals is the triggering of generation and accumulation of reactive oxygen species (ROS). Further action of ROS on various biomolecules is nonspecific. This review highlights various hydrolytic enzymes (glucanases and proteases) that affect the structural elements of fungal cells (cell walls, membranes), fungal quorum sensing molecules, fungal own protective agents (mycotoxins and antibiotics), proteins responsible for the adhesion and formation of stable highly concentrated populations in the form of biofilms. A wide range of the substrates for enzymes allows the use of various mechanisms of their antifungal actions. The prospects of combining two different types of antifungal agents (metals and enzymes) for mycelial fungi and yeast cells are discussed in this review. Special attention is paid to the possible influence of metals on activity of the enzymes and the possible effects of proteins on antifungal activity of metal-containing compounds.
ARTICLE | doi:10.20944/preprints202301.0421.v3
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Oncology; Immune Checkpoint Inhibition; PD-1; PD-L1; CTLA-4; Immune Related Adverse Events; Immunotherapy; Tumor Plasticity; Tumor Microenvironment; Optimum Therapy Duration
Online: 6 March 2023 (01:53:16 CET)
Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. This paper provides deep insight into immune related adverse events (irAEs) posing a major challenge and drawback to ICIT, and presents right management strategies for very complex complications. Moreover, for the first time in literature, a non-linear mathematical model is introduced to measure the ICIT success rate and to decide about the optimum ICIT duration. Furthermore, a strategy is presented to overcome or to delay the progression after initial good response in a subset of patients.
ARTICLE | doi:10.20944/preprints202002.0134.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: autophagy; autophagonizer; target identification of label-free compound; target validation; autophagic flux; autophagy inhibition; lysosomal integrity function of Hsp70
Online: 11 February 2020 (09:03:51 CET)
Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC-MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.