Neuroblastoma is the most common tumour in children under 1 year old, accounting for approximately 50% of infant cancer cases. Although current treatments are relatively efficacious against this cancer, associated adverse effects could be detrimental to growth and development. In contrast, glioblastoma accounts for 52% of brain tumours and has an extremely poor prognosis. Current chemotherapeutics include temozolomide, which has numerous negative side-effects and a low-effective rate. Previous studies have shown the manipulation of autophagy to be a promising method for targeting cancers, including glioblastoma. We sought to determine the effects of autophagic alterations in combination with current chemotherapies in both neuroblastoma and glioblastoma. Supplementing cisplatin or temozolomide with autophagy activator rapamycin stabilized cancer cell mitochondria, despite having little effect on apoptosis or oxidative stress. Autophagy inhibition via 3-methyladenine or hydroxychloroquine alongside standard chemotherapies enhanced apoptosis and oxidative stress, with 3-methyladenine also disrupting mitochondrial health. Importantly, combining hydroxychloroquine with 0.5 µM cisplatin or 50 µg/mL temozolomide was as or more effective than 2 µM cisplatin or 100 µg/mL temozolomide alone. Analyzing these interesting results, a combined treatment of autophagy inhibitor with a standard chemotherapeutic agent could help to improve patient prognosis and reduce chemotherapy doses and their associated side-effects.

Black ginseng is a type of processed ginseng that is traditionally used as herbal medicine in East Asian countries. It is prepared from fresh, white, or red ginseng by undergoing a process of steaming and drying nine times. However, the chemical differentiation of black ginseng with different processing levels is not well understood. The aim of this study is to propose a new method for discriminating and quantifying black ginseng. Six ginsenosides from black ginseng were accurately quantified, and based on this, the black ginseng samples were divided into uncompleted and completed black ginseng. Ultra-high-performance liquid chromatography-quadrupole-time of flight/mass spectrometry (UPLC-Q-TOF/MS) combined with a multivariate statistical analysis strategy was then employed to differentiate the two groups. A total of 141 ions were selected as analytical markers of black ginseng, with 45 of these markers being annotated by matching precise m/z and MS/MS data from prior studies.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival and other cellular processes and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to develop new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding site provides crucial insights for the drug discovery and development. Binding site similarities are helpful to understand polypharmacology, identifying potential off-targets and repurposing of known drugs. In this review, we focused on comparing binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed till date. Our review and analysis of several explored kinases might be useful to target new protein kinases for macrocyclic drug discovery.

With the rising prevalence of obesity, Non-Alcoholic Fatty Liver Disease (NAFLD) now affects 20-25% of the global population. NAFLD, a progressive condition associated with oxidative stress, can result in cirrhosis and liver cancer in 10% and 3% of patients suffering NAFLD, re-spectively. Therapeutic options are currently limited, emphasizing the need for novel treatments. In this study, we examined the potential of activating the transcription factor NRF2, a crucial player in combating oxidative stress, as an innovative approach to treating NAFLD. Utilizing a CRISPR-engineered human cell line, we were able to monitor the expression of heme oxygenase-1 (HMOX1), an NRF2 target, using a Nanoluc luciferase tag. Our model was validated using a known NRF2 activator, after which we screened 1200 FDA-approved drugs, unearthing six compounds (Disulfiram, Thiostrepton, Auranofin, Thimerosal, Halofantrine, and Vorinostat) that enhanced NRF2 activity and antioxidant response. These compounds demonstrated protec-tive effects against oxidative stress and lipid accumulation in vitro. Our study underscores the utility of CRISPR tagging with Nanoluc luciferase in identifying potential NRF2 activators, pav-ing the way for potential NAFLD therapeutics.

ACE2 impact on the severity of COVID-19 is widely discussed but still controversial. To estimate its role in aspects of the main risk factors and comorbidities, we involved post-COVID-19 patients in Ternopil region (Ukraine). Recruitment period was July 2020 to December 2021. Medical records, treatment modalities and outcomes were recorded and analyzed. Serum human ACE2 protein was measured with Cusabio ELISA kits (Houston, TX, USA). Statistical analysis was performed with SPSS21.0 software (SPSS Inc., Chicago, IL, USA). The level of ACE2 serum protein was significantly higher (p < 0.001) in patients with mild symptoms compared to more severe course of disease, and inversely had changed from 1 to 90 days after recovery. In patients with mild COVID-19, ACE2 level significantly decreased over time, while among critical patients, it increased by 34.1percent. Such results could be explained by ACE2 shedding from tissues into circulation. Loss of the membrane-bound form of the enzyme decreases the virus entry into cells. Our studies did not identify any sex-related ACE2 serum levels correlation. The most common comorbidities were hypertension, cardiovascular diseases, respiratory diseases and diabetes mellitus. All comorbidities except respiratory diseases contribute to the severity of disease and correlate with ACE2 blood serum level.

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169, an inhibitor of the decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1) in Mycobacterium tuberculosis (Mtb), showed anti-TB potential in animal model and piloted clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general shows extremely low aqueous solubility, which adversely affect the drug like property. To improve the compounds physiochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb in single digit nanomolar. The representative compound 37 displayed improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

The Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but also indirectly influences other cellular processes, such as cellular cycle and proliferation, growth, cell differentiation, angiogenesis, migration, adhesion and invasion. We used the SK-BR-3 breast cancer cell line, mesenchymal stem cells (MSCs), and tumor-associated fibroblasts (TAFs) in vitro for determining the changes induced by Ouabain in concentration of 10-5 M, 10-6 M, 10-8 M, 10-9 M on these cellular types, employing specific methods: SEM for morphological evaluation; immunocytochemistry, flowcytometry to assess immunophenotypical markers expression, cell cycle and Annexin V/PI assay for cellular proliferation and viability testing; flowchamber assay to evaluate functional adhesion behavior; RT-PCR for Na+/K+ ATPase subunits molecular expression. Being indicative of the pro-apoptotic and inhibitory effect of Ouabain on tumor invasion and metastasis, the results support the addition of Ouabain to the oncological therapeutic arsenal, trailing the “repurposing drugs” approach.

Background: Iron chelation medications (desferoxamine, desferasirox, desferiprone) are used to manage iron overload. These medications are partially excreted via the kidneys, desferoxamine and desferiprone excretes primarily in the urine, and desferasirox had about 8% excreted in the urine. Their use in severe kidney disease and dialysis patients is caution as “avoided” concerning adverse effects; however, there are reports safe use. This manuscript reviews the literature in this population. Data Sources: Pubmed: desferasirox, deferiprone, deferoxamine, kidney disease, ESKD, Dialysis. Case reports and case series that described experiences with using iron chelation medications in ESKD patients are included. Data also gathered from reading-related sources. Results: This is a review of desferoxamine, desferasirox, and deferiprone use in kidney disease from 1976 to the present time. Table 1 provides a summary of findings. These are mostly reports and brief descriptions of the experiences used in severe kidney disease and dialysis, but lack of randomized control trials and small number of participants. Conclusions: Iron chelation medications are important for treating iron overload but concerns with adverse effects. Due to limited medications available to treat iron overload in patients with severe kidney disease, their safe use has been reporting in the literature. This is an area that warrants further research.

Emerging infectious disease threats are becoming more frequent due to various social, political and geographical pressures including increased human-animal contact, global trade, transportation and changing climate conditions. As a result, the threat that emerging agents can be spread by blood contact or transfusion of blood products also becomes increasingly problematic. Blood transfusion is essential in treating patients with anemia, blood loss, and other medical conditions. However, these lifesaving components can become a vector for spreading diseases, particularly to vulnerable populations. New methods have been implemented on a global basis for prevention of transfusion transmission via plasma, platelet, and whole blood products. Implementing proactive pathogen reduction methods can significantly reduce the likelihood of disease transmission via blood transfusion, even for newly emerging agents whose transmissibility and susceptibility are still being evaluated as they emerge. In this review, we consider the Mirasol PRT system for blood safety which is based on a photochemical method involving Riboflavin and UV light. We provide examples of how emerging threats such as Ebola, SARS-CoV-2, Hepatitis E, monkeypox and other agents have been evaluated in real time regarding effectiveness of this method for reducing the likelihood of disease transmission via transfusion. Keywords: transfusion; blood; pathogen reduction; emerging infectious diseases.

Cardiovascular diseases (CVD) account for about 17.3 million annual deaths worldwide. 85% of these deaths occurred as a result of myocardial infarction (MI) and stroke. Chronic heart diseases, such as arterial hypertension (AH), coronary heart disease, various cerebrovascular diseases, dilated and hypertrophic cardiomyopathies are widespread, with a fairly high incidence of mortality and disability. Most of these diseases are characterized by cardiac arrhythmias, conduction and contractility disorders. Additionally, interruption of the electrical activity of the heart, the appearance of extensive ectopic foci and heart failure are all symptoms of a number of severe hereditary diseases. The molecular mechanisms leading to the development of CVD are associated with impaired permeability and excitability of cell membranes and mainly caused by dysfunction of cardiac Ca2+ channels. Acquired channelopathies are caused by metabolic disorders, increased tone of the sympathetic nervous system, age-related changes that lead to deterioration of coronary blood flow and hemodynamics. Currently known channelopathies, such as the long or short QT syndromes, Brugada and Lenegre syndromes, catecholaminergic polymorphic ventricular tachycardia, etc., are congenital and genetic disorders caused by mutations of genes "responsible" for the conductive properties of certain channel-forming proteins, including pore-forming subunits of Ca2+ channels. Over the past 50 years, more than 100 varieties of ion channels have been found in the cardiovascular system cells. The relationship between the activity of these channels and cardiac pathology, as well as the general cellular biological function, has been intensively studied on several cell types and experimental animal models in vivo и in situ. In this review, we discuss the origin of Ca2+ channelopathies and the role of Ca2+ channels of various types: L- R-, T-types voltage-gated calcium channels, RyR2, non-selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, transient receptor potential (TRPC, TRPM7, TRPA1) channels in the development of cardio-vascular pathology.

In the text, the synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilide derivatives of amino acids are described. They have shown inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, also including glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

The main problem in creating anti-coronavirus vaccines that target mainly proteins of the outer membrane of the virus remains the rapid variability of the RNA genome of the pathogen that encodes these proteins. In addition, the introduction of technologies that can provide affordable and fast production of flexible vaccine formulas that easily adapt to the emergence of new subtypes of SARS-CoV-2 is required. Universal oligonucleotide vaccine can take into account the dynamics of rapid changes in the virus genome, as well as be synthesized on automatic DNA synthesizers in large quantities in a short time. In this brief report, the effectiveness of four phosphorothioate constructs of the La-S-so type oligonucleotide vaccine will be evaluated for the first time on transgenic mice [B6.Cg-Tg (K18-ACE2)2]. In our primary trials, the oligonucleotide vaccine increased the survival rate of animals infected with SARS-CoV-2 and also reduced the destructive effects of the virus on the lung tissue of mice. The obtained results show the perspective of the development of vaccine constructs of the La-S-so type for the prevention of coronavirus infections, including those caused by SARS-СoV-2.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of death due to cancer. About 30% of patients with PCa who have been castrated develop a castration-resistant form of the disease (CRPC), which is incurable. In the last decade, new treatments that control the disease have emerged, slowing progression and spread, and prolonging survival while maintaining the quality of life. These include immunotherapies; however, we do not yet know the optimal combination and sequence of these therapies with the standard ones. All therapies are not always suitable for every patient due to co-morbidities or adverse effects of therapies or both, so there is an urgent need for further work on new therapeutic options. Advances in cancer immunotherapy with an immune checkpoint inhibition mechanism (e.g., ipilimumab, an anti-CTLA-4 inhibitor) have not shown a survival benefit in patients with CRPC. Other immunological approaches have also not given clear results, which has indirectly prevented breakthrough for this type of therapeutic strategy into clinical use. Currently, the only approved form of immunotherapy for patients with CRPC is a cell-based medicine, but it is only available to patients in some parts of the world. Based on the experience gained from recently completed clinical research on immunotherapy with dendritic cell-based immunohybridomas, the aHyC dendritic cell vaccine, for patients with CRPC, we highlight the current status, and possible alternatives that should be considered in the future.

Eurycomanone and eurycomalactone are known quassinoids present in the roots and stems of Eurycoma longifolia. These compounds had been reported to have cytotoxic effects, however, their mechanism of action in a few cancer cell lines have yet to be elucidated. This study was aimed to investigate the anti-cancer effects and mechanisms of action of eurycomanone and eurycomalactone in cervical (HeLa), colorectal (HT29) and ovarian (A2780) cancer cell lines via Sulforhodamine B assay. Their mechanism of cell death was evaluated based on Hoechst 33342 assay and in silico molecular docking toward DHFR and TNF-α as putative protein targets. Eurycomanone and eurycomalactone exhibited in vitro anti-cancer effects manifesting IC50 values of 4.58 ± 0.090 µM and 1.60 ± 0.12 µM (HeLa), 1.22 ± 0.11 µM and 2.21 ± 0.049 µM (HT-29), and 1.37 ± 0.13 µM and 2.46 ± 0.081 µM (A2780) respectively. They induced apoptotic cancer cell death in dose- and time-dependent manners. Both eurycomanone and eurycomalactone were also predicted to have good inhibitory potential as demonstrated by the docking into TNF-α with binding affinity of -8.83 and -7.51 kcal/mol, respectively, as well as into DHFR with binding affinity results of -8.05 and -8.87 kcal/mol, respectively. These results support the evidence of eurycomanone and eurycomalactone as anti-cancer agents via apoptotic cell death mechanism that could be associated with TNF-α and DHFR inhibition as among possible protein targets.

Targeted radionuclide therapy is become increasingly prominent as a nuclear medicine subspe-cialty. For many decades, treatment with radionuclides has been mainly restricted to the use of iodine-131 in thyroid disorders. Currently, radiopharmaceuticals, consisting of a radionuclide coupled to a vector that binds to a desired biological target with high specificity, are being de-veloped. The objective is to be as selective as possible at the tumor level, while limiting the dose received at the healthy tissue level. In recent years, a better understanding of molecular mecha-nisms of cancer, as well as the appearance of innovative targeting agents (antibodies, peptides, small molecules) and the availability of new radioisotopes, have enabled considerable advances in the field of vectorized internal radiotherapy with a better therapeutic efficacy, radiation safety and personalized treatments. For instance, targeting the tumor microenvironment, instead of the cancer cells, now appears as particularly attractive. Several radiopharmaceuticals for therapeutic targeting have shown clinical value in severals types of tumors and have been or will soon be approved and authorized for clinical use.

Caffeine is a naturally occurring alkaloid found in various plants. It acts as a stimulant, antioxidant, anti-inflammatory and even an aid in pain management, and is found in several over-the-counter medications. This naturally derived bioactive compound is the best-known ingredient in coffee and other beverages, such as tea, soft drinks, and energy drinks, and is the most widely consumed substance worldwide. Therefore, it is extremely important to research the effects of this substance on the human body. With this in mind, caffeine and its derivatives have been extensively studied to evaluate its ability to prevent diseases and exert anti-aging and neuroprotective effects. This review is intended to provide an overview of the effects of caffeine on cancer, cardiovascular, immunological, inflammatory, and neurological diseases, among others. The heavily researched area of caffeine in sports will also be discussed. Finally, recent advances in the development of novel formulations, in the form of dietary supplements of caffeine and nanocarriers, to enhance the bioavailability of caffeine and its beneficial effects will be discussed. On the other hand, caffeine may contribute to elevated blood pressure, anemia, and migraine.

Oncogenic fusion proteins, arising from chromosomal rearrangements, have emerged as prominent drivers of tumorigenesis and crucial therapeutic targets in cancer research. In recent years, the potential of small molecular inhibitors in selectively targeting fusion proteins has exhibited significant prospects, offering a novel approach to combat malignancies harboring these aberrant molecular entities. This review provides a comprehensive overview of the current state of small molecular inhibitors as therapeutic agents for oncogenic fusion proteins. We discuss the rationale for targeting fusion proteins, elucidate the mechanism of action of inhibitors, assess the challenges associated with their utilization, and provide a summary of the clinical progress achieved thus far. The objective is to provide the medicinal community with current and pertinent information and to expedite the drug discovery programs in this area.

Collagen has been accepted in drug delivery structures due to its biocompatible chemical, physicochemical and curative actions. The study aims to evaluate the effects of a bovine collagen hydrolysate (Clg) on the main photophysical and photodynamic properties of a new gallium (III) phthalocyanine (GaPc). The absorbance of GaPc and the conjugate GaPc-Clg showed a decrease of the intensive Q-band (681 nm) and a blue shift of the maximum (678 nm) with loss of UV-band (354 nm) for 40 mg/mL Clg. The fluorescence of GaPc was evaluated with strong emission peak at 694 nm (exc: 615 nm) which was lower for GaPc-Clg (691 nm). The quantum yield of 0.23 was obtained for GaPc which was reduced for GaPc-Clg (0.012). Photo- and dark cytotoxicity was studied by NRU-assay on pigmented melanoma cells (SH-4) and normal cell lines (BJ and HaCaT). The results suggested a slight reduction of cytotoxicity for the conjugate but almost double for the selectivity index (SI: 0.71 vs. 1.49 for HaCaT cells). The study showed that bovine collagen hydrolysate can lower the PDT activity of a powerful photosensitizer with phototherapeutic index: 819 to 360, but also minimized its dark toxicity as a positive effect in the photodynamic treatment.

Emotional instability and stress are main disturbances that condition the learning process, affecting both teachers and students. The main objective of this review is to analyze the influence of stress and emotions (as part of stress) on the learning process. The quality and intensity of emotions will not depend exclusively on a particular situation, but also on the subjective evaluation that the person makes of the situation in terms of a set of assessment dimensions. Emotions lead to sentimental, cognitive, behavioral and physiological changes, which will have a strong influence on intellectual performance. Stress is a physiological mechanism that the organism develops to adapt and survive in external and internal environments. Although it seems that it is a general pattern of response to emotions, it could be assumed that each emotion seems to have its own pattern of physiological reaction. In conclusion, extreme stress situations can generate anxiety and frustration in students. The activation of coping strategies constitutes a key mechanism for dealing positively with problems and challenges, generating positive emotions essential for the self-regulation of learning.

The theory that an itch inhibits pain has been refuted; however, previous research did not investigate this theory for interleukin-31 (IL-31)-induced itch. Previously, we have found that morphine-induced antinociception was partially reduced in IL-31 receptor A (IL-31RA)-deficient (IL-31RAKI) mice, indicating that IL-31RA may play an important role in morphine-induced peripheral antinociception. In the present study, we evaluated the effect of IL-31-induced analgesia on a 2,4,6-trinitrochlorobenzene (TNCB)-sensitized mice using a hot-plate test. This test evaluated the antinociceptive activity of morphine, and non-steroidal anti-inflammatory drugs (NSAIDs). Repeated pretreatment with IL-31 showed significant antinociceptive action. Furthermore, its combination with morphine, but not with NSAIDs, increased the analgesic action. In contrast, treatment with TNCB and capsaicin decreased antinociception. Moreover, TNCB increased IL-31RA expression in the dorsal root ganglia at 24 h, whereas capsaicin inhibited it. The comparative action of several analgesics on TNCB or capsaicin was evaluated using a hot-plate test, which revealed that the antinociceptive activity was decreased or disappeared in response to capsaicin-induced pain and in IL-31RAKI mice. These results indicate that the analgesic action of IL-31 involves the peripheral nervous system, which affects sensory nerve. These results provide a basis for developing novel analgesics using this mechanism.

Antibody-Drug Conjugates (ADCs) are a powerful therapeutic modality for cancer treatment. ADCs are multi-functional biologics in which a disease-targeting antibody is conjugated to an effector payload molecule through a linker. The success of currently used ADCs has been largely attributed to the development of linker systems which allow targeted release of cytocidal payload drugs inside cancer cells. Many lysosomal proteases are over-expressed in human cancers. They can effectively cleave a variety of peptide sequences, which can be exploited in the design of ADC linker systems. As a well-established linker, valine-citrulline-p-aminobenzyl carbamate (ValCitPABC) is used in many ADCs that are already approved or under preclinical and clinical development. Although ValCitPABC and related linkers are readily cleaved by cathepsins in the lysosome while remaining reasonably stable in human plasma, many studies have shown that they are susceptible to carboxylesterase 1C (Ces1C) in mouse and rat plasma, which hinders preclinical evaluation of the ADCs. Furthermore, neutropenia and thrombocytopenia, two of the most commonly observed dose-limiting adverse effects of ADCs, are believed to result from the premature hydrolysis of ValCitPABC by human neutrophil elastase. In addition to cathepsin-cleavable linkers, there is also growing interest in legumain-sensitive linkers for ADC development. Increasing plasma stability while maintaining lysosomal cleavability of ADC linkers is an objective of intensive current research. This review reports recent advances in the design and structure-activity relationship studies of various peptide/peptidomimetic linkers in this field.

In an era of unparalleled technical advancement, the pharmaceutical industry is struggling to transform data into increased research and development efficiency, and as a corollary, new drugs for patients. Here, we briefly review some of the commonly discussed issues around this counterintuitive innovation crisis. Looking at both industry and science related factors, we posit that traditional preclinical research is front-loading the development pipeline with data and drug candidates that are unlikely to succeed in patients. Applying a first principles analysis, we highlight the critical culprits and provide suggestions as to how these issues can be rectified through pursuit of a Human Data-driven Discovery (HD3) paradigm. Consistent with other examples of disruptive innovation, we propose that new levels of success are not dependent on new inventions, but rather the strategic integration of existing data and technology assets. In support of these suggestions, we highlight the power of HD3, through recently published proof-of-concept applications in the areas of drug safety analysis and prediction, drug repositioning, rational design of combination therapies and the global response to the Covid19 pandemic. We conclude that innovators must play a key role in expediting the path to a largely human focused, systems-based approach to drug discovery and research.

The functions of annexin A1 (ANXA1) that is expressed on membranes and in cytoplasmic granules have been fully described. Nonetheless, the role of this protein in protecting against DNA damage in the nucleus is still emerging and requires further investigation. Here, we investigated the involvement of ANXA1 in DNA damage response in placental cells. Placenta was collected from ANXA1 knockout mice (AnxA1-/-) and pregnant women with gestational diabetes mellitus (GDM). The placental morphology and ANXA1 expression, which are related to the modulation of cellular response markers in the presence of DNA damage, were analyzed. Total area of AnxA1-/- placenta was smaller because of reduced labyrinth zone, enhanced DNA damage, and impaired base excision repair (BER) enzymes, which resulted in the induction of apoptosis in the labyrinthine and junctional layers. The placentas from pregnant women with GDM showed reduced expression of AnxA1 in the villous compartment, increased DNA damage, apoptosis, and reduction of enzymes involved in the BER pathway. Our translational data provide valuable insights into the possible involvement of ANXA1 in the response of placental cells to oxidative DNA damage and represent advancement in investigations on the mechanisms involved in placental biology.

Abstract: Hyperglycemia caused cardiac cell damage by increasing ROS production in diabetic complications. The current study will prove the antioxidant activity of Swietenia macrophylla (S. macrophylla) extract nanoparticles as a protector against Streptozotocin (STZ)-induced cardiac cell damage. In this research, high-energy ball milling is used to make S. macrophylla extract nanoparticle. Furthermore, characterize the size of S. macrophylla extract nanoparticles with Dynamic Light Scattering (DLS). Forty male rats were divided randomly into five groups. Control group: rats received orally aqua dest; Diabetic group: rats were injected STZ intraperitoneally; S. macrophylla group: rats were injected STZ and given orally with S. macrophylla extract nanoparticles. The DLS showed that the S. macrophylla extract nanoparticles size was 91.50 ± 23.06 nm. Injected with STZ significantly increased cardiac tissue of MDA levels, serum of CK-MB and LDH levels. STZ also significantly reduced expression of Nrf2, level of SOD and GPx in cardiac tissue compared with control group (p<0.05). In contrast, administration of S. macrophylla extract nanoparticles can prevent STZ-induced cardiac cell damage by decreasing level of CK-MB and LDH in serum, and level of MDA in cardiac tissue. S. macrophylla extract nanoparticles also significantly increments Nrf2 expression, SOD and GPx levels in cardiac tissue. These effects are related to the prevention of cardiac histopathological alteration (degeneration and necrosis) in diabetic rats. These results suggest that S. macrophylla nanoparticles might be a potential cardioprotective agent against STZ-induced cardiac cell damage due to its antioxidant properties

Humans have extremely variable skin pigmentation and melanin production influenced by genetics, UV exposure, and some medications. A significant number of skin illnesses that result in pigmentary abnormalities have an impact on patients’ physical appearance as well as their psychological and social well-being. Skin pigmentation can be divided into two basic categories: hyperpigmentation, where pigment appears to overflow, and hypopigmentation, where pigment is reduced. Albinism, melasma, vitiligo, Addison's disease, and post-inflammatory hyperpigmentation, which can be brought on by eczema, acne vulgaris, and drug interactions, are the most common skin pigmentation disorders in clinical practice. Anti-inflammatory medications, antioxidants, and medications that inhibit tyrosine, which prevents the production of melanin, are all possible treatments for pigmentation problems. Skin pigmentation can be treated orally and topically with medications, herbal remedies, and cosmetic products, but a doctor should always be consulted before beginning any new medicine or treatment plan. This review article explores the numerous types of pigmentation problems, their causes, and treatments, as well as the 25 plants, four marine species, and 17 topical and oral medications now on the market that have been clinically tested to treat skin diseases.

A mathematical model of energy metabolism in erythrocyte-bioreactors loaded with alcohol dehydrogenase and acetaldehyde dehydrogenase was constructed and analyzed. Such erythrocytes can convert ethanol to acetate using intracellular NAD and, thus, can be used to treat an alcohol intoxication. Analysis of the model reveals that the rate of ethanol consumption by the erythrocyte-bioreactors increases proportionally to activity of incorporated ethanol-consuming enzymes until their activity reaches a specific threshold level. When the ethanol-consuming enzyme activity exceeds this threshold, the steady state in the model becomes unstable and the model switches to an oscillation mode caused by a competition of glyceraldehyde phosphate dehydrogenase and ethanol-consuming enzymes for NAD. An amplitude and period of metabolite oscillations first increase with the increase in the activity of e encapsulated enzymes. A further increase in these activities leads to a loss of the glycolysis steady state, and a permanent accumulation of glycolytic intermediates. The oscillation mode and the loss of the steady state can lead to osmotic destruction of erythrocyte-bioreactors due to an accumulation of intracellular metabolites. Our results demonstrate that the interaction of enzymes encapsulated into erythrocyte-bioreactors with erythrocyte metabolism should be taken into account in order to obtain an optimal efficacy of these bioreactors.

Acute and chronic bone infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA), remains a major complication and therapeutic challenge. It is documented that local administration of vancomycin offers better results than the usual routes of administration (e.g. intravenous) when ischemic areas are present. In this work, we evaluate the antimicrobial efficacy against S. aureus and S. epidermidis and analyzed the potential cytotoxic effect of a novel hybrid 3D-printed scaffold based on poly(caprolactone) and chitosan loaded with different vancomycin concentrations (1, 5, 10 and 20%). For this purpose, vancomycin release was measured by means of HPLC, and the biological response of ah-BM-MSCs in the presence of the scaffolds was evaluated in terms of cytotoxicity (LDH activity), proliferation (AlamarBlueⓇ) and osteogenic differentiation (ALP activity, Alizarin Red staining). In addition, two cold plasma treatments were evaluated to improve the adhesion of hydrophobic polymers to hydrogels. The hybrid PCL/CS/Van scaffolds tested were found to be biocompatible, bioactive, and bactericide, as demonstrated by no cytotoxicity or functional alteration and by bacterial inhibition. Our results suggest that the scaffolds developed would be excellent candidates to be used in a wide range of biomedical fields such as drug delivery systems or tissue engineering applications.

Sepsis is a life-threatening condition caused by a dysregulated host response to an invading pathogen such as multidrug-resistant bacteria. Despite recent advancements, sepsis is a leading cause of morbidity and mortality, resulting in a significant global impact and burden. This condition affects all age groups, with clinical outcomes depending mainly on timely diagnosis and appropriate early therapeutic intervention. Because of the unique features of nanosized systems, there is a growing interest in developing and designing novel solutions. Nanoscale-engineered materials allow a targeted and controlled release of bioactive agents, resulting in improved efficacy with minimal side effects. Additionally, nanoparticle-based sensors provide a quicker and more reliable alternative to conventional diagnostic methods for identifying infection and organ dysfunction. Despite recent advancements, fundamental nanotechnology principles are often presented in technical formats that presuppose advanced chemistry, physics, and engineering knowledge. Consequently, clinicians may not grasp the underlying science, hindering interdisciplinary collaborations and successful translation from bench to bedside. In this review, we abridge some of the most recent and most promising nanotechnology-based solutions for sepsis diagnosis and management using an intelligible format to stimulate a seamless collaboration between engineers, scientists, and clinicians.

Among cross-sectional imaging modalities, computed tomography (CT) is more available and faster; however, magnetic resonance (MR) performs better in terms of sensitivity and specificity, due to its higher contrast resolution. The appearance of peritoneal deposits on CT and MR depends mainly on the primary tumour histology: in case of unknown primary tumour (3-5% of cases), their behaviour at imaging may provide insights on the tumour origin. The time-point of tumour evolution, previous or ongoing treatments and the peritoneal spaces where they occur, also play an important role in determining the appearance of peritoneal deposits. Thus, knowledge of peritoneal anatomy and fluid circulation is mandatory in detection and characterization of peritoneal deposits. Several benign and malignant conditions may show similar imaging features that overlap those of PC, making the differential diagnosis challenging. Clinical history, laboratory findings and previous imaging examinations must be considered to achieve the correct diagnosis.

The objective of this study was to compare the pathogens and susceptibilities of the current automated rule-based technology (RBT) antibiogram with one manually collected through chart review with additional rules applied. This study was a 2-year, retrospective cohort study and included all bacterial cultures within the first 30 days from patients admitted to a single Burn Center. The current RBT antibiogram served as the control and new antibiogram versions were created using additional rules and compared to the control. Six-hundred fifty-seven patients were admitted (61% excluded for lack of cultures). Fifty-nine percent had at least one hospital acquired risk factor with over one-third having recent illicit drug use and one-third having a recent hospitalization. Of the 410 cultures included, 57% were Gram-negative and half were from wound infections. Sensitivities were significantly different when comparing manual and the RBT version after including factors, such as days since admission, presence of hospital acquired risk factors, or previous antibiotic courses. Recommended empiric Gram-negative antibiotics changed from double coverage to a single β-lactam with > 90% susceptibility. The susceptibilities between first and subsequent courses were dramatically different. Before developing an antibiogram or interpreting the output, it is important to consider which automated criteria are utilized, especially for units with extended lengths of stay.

NCX 470, a nitric oxide (NO)-donating bimatoprost, was shown to ameliorate ocular hemodynamics and retinal physiology in rabbits following endothelin-1 (ET-1)-induced ischemia/reperfusion. Here we used the same model to compare NCX 470 (0.1% bid) to Lumigan® (bimatoprost 0.01% ophthalmic solution, LUM) and bimatoprost administered at equimolar dose as NCX 470 (0.072%, BIM). Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI) and electroretinogram (ERG) were computed prior to treatment and at various time-points thereafter. Gluthatione (GSH), 8-Hydroxy-2-deoxyguanosine (8-OH2dG), Interleukin-1beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and Caspase-3 protein expression and activity were determined in retina at week 6. ET-1 increased IOP (VEHIOP_Baseline=20.5±0.8 and VEHIOP_Week6=24.8±0.3mmHg) and OA-RI (VEHOA-RI_Baseline=0.36±0.02 and VEHOA-RI_Week6=0.55±0.01) while it reduced rod/cone responses. Oxidative stress, inflammation and apoptotic markers were also increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6=18.1±0.6mmHg) and OA-RI (NCX 470OA-RI_Week6=0.33±0.01) changes and restored ERG amplitude; these effects were only partially shared by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation and apoptosis in retina of treated eyes. BIM and LUM were numerically less effective on these parameters. Data suggest that NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction consequent to ischemia/reperfusion via both, NO- and bimatoprost-mediated mechanisms.

Severe combined immunodeficiency (SCID) is a primary inherited immunodeficiency that could be fatal, usually due to opportunistic infections caused by bacteria, viruses, fungi, and protozoa if left untreated. Opportunistic infections are the most common presentation of SCID these include viral, fungal, or intracellular bacteria, and infection should prompt immunological investigation. This review aimed to provide a comprehensive approach to the microrganisms associated with severe combined immunodeficiency (SCID) and its management. The authors described SCID as a syndrome and summarized the different microorganisms that affect children and how they are managed.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), defines as an idiopathic, chronic, relapsing, inflammatory disease affecting the gastrointestinal tract and leading to chronic damage. Endoscopy with biopsies is considered the gold standard for IBD diagnosis, whereas magnetic resonance (MRI) for CD extension and complication assess-ment. However, the latter are invasive procedures; thus, the need for a reliable, accessible and noninvasive way to perform IBD diagnosis and monitoring in the tight control era, like intestinal ultrasound (IUS) is. Compared to endoscopy and MRI, IUS has shown reliable diagnostic accuracy in assessing CD and UC severity and extension. Performing IUS in a point-of-care setting (POCIUS) can guide the clinician in driving the diagnostic and therapeutic pathway, thus accel-erating clinical decisions. POCIUS performed with pocket devices can represent the future of physical examination in outpatient or inpatient examination. Accordingly, we performed a liter-ature review about the application of IUS in CD and UC diagnosis. Furthermore, we explored the technical aspects of this imaging technique and its application in a point-of-care setting.

Our prior studies have shown that B type Natriuretic Peptide (BNP) decreases absorption from the gastrointestinal (GI) tract. Since non-muscle myosin-type II (NMM-II) is known to have a role in epithelial tight junction regulation, we aimed to test whether BNP has an effect on the localization and expression of NMM-II in the intestinal villi. We treated wild type mice with a 10 ng/g intravenous bolus of BNP followed by infusion of BNP at 1ng/g/minute vs. vehicle control. The mice were then euthanized and intestinal tissue isolated and sectioned. The tissue was immune-stained for NMM-II and examined using fluorescence microscopy. The tissue section not treated with antibody to NMM-II was used as a methodological control to evaluate the non-specific binding. Scanning electron micrographic images were taken to compare structural differences between the two groups. Western blotting was performed to compare the regional protein expression of NMM-II and associated proteins including smooth muscle actin, kinesin, and E cadherin in small intestinal tissue between BNP vs. vehicle infused mice. Fluorescence microscopy revealed markedly increased localization of NMM-II at the crypts and core of intestinal villi of the jejunum, ileum and colon of BNP treated mice compared to vehicle. Transmission electron microscopy revealed that the microvilli of BNP treated mice assumed the distinctive appearance of ‘relaxed’ microvilli compared to vehicle. Such decrease in contractility was previously shown to decrease para-cellular permeability of epithelia. Our observation indicates that BNP alters the localization of NMM-II in intestinal villi and makes the intestinal villi structures assume a state of decreased permeability of the apical junctional complex. Further characterization of this process and understanding the specific mediators involved could lead to the identification of novel therapeutic targets for various disease states such as heart failure and malabsorption.

Effective communication is key for healthcare providers to provide optimal care for patients. Pharmacists’ fluency in a patient’s native language is vital to communicate effectively. Additionally, language concordance improves patients’ trust and ensures health equity. In the United States (US), Hispanics are the largest minority group, but only 36% of the pharmacy schools in the US offer Spanish courses in their curriculum. Conversely, Middle Eastern countries have implemented English as the language of instruction in pharmacy schools, though the native language of the patient population is Arabic. The discrepancy between the language of education and the language used by patients might lead to communication problems, thus limiting a pharmacist’s role in practice. This review aims to describe the efforts of pharmacy schools both in the US and Middle Eastern countries to incorporate second language (Spanish and Arabic, respectively) in their curriculum. Spanish language content has scarcely been introduced into the pharmacy curriculum in the US either as didactic elements (elective courses, lab sessions, modules within a course, or co-curricular programs) or as language immersion experiences (rotations and internships nationally or abroad). In Arabic-speaking countries, an Arabic course was introduced to the pharmacy curriculum to enhance students’ communication skills. This review provides an overview of what has been done in various pharmacy programs to prepare students for adequate multilingual speaking. The findings reveal the need for additional strategies to assess the impact of language courses on student performance and patient experience, as well as language competence in pharmacists and pharmacy students.

Based on the marine natural products piperafizine B, X334 and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DPK) derivatives (1-2, 4-6, 8-16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against cell lines A549 and Hela. The MTT assay results showed that the derivatives 6, 8-12 and 15 had moderate to good anticancer capacities with the IC50 values ranging from 0.7 to 8.9 μM. Among them, compound 11 with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3- and 6-positions of 2,5-DPK ring, respectively, displayed good inhibitory activities to both cancer cells A549 (IC50 = 1.2 μM) and Hela (IC50 = 0.7 μM). It could also induce apoptosis and obviously block the cell cycle progression at G2/M phase in both cells at 1.0 μM. The electron withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and X334, these semi-N-alkylated derivatives have high liposolubilities (&gt; 1.0 mg•mL-1). Compound 11 can be further developed aiming to the discovery of novel anticancer candidate.

In recent years, the FDA has approved numerous antitumor drugs that are mutation-based for clinical use. These drugs have improved the precision of treatment and reduced adverse effects and side effects. Personalized therapy is a prominent and hot topic of current medicine and also represents the future direction of development. With the continuous advancements in gene sequencing and high-throughput screening, research and development strategies for personalized clinical drugs have developed rapidly. This review elaborated the recent personalized treatment strategies, which include artificial intelligence, multi-omics analysis, chemical proteomics, and computation aided drug design. These technologies rely on the molecular classification of diseases, the global signaling network within organisms, and new models for all targets, which significantly support the development of personalized medicine. Meanwhile, we summarized chemical drugs such as lorlatinib, osimertinib, and other natural products that deliver personalized therapeutic effects based on genetic mutations. This review also highlights potential challenges in interpreting genetic mutations and combining drugs, while providing new ideas for the development of personalized medicine and pharmacogenomics in cancer study.

Regeneration of biological tissues in medicine is challenging, and 3D bioprinting offers an innovative way to create functional multicellular tissues. One common way in bioprinting is bioink which is one type of the cell-loaded hydrogel. For clinical application, however, the bioprinting still suffers from satisfactory performance, e.g. in vascularization, effective antibacterial, immunomodulation and regulation of collagen deposition. Many studies have incorporated different bioactive materials into the 3D printed scaffolds to optimize the bioprinting. Here, we review a variety of additives added to the 3D bioprinting hydrogel. The underlying mechanisms and methodology for biological regeneration are important and will provide useful basis for future research.

Dysregulation of the arsenal of cells, growth factors, cytokines, proteases, and proteins involved in wound healing (WH), could delay the healing process. Plants and plant-derived molecules (PDMs) have been used as medicines for skin wounds. This study aimed to select and evaluate the pro-healing capacity of PMDs. Thirty-three PDMs and 10 therapeutic targets (TTs) were chosen for molecular docking and PDMs: aristolochic acid (AA), α-copaene, selinenes, β-caryophyllene (BC), and BCoxide, and TTs: metalloproteinase (MMP) 3, MMP13, and tumor necrosis factor (TNF α) for molecular dynamics. The bests inhibitor was AA, but because of its toxicity, BC and BCoxide were chosen for evaluation in HaCat cells and BALB/c mice excisional model. Both compounds were not toxic, and higher percentages of lesion area closure (LAC) were induced by BC treatment (p<0.05). All mice healed; however, an initial delay of LAC was induced by 0.05, 0.1% BCoxide, 0.1% BC, and allantoin. At the end of treatment, lower numbers of mast cells, level of cellular infiltrates (except 1% BCoxide and 0.05, 0.5%BC), epidermal thickness tendency (except 0.1, 0.5% BCoxide), and higher values of SC-thickness, and collagen fibers only by 0.5% BC treatment compared with untreated control (p<0.05) were observed. Our results show that BC is a promising multitarget candidate for wound healing treatment and optimization campaigns.

The purpose of this study is to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) to improve the oral absorption of poorly water-soluble Olaparib. Through the solubility test of Olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients for use in SMEDDS manufacturing were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. Various physicochemical properties of microemulsion incorporating Olaparib were confirmed by investigating the particle morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and oral absorption of Olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul MCM EP/NF 10%, Labrasol 80% and PEG 400 10%. Fabricated nano-sized microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that it was maintained well without any problems of either physical or chemical stability. The 5 min initial dissolution of Olaparib in fabricated formulations was improved by 10.6 times (pH1.2), 14.8 times (pH6.8) and 14.8 times (distilled water) compared to the values of Olaparib powder. The dissolution at 120min was 45.4±4.0%(pH1.2), 53.5±1.1% (pH6.8) and 58.1±1.00% (distilled water) in Olaparib powder but has been significantly improved by 1.7 times (74.8±1.9%), 1.6 times (84.2±0.3%) and 1.5 times (81.2±0.7%) in SMEDDS. Associated with the high dissolutions of Olaparib in fabricated microemulsions, the pharmacokinetic parameters were also greatly improved. The Cmax and AUCinf of Olaparib in the prepared microemulsion were increased 4.2- and 3.2-fold, respectively, compared to powder. Taken together with the results mentioned above, the microemulsion system could be an effective tool as an oral delivery formulation for Olaparib. Additionally, our results demonstrate that the SMEDDS systems comprising Capmul MCM, Labrasol and PEG 400 could be a useful option for improvement of several other poorly water-soluble drugs with physico-chemical properties similar to Olaparib.

Glioblastoma (GBM) is a major type of primary brain tumors without ideal prognosis and it’s necessary to find novel compound possessing therapeutic effect. Chrysomycin A (Chr-A) has been reported to inhibit the proliferation, migration and invasion of U251 and U87-MG cells, but the mechanism of Chr-A against glioblastoma in vivo and whether Chr-A modulates apoptosis of neuroglioma cells is unclear.The present study was to elucidate the potential of Chr-A against glioblastoma in vivo and how Chr-A modulates apoptosis of neuroglioma cells. Briefly, The an-ti-glioblastoma activity was assessed in human glioma U87 xenografts nude mice. Chr-A-related targets were identified by RNA-seq. Apoptotic ratio and caspase 3/7 activity of U251 and U87-MG cells were assayed by flow cytometry. Apoptosis-related proteins and possible molecular mecha-nism were validated via Western blotting. The results showed that Chr-A treatment significantly inhibits glioblastoma progression in xenografts nude mice, and enrichment analysis suggested that apoptosis, PI3K-Akt and Wnt signaling pathway were involved in the possible mechanism. Chr-A increased apoptotic ratio and the activity of caspase 3/7 in U251 and U87-MG cells. Western blot revealed that Chr-A broke the balance between Bax and Bcl-2 activating caspase cascade re-action and downregulated the expression of p-Akt and p-GSK-3β, suggesting that Chr-A may contribute to glioblastoma regression modulating Akt/GSK-3β signaling pathway to promote apoptosis of neuroglioma cells in vivo and in vitro. Therefore, Chr-A may hold therapeutic promise for glioblastoma.

Multidisciplinary research efforts on potential COVID-19 vaccine and therapeutic candidates have increased since the pandemic outbreak of SARS-CoV-2 in 2019. This search has become imperative due to the increasing emergences and limited widely available medicines. The presence of bioactive anti-SARS-CoV-2 molecules was examined from various plant sources. Among them is a group of proteins called lectins that can bind carbohydrate moieties. In this article, we present ten novel, chitin-specific Hevein-like lectins that were derived from Selaginella moellendorffii v1.0's genome. The capacity of these lectin homologs to bind with the spike protein of SARS-CoV-2 was examined. Using the HDOCK server, 3D-modeled Hevein-domains were docked to the spike protein's receptor binding domain (RBD). The Smo446851, Smo125663, and Smo99732 interacted with Asn343-located complex N-glycan and RBD residues, respectively, with binding free energies of -17.5, -13.0, and -26.5 Kcal/mol. The normal-state analyses via torsional coordinate association for the Smo99732-RBD complex using iMODS is characterized by overall higher stability and minimum deformity than the other lectin complexes. The three lectins interacting with carbohydrates were docked against five individual mutations that frequently occur in major SARS-CoV-2 variants. These were in the spike protein’s receptor-binding motif (RBM), while Smo125663 and Smo99732 only interacted with the spike glycoprotein in a protein-protein manner. The precursors for the Hevein-like homologs underwent additional characterization and their expressional profile in different tissues was studied. These in-silico findings offered potential lectin candidates targeting key N-glycan sites crucial to the virus's virulence and infection.

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

Cell therapy has used mesenchymal stem cells (MSCs) which in cell culture are multipotent progenitors, capable of producing a variety of cells limited to the mesoderm layer. There are two types of MSCs sources: 1) adult MSCs, which are obtained from the bone marrow, adipose tissue, peripheral blood, and dental pulp; and 2) neonatal tissue-derived MSCs, obtained from extra-embryonic tissues such as the placenta, amnion, and umbilical cord. Until April 2023, there are 1,120 registered clinical trials using MSCs therapies worldwide, but there are only 12 MSCs therapies that have been approved by regulatory agencies for commercialization. Nine of the twelve approved MSCs products are from Asia, with South Korea being the country with the most approved therapies. In the future, MSCs will play an important role in the treatment of many diseases. However, there are many issues to deal with before their application and usage in medical practice. Some strategies have been proposed to face these problems with the hope of reaching the objective of applying these MSCs therapies at optimal therapeutic levels.

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here we present an overview of a novel integrated methodology for rapid assessment of such efficacy, particularly against emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of antimicrobial efficacy of a single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) automated collection of longitudinal time-kill data in an optical-density instrument; (b) processing of collected time-kill data with the aid of a mathematical model to de-termine optimal dosing regimens under clinically relevant pharmacokinetics for a single or mul-tiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for refinement of optimal data collection and processing are discussed.

In the wake of the Covid-19 crisis, a need has arisen to prevent and treat two related conditions, Covid vaccine injury and long Covid, both of which have a significant vascular component. Therefore, the management of these conditions require the development of strategies to prevent or dissolve blood clots and restore circulatory health. This review summarizes the evidence on strategies that can be applied to treat both long and vaccine injuries based on similar mechanisms of action.

The rapid rise in research and development following the discovery of photodynamic therapy to establish novel photosensitizers and overcome the limitations of the technology soon after its clinical translation has given rise to a few significant milestones. These include several novel generations of photosensitizers, the widening of the scope of applications, leveraging of the offerings of nanotechnology for greater efficacy, selectivity for the disease over host tissue and cells, the advent of combination therapies with other similarly minimally invasive therapeutic technologies, the use of stimulus-responsive delivery and disease targeting, and greater penetration depth of the activation energy. Brought together, all these milestones have contributed to significant enhancement of what is still arguably a novel technology. Yet the major applications of photodynamic therapy still remain firmly located in neoplasms, from where most of the new innovations appear to launch to other areas, such as microbial, fungal, viral, acne, wet age-related macular degeneration, atherosclerosis, psoriasis, environmental sanitization, pest control, and dermatology. The core value proposition of combinations of photodynamic therapy is that they enhance the leading alternative and are proposed to overcome challenges of the leading clinical anticancer and antibacterial methods, mainly due to its inherent barriers against the emergence of resistance and its rapid development of targeted and high precision therapy. Combinations with chemotherapy and radiotherapy and demonstrated applications in mop-up surgery adventitiously promise to repurpose these top three clinical tools. This review will navigate the vast and increasing innovations that have been created so as to obviate novel areas of further innovation.

Gap junctions (GJs) made of connexin-43 (Cx43) are important for the conduction of electrical impulses in the heart. Modulation of Cx43 activity may be useful in the treatment of cardiac arrhythmias and other dysfunctions. Search of novel GJ modulating agents using molecular docking approach allows to predict the binding affinities that often significantly differ from experimentally estimated their potencies. The objective of this study was to demonstrate that Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using the QSAR model and molecular docking, we evaluated the known Cx43 GJ inhibitors, suggested a new one, and tested it experimentally. Our QSAR model predicted the concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds and estimated the correlation between predicted and experimental IC50ies (pIC50 and eIC50). This led to suggestion of monocyclic monoterpene d-limonene as putative Cx43 inhibitor with pIC50 = 1.07. In turn, dual whole-cell patch-clamp measurements provided eIC50=1.41. The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR model well correlated with their eIC50ies (R = 0.88) in contrast to pIC50s obtained from molecular docking (R = 0.42). However, the molecular docking suggested that inhibitor potency may depend on their docking sites on Cx43.

Background: Overall survival is the most important outcome for treatment response in feline chronic kidney disease (CKD). Beraprost has been shown to reduce the kidney function decline in cats with International Renal Interest Society (IRIS) stage 2 and 3 CKD. However, association with prolonged survival has not yet been examined. Objective: To assess the relationship between beraprost and overall survival in cats with CKD in real clinical practice. Animals: Client-owned cats with IRIS stage 3 CKD (n = 134), evaluated between 2017 and 2020. Methods: Retrospective cohort study based on data from electronic medical records of one hospital. Results: Multivariable Cox regression models on all treatment effects showed that beraprost only was related to better survival (P = 0.028). The cohort was divided into “beraprost therapy” and “no beraprost therapy” groups, and survival analyses revealed that overall survival was significantly longer in the beraprost therapy group, using Kaplan-Meier curves (P = 0.004). However, baseline phosphate is known to be an important prognostic indicator and was not well balanced between the two groups. Therefore, a subcohort of 97 cats was selected (those having baseline phosphate < 6.0 mg/dL) that allowed for this parameter to be balanced between groups. The survival data in this subcohort was consistent with that of the overall study cohort. Conclusions: In feline patients with CKD, beraprost therapy was associated with better overall survival.

Since 2012, the northeast of Tunisia has been experiencing an emergence of dog rabies. Published data revealed that the disease is widespread in the north of Tunisia. Even with studies on rabies, lacking knowledge on the associated risk factors was highlighted. Therefore, we conducted a case-control study on dog rabies in northeast Tunisia to identify potential risk factors for dog rabies occurrence. The cases group (n=77) included positive dog rabies confirmed at the referral laboratory using Fluorescent Antibody Test (FAT) in 2014 and 2018. The controls group (n=77) involved all negative cases received at the laboratory and 15-days quarantine dogs that received a certificate of absence of rabies after the observation period. Univariate and multivariate logistic regression was conducted to explore the risk factors (age, sex, breed, confinement, vaccination status, presence of bites, owned or not and origin of dogs, sector, presence of rabies cases, and slaughterhouses, etc.…) related to the occurrence of rabies. The final logistic regression model revealed that unconfined dogs were almost twice as likely to be affected as confined dogs (OR=1.9; 95% CI: 1.17 to 3.27). The odds of rabies occurrence were 25 times higher in areas where rabies cases have been reported between 3 months and 1 year compared to the uninfected areas (25.7; 95% CI: 3.02-219.14). Similarly, the risk of rabies is significantly higher in dogs born in the home to the owner bitch (OR=2.41; 95% CI: 1.14-5.13). Living in areas with rabies cases in the last three months increases by 2.8 times the risk of getting rabies (2.8; 95% CI: 1.16-6.77). However, vaccination reduces by 1.6 times the risk of contracting rabies (0.6; 95% CI: 0.38-0.97). Our findings provide reliable data on dog rabies that will be very useful for decision-makers and could contribute to improving the ongoing national control program of rabies.

Toxoplasma gondii (T. gondii) is one of the most common parasites that infect humans. The parasite exists in approximately 40 million people in the United States. Latent infections are frequently associated with tissue cysts of T. gondii in the skeletal muscle and brain tissue that can lead to mental disorders, congenital disorders, and vision dysfunction. Furthermore, self-directed violence, impulsivity, and aggression are associated with T. gondii infection. Dopamine is associated with human behavior including pleasure, aggression, memory, and substance use disorder; however, the result of the studies on the association of T. gondii infection and drugs of abuse are not well understood. The frequency of substance use may be associated with substance-induced modification of dopamine-receptor densities and basal dopaminergic activity. Likewise, T. gondii can directly or indirectly influence dopaminergic activity in infected cells. Based on this hypothesis, the current paper aimed to systematically review all published literature on the association between drugs of abuse and T. gondii infection. Systematic review of controlled studies on T. gondii infection and substance use effects in adults were searched on the electronic databases. Studies have shown that individuals infected with T. gondii display increased risky behavior, such as excessive alcohol consumption. Furthermore, it was observed that T. gondii seropositive subjects had a reduced likelihood of self-reported substance use compared to T. gondii seronegative subjects. This study confirms that SUD is a potential risk factor for behavioral and psychiatric complications associated with T. gondii infection. Ultimately T. gondii infection in the context of drug dependence and the development of SUD remain to be elucidated. Therefore, it is necessary to conduct further research characterizing the mechanisms associated with dopamine metabolism of drug dependence and withdrawal in the context of a T. gondii infection, evaluating the role of inflammation, and identifying potential drug-and-sex specific underpinnings of these associations.

Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option to frozen tissues, we developed a streamlined protein extraction protocol for evaluating disease-specific seeding in FFPE human brain. We evaluated the protein extraction efficiency of different tissue preparations, deparaffinizations, and protein extraction buffers using formaldehyde-fixed and FFPE tissue of a single Lewy body disease (LBD) subject. Alternatively, we incorporated heat-induced antigen-retrieval and dissociation using a commercially available kit. Our novel protein extraction protocol has been optimized to work with 10 sections of 4.5-µm-thickness or 2-mm-diameter micro-punch of FFPE tissue that can be used to seed SAAs. We demonstrated that extracted proteins from FFPE still preserve seeding potential and further show disease-specific seeding in LBD and multiple system atrophy. To the best of our knowledge, our study is the first to recapitulate disease-specific αSyn seeding behavior in FFPE human brain, with structural validation. Our findings open new perspectives in re-evaluating archived human brain tissue, extending the disease-specific seeding assays to larger cohorts to facilitate molecular subtyping of synucleinopathies.

Measles is a highly contagious airborne disease that is endemic in many developing countries with low levels of vaccination coverage. In this paper, we propose a deterministic compartmental mathematical model for measles disease dynamics. We establish the global stability conditions for the disease-free and endemic equilibria using the Lyapunov function stability method. \textcolor{red}{Using arbitrary parameters it is obtained that the proposed model exhibits forward bifurcation}. Numerical integration using MATLAB software was used to simulate the model solution of the forward problem. We calibrate the proposed model to estimate the parameters with a 95\% confidence interval (CI) using real data from Ethiopia by formulating an inverse problem. We notice that the model fits well with the real data of Ethiopia. The estimated basic reproduction number ($R_0$) is found to be $R_0=1.3973$ which proves that the disease is endemic. It is also obtained from the local sensitivity analysis that reducing the transmission rate and increasing the vaccination rate could effectively minimize the $R_0$.

Curcumin is a natural dietary polyphenol which that possesses potent anti-aging and neuroprotective properties through various mechanisms and signaling pathways. This study aimed to investigate the effect of curcumin on factors involved in neurogenesis and angiogenesis in the aged brain. Old female Wistar rats were divided into three equal groups (n=7): control, sham, and curcumin (received curcumin, i.p., 30 mg/kg and 5 days/week for 8 weeks) rats. Curcumin treatment caused a significant increase in the vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF) and anti-apoptotic protein BCl-2 in the brains of aging rats but no significant effect on anti-apoptotic Bax protein. Additionally, curcumin attenuated brain lipid peroxidation and decreased transforming growth factor β1 (TGF-β1). These results suggested that curcumin possesses neuroprotective effects against brain aging, which were mediated by improvment in neurogenesis and angiogenesis. Also, curcumin could alleviate brain aging which may be due to attenuating oxidative stress, inhibiting apoptosis and down-regulating TGF-β1, which in turn enhances VEGF and BDNF. Therefore, curcumin has potential therapeutic value in the treatment of neurological apoptosis, neurogenesis and angiogenesis changes caused by brain aging.

Depression and obesity are highly comorbid with one another, with evidence for bidirectional causal links between each disorder and a shared biological basis. The available evidence suggests that genetic factors play a major role in influencing both the occurrence of comorbid depression and obesity, their courses, and their response to existing treatments. The current paper is a scoping review of studies that have evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Based on a search of the PubMed and EMBASE databases, 28 studies were included in this review, covering 54 candidate genes. Positive associations were identified for fourteen genetic loci (AKR1C2, APOA5, COMT, DAT1, FTO, KCNE1, MAOA, MC4R, MCHR2, NPY2R, NR3C1, Ob, PCSK9 and TAL1). Replicated findings across two or more independent samples were observed for the FTO and MC4R genes. Many of these gene products represent novel molecular targets for the pharmacological management of obesity which are not pharmacologically influenced by existing anti-obesity or antidepressant medications. The implications of these associations for future drug development are discussed, with an emphasis on recent evidence on the polygenic architecture of comorbid depression and obesity, and on a precision medicine approach to these conditions.

The effect of SARS-CoV-2 pandemic has been subsided significantly following the rapid development of vaccine. However, patients with cancer and immunosuppressed state, who are more prone to mortality and morbidity due to this infection, were excluded from majority of the vaccine trials. Moreover, suggested dose modification for cancer and immunosuppressed patients are often not followed because of lack of awareness or unavailability of vaccination schedule. This review will try to bridge this knowledge gap by summarizing the current suggestions of dose modification of COVID-19 vaccine for patients with cancer and immunosuppression.

Background: Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e., osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.), which suggests a close association. In this study, we examined the relationship between vitamin D levels and LTL in older participants of the UK Biobank. Methods: Data were collected from the UK Biobank. Participants aged 60 and older (n=148,321) were included. Baseline LTL was measured using a multiplex qPCR technique and expressed as the ratio of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Se-rum 25-hydroxyvitamin D (25OHD) was stratified by z score and linked to LTL in a linear regression model adjusting for covariates. Results: Compared to the medium level, a low (in the range of 16.6 nmol/L, 29.7 nmol/L) or extremely low (≤ 16.6 nmol/L) level of serum 25OHD was associated with shorter LTL: 0.018 SD (standardized β= -0.018, 95% CI -0.033 to -0.003, P=0.022) and 0.048 SD (standardized β= -0.048, 95% CI -0.083 to -0.014, P=0.006), respectively. Additionally, the high serum 25OHD groups (> 95.9 nmol/L) had 0.038 SD (standardized β= -0.038, 95% CI -0.072 to -0.004, P=0.030) shorter mean LTL than the group with medium 25OHD levels. The associations above were adjusted for multiple variables. Conclusion: In this population-based study, we identified an inverted U-shape relationship between LTL and vitamin D status. Whether high or low vitamin D-associated shorter LTL is mechanistically related to age-related conditions remains to be elucidated.

The choice of antibiotic regimens to use in patients presenting with diabetic foot osteomyelitis and their duration differs according to the situation. Antibiotics play a more important role in the medical option where no infected bone has been resected while their role is reduced but not negligible in the case of surgical options. Some studies have reported the presence of biofilm structures in bone samples taken from patients with diabetic foot osteomyelitis which raises the question of the place of anti-biofilm antibiotic regimens in this setting. During the last two decades, clinical studies have suggested a potential benefit for anti-biofilm antibiotics, mainly rifampicin against staphylococci and fluoroquinolones against gram-negative bacilli. No data from randomized controlled studies have however been reported so far. The present work provides a summary of the available data on the question of the place of anti-biofilm antibiotics for the treatment of diabetic foot osteomyelitis but also the potential limitations of such treatments.

The COVID-19 pandemic has posed an unprecedented challenge to healthcare and the available solutions are unsatisfactory. Classical homeopathy may have a role to play in alleviating this burden. Covid cases treated with homeopathy was curated with the intention to provide basic information for further studies. The results are promising although far from being definitive. 367 patients considered were for statistical analysis, the mean age of the participants was 42.75 years, and males and females were 166 and 201 respectively. The mean follow-up period was 6.5 (SD 5.3) days, with a median of 1 homeopathic remedy used per case. 192 patients were diagnosed by RT–PCR, 111 by the WHO clinical criteria and 64 via retrospective antibodies. According to the WHO criteria, 255 were confirmed cases, 61 were probable cases, and 51 were suspected cases. It was seen that 73.8% of covid patients improved under homeopathic treatment, even those among severe disease 78.6%. Correlational analyses showed that presence of fever was associated with more likelihood of improvement and increasing age and a greater number of homeopathic remedies required in a case were associated negatively with improvement. However, it was seen that severe cases were more likely to improve under homeopathic treatment.

Introduction: Individuals with gout are at higher risk of developing chronic conditions, such as diabetes, chronic kidney disease (CKD), and cardiovascular diseases. In this study, the association between urate-lowering therapy (ULT) use and the prevalence of these conditions was evaluated. Methods: This observational, cross-sectional pharmacoepidemiologic study used the 2013-2018 biannual cycles of the National Health and Nutrition Examination Survey. The inclusion criteria were adults 30 years of age and older with a diagnosis of gout. The association between ULT treatment status and dyslipidemia, coronary heart disease, heart failure, hypertension, and chronic kidney disease was evaluated, as well as associations with select clinical laboratory biomarkers. Results: Use of ULT was 28.9% (95%CI 24.3%-33.9%). There was no significant association between ULT use and the prevalence of heart failure, coronary heart disease, hypertension, or dyslipidemia (p>0.05). Those on ULT had a lower mean eGFR compared to those not on treatment (68.03 versus 74.74 mL/min/1.73m², p=0.014). LDL- and HDL- and total cholesterol were significantly lower among those receiving ULT treatment (p<0.05). Conclusion: ULT use continues to be low among those with gout. Those on ULT were more likely to be diagnosed with CKD, college graduates and above, older males, and obese. Clinical guidelines conditionally recommend ULTs in co-morbid kidney disease; while our results may reflect guidelines recommendation for ULT use in CKD patients, worsening kidney function while taking ULT is unlikely. Further research is necessary to determine the long-term impact of ULTs on kidney function and cardiovascular biomarkers.

Lipid mesophases are being intensively studied as potential candidates for drug-delivery purposes. Extensive experimental characterization has unveiled a wide palette of release features depending on the nature of the host lipids and of the guest molecule, as well as on the environmental conditions. However, only few simulation works have addressed the matter, which hampers a solid rationalization of the richness of outcomes observed in experiments. Particularly, to date there are no theoretical works addressing the impact of hydropathy on the transport of a molecule within lipid mesophases, despite the significant fraction of hydrophobic molecules among currently-available drugs. Similarly, the high heterogeneity of water mobility in the nanoscopic channels within lipid mesophases has also been neglected. To fill this gap, we introduce here a minimal model to account for these features in a lamellar geometry, and systematically study the role played by hydropathy and water-mobility heterogeneity by Brownian-dynamics simulations. We unveil a fine interplay between the presence of free-energy barriers, the affinity of the drug for the lipids, and the reduced mobility of water in determining the net molecular transport. More in general, our work is an instance of how multiscale simulations can be fruitfully employed to assist experiments in release systems based on lipid mesophases.

Age-related disorders of the musculoskeletal system including sarcopenia, osteoporosis and arthritis represent some of the most common chronic conditions worldwide, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. Collectively, these conditions involve multiple tissues, including skeletal muscle, bone, articular cartilage and the synovium within the joint lining. In this review, we discuss the potential for oligonucleotide therapies to combat the unmet clinical need in musculoskeletal disorders by evaluating the successes of oligonucleotides to modify candidate pathological gene targets and cellular processes in relevant tissues and cells of the musculoskeletal system. Further, we discuss the challenges that remain for the clinical development of oligonucleotides therapies for musculoskeletal disorders and evaluate some of the current approaches to overcome these.

Aging kills 100,000 people a day - more than any other cause of death combined. The exact causes of aging have been much discussed, but the most pressing issue with regard to aging appears to me to be lipofuscin accumulation. That is, the accumulation of indigestible cellular garbage that needs to be removed from our cells, then the body. In this piece, I will explain why I think “getting rid of the garbage” should be at least one of our main goals with regard to longevity research for now.

Uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) are a safe and effective treatment option for various musculoskeletal pathologies. However, it is unknown whether the composition of the final cell suspension systematically varies with the subject's individual age, sex, body mass index and ethnicity. UA-ADRCs were isolated from lipoaspirate from n=232 subjects undergoing elective lipoplasty using the Transpose RT system (InGeneron, Inc.; Houston, TX, USA). The UA-ADRCs were assessed for the number of nucleated cells, cell viability and the number of viable nucleated cells per gram of adipose tissue harvested. Cells from n=37 subjects were further characterized using four-channel flow cytometry. The present study shows, for the first time, that key characteristics of UA-ADRCs can be independent of the subject's age, sex, BMI and ethnicity. This result has important implications for the general applicability of UA-ADRCs in regeneration of musculoskeletal tissue. Future studies must determine whether in-dependence of key characteristics of UA-ADRCs of the subject's individual age, sex, BMI and eth-nicity only applies to the system used in the present study, or also to others of the more than 25 different experimental methods and commercially available systems used to isolate UA-ADRCs from lipoaspirate that have been described in the literature.

Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. Here, I explore the possibility that the accumulation of lipofuscin to some extent underlies all other categories of age-related damage as defined by Dr. Aubrey de Grey. I do not think that lipofuscin removal will reverse/prevent all forms of aging, just the major component facing us currently. In this piece, I will review what is known about lipofuscin accumulation from evolutionary and mechanistic standpoints and discuss ways of removing it from non-dividing (or slowly-dividing) cells.

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary P. aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, however had no difference in bacterial burden. Utilising a model of P. aeruginosa LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/β, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment.

In the chronic phase of chikungunya virus (CHIKV) infection, excessive inflammation manifests as incapacitating joint pain and prolonged arthritis. Arthritis resulted from a large influx of infiltrating immune cells driven by pro-inflammatory cytokines and chemokines originating from the toll-like receptor (TLR)-mediated innate antiviral response. This study investigated fisetin's ability to modulate TLR-mediated antiviral responses against CHIKV in Huh7 cells. The CHIKV inhibitory potential of fisetin was assessed by plaque-forming unit assay, virus yield reduction assay, and bright-field microscopy (cytopathic effect, immunofluorescence). Fisetin’s modulatory potential on TLR-mediated antiviral response was evaluated by immunofluorescence assay (expression of TLR proteins), qRT-PCR (mRNA level of antiviral genes), human cytokine array, and immunoblotting of key transcription factors. The present study showed fisetin induced the expression of the antiviral genes at an early time-point by promoting the phosphorylation of IRF3 and IRF7. Fisetin reduced excessive inflammatory cytokine responses in CHIKV-infected Huh7 cells by impeding the over-phosphorylation of NF-κB. Fisetin also reduced CHIKV-induced cytopathic effects in CHIKV-infected Huh7 cells. Altogether, our study suggests that fisetin modulates TLR-mediated antiviral responses by affecting the CHIKV-induced inflammatory responses.

Epigenetic reprogramming using cyclic expression of Yamanaka factors has been demonstrated to rejuvenate on a systemic level in animal models with no obvious deleterious effects. Here we discuss a strategy for cyclic and systemic expression of Yamanaka factors in wild-type animals amenable for adaptation as a human therapy. This is based on the use of the little- known Amsacta moorei Entomopoxvirus vector in combination with microbubble mediated focused ultrasound-driven blood vessel permeabilization to facilitate the system-wide distribution of the virus.

The primary purpose of this study was to determine the prevalence of drug-drug interaction (DDI) and duplicate therapy in chronic patients in a completely random study population engaged in digital health apps. In this cross-sectional study, polypharmacy checks for 100 completely anonymous patients were analyzed for the occurrence of DDIs and duplicate therapy. Logistic regression models were used to identify factors associated with DDIs and duplicate therapy. DDIs and duplicate therapy prevalence were 34% and 33%, respectively. Chi-Square test discovered a significant association between the DDIs and duplicate therapy variables. Logistic regression models showed a strong association between the number of medications taken and higher odds of DDIs occurring in our population only. In conclusion, our study shows that polypharmacy is a determining factor for the occurrence of unwanted DDIs, and the prevalence of duplicate therapy and DDIs is around 33%, increasing an issue regarding patient safety and its burden to the healthcare system.

Background: Monitoring of antibiotic prescription practices in hospitals is essential to assess and facilitate appropriate use. This is relevant to halt the progression of antimicrobial resistance. Methods: Assessment of antibiotic prescribing patterns and completeness of antibiotic prescriptions among out-patients in 2021 was conducted at the University Hospital of Kwame Nkrumah University of Science and Technology in the Ashanti region of Ghana. We reviewed electronic medical records (EMR) of 49,660 patients who had 110,280 encounters in the year. Results: The patient encounters yielded 350,149 prescriptions. Every month, 33-36% of patient encounters resulted in antibiotic prescription, higher than the World Health Organization’s (WHO) recommended optimum of 27%. Almost half of the antibiotics prescribed belonged to WHO’s Watch group. Amoxicillin-clavulanic acid (50%), azithromycin (29%), ciprofloxacin (28%), metronidazole (21%), and cefuroxime (20%) were the most prescribed antibiotics. Antibiotic prescribing parameters (indication, name of drug, duration, dose, route and frequency) were documented in almost all prescriptions. Conclusions: Extending antimicrobial stewardship to the out-patient settings by developing standard treatment guidelines, an out-patient specific drug formulary and antibiograms can promote rational antibiotic use at the hospital. The EMR system of the hospital is a valuable tool for monitoring prescriptions that can be leveraged for future audits.

There is a need to further characterize the antibody response to vimentin in relation to it possible involvement in pathogenicity of sarcoidosis, and other lung disorders. Objectives: We investigated serum samples from patients with sarcoidosis, healthy and diseased control subjects to evaluate levels and frequency of these antibodies. Materials and methods. A retrospective-prospective comparative study was performed in the years 2014-2017. 188 serum samples were examined for presence of autoantibodies to mutated citrullinated vimentin (anti-MCV). Patients with elevated anti-MCV levels were tested for antibodies to a cyclic citrullinated peptide (anti-CCP) and citrullinated vimentin (anti-Sa). Additionally, sera from 93 patients with sarcoidosis and 40 healthy subjects were evaluated for the presence of autoantibodies to non-modified vimentin. In all cases ELISA assays was used. The results were considered statistically significant at p-value less than 0.05. Results of the study. The high concentrations of anti-MCV. antibodies were more frequent in patients with sarcoidosis (40.9% of the cases, 38/93), compared to the control groups (23.6% and 25.0% of cases, respectively). In sarcoidosis, clinical symptoms similar to the autoimmune pathology were described. A moderate positive correlation between the anti-MCV and anti-Sa antibodies (r = 0.66) was found in 13 patients with sarcoidosis. There was no significant difference between the levels of the anti-MCV and the anti-CCP in patients with non-infectious lung diseases and the healthy control group. Conclusion. A high level of anti-MCV antibodies in patients with sarcoidosis characterizes the presence of an autoimmune process that is not related to citrullination. The absence of a significant difference in the level of antibodies to modifications of vimentin in patients with sarcoidosis may indicate the autoimmune process.

Objective: To describe technique of platelet rich plasma injection into the olfactory cleft in patients with long-term COVID-19 olfactory dysfunction. Methods: The technique starts with the blood extraction and the isolation of PRP through a 10-min centrifugation (4,200 rpm). The supernatant was injected in nasal regions with a 27-G needle after a local anesthesia with Xylocain 10% spray. The injection was performed through a 0° rigid optic. Precisely, several points of 0.2–0.5 mL were performed in the nasal septum in regard of the head of the middle turbine, and in the head of the middle turbine in both sides. Clinical, psychophysical and pain outcomes were evaluated pre- to post-injection. Results: A 22-year-old female with 24-month post-COVID-19 anosmia was recruited for the injection of PRP. The olfactory cleft endoscopic scale score was 0 and the threshold, discrimination and identification scores were 1, 8 and 0, respectively. The Olfactory Disorder Questionnaire score was 51. The patient benefited from the injection of 2.2 mL of PRP in nasal regions, which was done without complication. The procedure pain level was 2/10, while the local anesthesia with xylocaine 10% was judged as the most annoyance step with a score of 3/10. At 2-month post-injection, the TDI scores reached 16, 16, and 16 (48), while the Olfactory Disorder Questionnaire was 73. The patient described its recovery as very rapid, lasting 3-4 days, and occurring 3-week post-injection. Conclusion: The injection of PRP into the olfactory cleft is a safe and easiness new approach that may improve the recovery of smell sense.

Providing patient-centered care to manage chronic pain and opioid use disorder (OUD) is associated with improved health outcomes. However, adopting a holistic approach to providing care is often challenging in rural communities. This study aims to identify and contrast challenges to providing patient-centered care from the perspective of patients and providers. A participatory design approach was adopted to elicit the perceptions of providers and patients with lived experiences of chronic pain and OUD in Jefferson County, Wisconsin. Two focus groups were conducted with each stakeholder group to identify problems that participants face with respect to chronic pain management and OUD and possible solutions. Four interviews were conducted with providers experienced in chronic pain management. Analysis of focus group sessions and interviews show consensus among patients and providers that lack of behavioral health and recovery resources create barriers to effectively manage OUD and chronic pain. However, there was discordance among the two groups about other barriers such as patient and provider attitudes, tapering approach, and access to medications for OUD. This tension among patients and providers can influence patients’ retention in therapy. More efforts are needed to mitigate stigma among providers in rural communities and support psychosocial needs of patients.

Human pluripotent stem cells (hPSCs) have become a powerful tool to generate various kinds of cell types comprising the human body. Recently, organoid technology emerged as a platform to build a physiologically relevant tissue-like structure from the PSCs, which provides a more relevant three-dimensional microenvironment to the actual human body than the conventional monolayer culture system for transplantation, disease modeling, and drug development. Although it holds so many advantages, the organoid culture system still has various problems related to culture methods, which became a challenge to get similar physiological properties to their original tissue counterparts. Here, we discuss the current development of organoid culture methods, including the problem that may arise from the currently available culture systems as well as the possible approach to overcoming the current limitation and improving their optimum utilization for translational application purposes.

Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of the longitudinal ligament (OPLL), osteophytes around the large joint, and enthesopathy in the Achilles tendon), the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT) and the subsequent progression of chronic kidney disease (CKD). In addition, these patients exhibit the typical phenotypes of osteomalacia, such as pseudofracture and fracture in weight-bearing bones, odontitis, and tooth abscess. The mechanism underlying enthesopathy development is unknown; however, a common underlying mechanism among XLH and autosomal recessive hypophosphatemic rickets, ARHR1.2, due to mutations in PHEX, DMP1, and ENPP1, is assumed. Clarification of the pathogenesis and drug discovery for this complication is an urgent issue to address, as many adult XLH patients suffer subsequent debilitating nervus symptoms or impingement syndrome, and existing treatments are ineffective. Severe SHPT and THPT are associated with conventional therapy, including active vitamin D and phosphate supplementation, and complicated and careful adjustment of the dosage by experienced clinicians is required to avoid SHPT/THPT. Burosumab is a very effective therapy without risk for the development of SHPT/THPT. However, the indication of this drug should be carefully considered along with the cost-effectiveness, guidelines or recommendations and health care system of each country.

Drug repurposing is an attractive strategy for developing new antibacterial molecules. Herein, we evaluated the in vitro antibacterial, antibiofilm, and antivirulence activities of eight FDA-approved “non-antibiotic” drugs, comparatively to tobramycin, against selected Pseudomonas aeruginosa strains from cystic fibrosis patients. MIC and MBC values were measured by broth microdilution methods. Time-kill kinetics was studied by the macro dilution method, and synergy studies were performed by checkerboard microdilution assay. The activity against preformed biofilm was measured by crystal violet and viable cell count assays. The effects on gene expression were studied by real-time quantitative PCR, while the cytotoxic potential was evaluated against IB3-1 bronchial CF cells. Ciclopirox, 5-fluorouracil, and actinomycin D showed the best activity against P. aeruginosa planktonic cells and, therefore, underwent further evaluation. Time-kill assays indicated actinomycin D and ciclopirox, contrarily to 5-fluorouracil and tobramycin, have the potential for bacterial eradication, although with strain-dependent efficacy. Ciclopirox was the most effective against the viability of the preformed biofilm. A similar activity was observed for other drugs, although they stimulate EPS production. Ribavirin showed a specific antibiofilm effect, not dependent on bacterial killing. Exposure to drugs and tobramycin generally caused hyperexpression of the virulence traits tested, except for actinomycin D, which downregulated the expression of alkaline protease and alginate polymerization. Ciclopirox and actinomycin D revealed high cytotoxic potential. Ciclopirox and ribavirin might provide chemical scaffolds for anti-P. aeruginosa drugs. Further studies are warranted to decrease ciclopirox cytotoxicity and evaluate the in vivo protective effects.

The interleukin 6 (IL-6) receptor blocking antibody tocilizumab was repurposed in the coronavirus pandemic with the intention of blocking the excess inflammatory activation associated with severe disease. We retrospectively evaluated the response to tocilizumab based on measured levels of IL-6 as well as other inflammatory markers. In the sample of 41 patients with measured levels, 16 received tocilizumab. In patients who received tocilizumab, there was a statistically significant relationship between both higher IL-6 levels and measured acute phase reactants with mortality, but not in those who did not. Additionally, an improved mortality after tocilizumab was suggested with those with higher IL-6 measurements, but not in those with lower levels, but this finding failed to achieve statistical significance (p=0.14). Though this study is limited by a small sample size and retrospective design, an association is suggested between higher IL-6 levels and improved mortality after tocilizumab.

The aim of this review is to present the Quality by Design (QbD) model as a suitable methodology to perform research in the academic Costa Rican institutions that teach Pharmacy. Pubmed, Science Direct, and Google Scholar databases were screened for original and review papers, as well as short communications published not more than 10 years ago. Publications were screened by title and abstract. Relevant references were used to develop three important themes: The University’s Research Model in Costa Rica, QbD Model, and QbD as a Research Methodology for Industrial Pharmacy in the Academy. In this sense, the QbD model is a great methodology for carrying out research projects regarding Pharmaceutical Sciences but especially for Drug Development. Academic research based on this model enables training and developing practical, scientific, and leadership skills in pharmacy students. The generated knowledge can be shared in the classrooms, which represents an ideal environment to communicate their research results and to foster collaborative work between researchers, professors, and students. The participation of all these actors allows a high level of commitment to research work, which benefits the scientific advancement of the university and society. It is important to visualize the student body as potential key actors in the research process, encouraging in them the desire to become trained scientific researchers who want to pursue a career in the academy, giving continuity to it.

Sex differences are essential factors in disease etiology and manifestation in many diseases such as cardiovascular disease, cancer, and neurodegeneration (1). The biological influence of sex differences (including genomic, epigenetic, hormonal, immunological, and metabolic differences between males and females) and the lack of biomedical studies considering sex differences in their study design has led to several policies. For example, the National Institute of Health’s (NIH) sex as a biological variable (SABV) and Sex and Gender Equity in Research (SAGER)) policies to motivate researchers to consider sex differences (2). However, drug repurposing, a promising alternative to traditional drug discovery by identifying novel uses for FDA-approved drugs, lacks sex-aware methods that can improve the identification of drugs that have sex-specific responses (1,3–5). Sex-aware drug repurposing methods either select drug candidates that are more efficacious in one sex or deprioritize drug candidates based on if they are predicted to cause a sex-bias adverse event (SBAE), unintended therapeutic effects that are more likely to occur in one sex. Computational drug repurposing methods are encouraging approaches to develop for sex-aware drug repurposing because they can prioritize sex-specific drug candidates or SBAEs at lower cost and time than traditional drug discovery. Sex-aware methods currently exist for clinical, genomic, and transcriptomic information (3,6,7). They have not expanded to other data types, such as DNA variation, which has been beneficial in other drug repurposing methods that do not consider sex (8). Additionally, some sex-aware methods suffer from poorer performance because a disproportionate number of male and female samples are available to train computational methods (3). However, there is development potential for several different categories (i.e., data mining, ligand binding predictions, molecular associations, and networks). Low-dimensional representations of molecular association and network approaches are also especially promising candidates for future sex-aware drug repurposing methodologies because they reduce the multiple hypothesis testing burden and capture sex-specific variation better than the other methods (9,10). Here we review how sex influences drug response, the current state of drug repurposing including with respect to sex-bias drug response, and how model organism study design choices influence drug repurposing validation.

Background: The fulminant course of COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents with a high mortality rate and still lacks a causative treatment. C-reactive protein (CRP) has been shown to increase dramatically during the disease progression and correlates with deleterious outcomes. Selective CRP apheresis can reduce circulating CRP levels fast and effective. Methods: Seven hospitalized patients with documented severe COVID-19 progression, elevated CRP plasma levels (> 100 mg/L) and signs of respiratory failure were treated with CRP apheresis. 2-12 CRP apheresis sessions were performed generally in 24 h time intervals and depending on CRP plasma levels. Results: CRP apheresis reduced CRP plasma levels by up to 84% within a few hours, without exhibiting side effects in any patient. Despite signs of severe lung infiltration in all patients, only one patient died. The other patients showed improvements within the chest x-ray after CRP apheresis and were able to recover regardless of intubation and/or ECMO (4 patients). All remaining six patients were discharged from the hospital in good clinical condition. All patients had comorbidities. Conclusions: This case series presents a mortality rate of only 14%, which is dramatically lower than expected from the presented CRP levels as well as comorbidities and ventilation require-ments. Our clinical observations regarding the here presented seven patients support the hypoth-esis that CRP is a candidate to be therapeutically targeted in the early stage of severe COVID-19.

Extremely low concentrations of ciprofloxacin may select for antimicrobial resistance. A recent global survey found that ciprofloxacin concentrations exceded safe levels at 64 sites. We assessed if national median ciprofloxacin concentrations in rivers were associated with fluoroquinolone resistance in Escherichia coli. Methods Spearman’s regression was used to assess the country-level association between the national prevalence of fluoroquinolone resistance in E. coli and the median ciprofloxacin concentration in the countries rivers. Results The prevalence of fluoroquinolone resistance in E. coli was positively correlated with the concentration of ciprofloxacin in rivers (ρ=0.36; P=0.011; N=48). Conclusions Steps to reducing the concentrations of fluoroquinolones in rivers may help prevent the emergence of resistance in E. coli and other bacterial species.

Complex diseases are prevalent medical conditions which are characterized by strong inter-patient differences in symptom profiles, disease trajectory and treatment response. The challenges in understanding and managing these diseases are due to their complex pathophysiology, comprising of a combination of genetic and environmental factors. The traditional model of disease assumes a clear distinction between health and disease, as well as between different diagnoses, but recent findings with regards to diseasomes and network pleiotrophy suggest that this dogma is not useful in understanding complex diseases. This paper presents a novel model, in which the individual disease burden is determined as a function of molecular, physiological and pathological factors simultaneously: disease(symptoms(traits(genes AND environment))). From this a high-dimensional space is defined which includes all individual disease burdens, ranging from healthy (i.e. low disease burden) to multi-morbidity (i.e. high disease burden), termed the disease landscape. This model provides a novel way to conceptualize human physiology and pathophysiology in the context of complex diseases and may present a useful concept to simultaneously address the strong interindividual heterogeneity of diagnose cohorts as well as the lack of clear distinction between diagnoses and health and disease, thus facilitating the progression towards personalized medicine.

Avian mutations in vaccine strains obtained from embryonated eggs could impair vaccine effec-tiveness. We performed a systematic review and meta-analysis of the adjusted relative vaccine effectiveness (arVE) of seed cell-cultured influenza vaccines (ccIV) compared to egg-based influ-enza vaccines (eIV) in preventing laboratory-confirmed influenza related outcomes (IRO) or IRO by clinical codes, in subjects 18 and over. We completed the literature search in January 2021; ap-plied exclusion criteria, evaluated risk of bias of the evidence, and performed heterogeneity, pub-lication bias, qualitative, quantitative and sensitivity analyses. All estimates were computed us-ing a random approach. International Prospective Register of Systematic Reviews, CRD42021228290. We identified 12 publications that reported 26 adjusted arVE results. Five publications reported 13 laboratory confirmed arVE and seven reported 13 code-ascertained arVE. Nine publications with 22 results were at low risk of bias. Heterogeneity was explained by season and risk of bias. We found a significant 11% (8 to 14%) adjusted arVE favoring ccIV in preventing any IRO in the 2017-2018 influenza season. The arVE was 3% (-01 to 7%) in the 2018-2019 influenza season. We found moderate evidence of a significant advantage of the ccIV in preventing IRO, compared to eIV, in a well-matched A(H3N2) predominant season.

The aim of this study was to evaluate the Hapo ms, a passive upper limbs exoskeleton developed to assist workers for tasks with arms in front of the body. Twelve participants had to perform a static task, a manual handling task and a load carrying task two times: with and without the exoskeleton. In all cases subjective (perceived effort in arm and back areas, comfort) and objective (muscular activity, postural balance) criteria were evaluated. Results have shown a decrease in anterior deltoid (-12 to -18% depending of the task) and in biceps brachii (-19% to -33% depending of the task) muscular activity. No significant difference was pointed out in back muscle and postural balance was not significantly perturbed due to the wear of the exoskeleton. Finally, perceived effort reduction was observed during the three tasks (except in back area for task 1). To conclude, the Hapo ms seems well adapted to assist upper arms during tasks with arms in front of the body.

Purpose:To explore (theoretically) the key parameters and their influence on the time profiles of photosensitizer (riboflavin), free radicals, singlet oxygen, oxygen and the efficacy of corneal collagen crosslinking (CXL)in both type-I and oxygen-mediated type-II mechanisms, specially the role of oxygen and the initiator regeneration. Methodology:Coupled kinetic equations are derived and numerically solved under the quasi-steady state condition for the 2-pathway mechanisms of CXL. The key parameters explored include (bI, V, Q', K, K',Q,P) and their influence on the time profiles of photosensitizer (riboflavin, C), radicals (R), singlet oxygen(S), oxygen (X) and efficacy (E), parameters of (K,K',Q) define the relative strength of type-I and type-II process. The oxygen depletion profile, X(t), and the associated singlet oxygen, S(t), depend on the parameters of V, Q' and the initial value of oxygen. The coupling strength given by (bI) governs almost all profiles, where b is an effective absorption parameter and I is the UV light intensity.Results:Our numerical method for CXL dynamic profiles demonstrated the following important features: (i) Type-I and type-II coexit in CXL, in the presence of oxygen. However, there is no type-II when oxygen is depleted or in a condition without oxygen. (ii) Type-I with bimolecular termination, the radical R(t) is a function of [K'(bIgC)]^0.5, leading to the steady-state efficacy given by a scaling law of 1/(bI)^0.5, in contract to that of type-II which is almost independent to the light intensity. (iii) The depletion rate (2 to 5 minutes) of X(t) is much faster than that of C(t) (10 to 20 minutes), (iv) Thepure type-II profile, has a transition point from straight line to saturating curve and matches the depletion point of singlet oxygen S(t). (v) Improved CXL efficacy of type-I and type-II may be achieved by external supply of photoinitiator (riboflavin) and oxygen, respectively.

Pulmonary fibrosis causes scar tissue formation that disrupts the functioning of the lungs. Uncaria gambir (Hunter) Roxb (hereafter gambir)—a plant native to West Sumatra in Indonesia—contains flavonoid (+)-catechin and has strong antioxidant activity, and it can be used to combat pulmonary fibrosis. This random in vivo experimental study analyzed the antifibrotic effect of gambir on the lungs of rats with bleomycin-induced fibrosis. The subjects were 10 groups of 10-week-old male rats weighing around 200–250 g. All groups were terminated at the end of the seventh week or on day 50. The lungs were cleaned, and tissues were taken to analyze inflammatory cell counts and TGF-β1 levels using bronchoalveolar lavage (BAL) with ELISA; type I collagen and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels using immunohistochemistry (IHC); and activation of NF-κB using ELISA and Western blot assays. The most severe histopathological characteristic based on the modified Ashcroft score was in the bleomycin group (BG), whereas the mildest was in the 262 mg/kg of bodyweight antifibrotic gambir-dosed group (AF G262). The results showed a significant difference in the BAL inflammatory cell count (p = 0.017; p &lt; 0.05). AF G262 differed most from the other antifibrotic groups in terms of the number of inflammatory cells (0.63), TGF-β1 levels (3.80), and NF-κB levels (0.48), followed by the 131 mg/kg of bodyweight antifibrotic gambir-dosed group (AF G131), which also differed most from other antifibrotic groups in terms of NF-κB (0.48), TIMP-1 (11.74), and collagen I (14.50) levels. Western blot analysis showed that the fibropreventive and antifibrotic groups had a specific band size of p65, whereas no specific band binding existed in the control group. This study concluded that the administration of AF G262 could improve fibrosis by lysing the extracellular matrix (ECM) in rat lungs.

Chronic and non-healing wounds demand personalized and more effective therapies for treating complications and improve patient adherence. This work aims to develop a suitable chitosan-based scaffold to provide 24 hours controlled release of DKT, by taking advantage of chitosan’s thermo-responsive behavior as well as local hyperthermia in wounds. Three formulation prototypes were developed using chitosan (F1), 2:1 chitosan: PVA (F2), and 1:1 chitosan:gelatin (F3). Compatibility tests were done by DSC, TG, and IR spectroscopy. SEM was employed to examine the morphology of the surface and inner layers from the scaffolds. In vitro release studies were performed at 32 °C and 38 °C to evaluate the release profiles, which were later adjusted to different kinetic models for the best formulation. F3 showed the most controlled release of DKT at 32 °C for 24 hours (77.75 ± 2.72 %), and reduced the burst release in the initial 6 hours (40.18 ± 1.00 %), while at 38 °C the release reached 88.52 ± 2.07 % at 12 hours. The release profile for this formulation fits with Hixson-Crowell and Korsmeyer-Peppas kinetic models at both temperatures. Therefore, the developed chitosan/gelatin thermo-responsive scaffold provides a suitable system for wound healing with a controlled release of DKT for 24 hour-use, which can overcome adherence issues and wound complications.

: Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process enables the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metallopro-teinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Like in an optimized "biorector," disturbance can lead to prolonged healing. One of the earliest investigated local factors is the pH of wounds, studied in close relation to the local perfusion, oxygen tension, and lactate concentration. Granulation tissue with the wrong pH can hinder fibroblast and keratinocyte division and pro-liferation, as well as skin graft takes. Methods for influencing the pH have been tested, such as occlusion and acidification by the topical application of acidic media. In most trials, this has not changed the wound's pH to an acidic one, but it has reduced the strong alkalinity of deeper or chronic wound. Energy provision is essential for all repair processes. New insights into the metabolism of cells have changed the definition of lactate from a waste product to an indispensable energy provider in normoxic and hypoxic conditions. Neovascularization depends on oxygen provision and lactate, signaling hypoxic conditions even under normoxic conditions. An appropriate pH is necessary for successful skin grafting; hypoxia can change the pH of wounds. This review describes the close interconnections between the local lactate levels, metabolism, healing mechanisms, and pH. Furthermore, it analyzes and evaluates the different possible ways to support metabolism, such as lactate enhancement and pH adjustment. The aim of wound treatment must be the optimization of all these components. Therefore, the role of lactate and its influence on wound healing in acute and chronic wounds will be assessed.

BackgroundIt is unclear what underpins the large global variations in the prevalence of fluoroquinolone resistance in gram-negative bacteria. We tested the hypothesis that different intensities in the use of quinolones for food-animals plays a role. MethodsWe used Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in human infections with Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was correlated with the use of quinolones for food producing animals. Linear regression was used to assess the relative contributions of country-level quinolone consumption for food-animals and humans on fluoroquinolone resistance in these 4 species. ResultsThe prevalence of fluoroquinolone resistance in each species was positively associated with quinolone use for food-producing animals (E. coli [ρ=0.55; P<0.001], K. pneumoniae [ρ=0.58; P<0.001]; A. baumanii [ρ=0.54; P=0.004]; P. aeruginosa [ρ=0.48; P=0.008]). Linear regression revealed that both quinolone consumption in humans and food animals were independently associated with fluoroquinolone resistance in E. coli and A. baumanii. ConclusionsReducing quinolone use in food-producing animals may help retard the spread of fluoroquinolone resistance in various gram negative bacterial species.

Relapses and resistance to therapeutic agents are major barriers for treatment of acute myeloid leukemia (AML) patients. This unfavorable circumstance emphasizes the need for new strategies targeting drug-resistant cells. As IDH mutation is present in the preleukemic stem cells and systematically conserved at relapse, targeting mutant IDH cells would be essential to achieve a long-term remission in the AML subgroup with IDH mutation. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutation, we showed that the presence of IDH mutation through the production of an oncometabolite (R)-2-HG induces vitamin D receptor related transcriptional programs, priming these AML cells to differentiate with pharmacological doses of ATRA or/and VD. This activation occurs in a CEBP-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutation and vitamin D pathway to differentiate in AML, revealing a novel therapeutic approach easily transferable/immediately applicable in clinics for this subgroup of AML patients.

To resolve the controversial issues of UV-light-initiatedcornealcollagen cross-linking (CXL) by theoretical formulas and measured clinical outcomes. The controversial issues are addressed and resolved by analytical formulas including: the validation of Bunsen Roscoe law (BRL), the cutoff light intensity, the minimum corneal thickness, the demarcation line depth, the role of oxygen riboflavin (RF) concentration. The overall CXL efficacy is governed by UV-A light intensity, dose, exposure time, mode of exposure (pulsed or CW), riboflavin concentration, diffusion and drops pre-operation and interoperation administration, concentration of oxygen in the stromal tissue (pre-op and inter-op), and environmental conditions. The length of the riboflavin presoaking time and viscosity of the riboflavin film also affect the crosslink depth. Analytic formulas are derived for the scaling laws for type-I and type-II efficacy, given by the square-root of light intensity, and light dose, respectively. The controversial issues of CXL may be partially resolved via analytic formulas, and compared with measurements. The scaling laws of type-I and type-II efficacy are different and given by analytic formulas. Our formulas also predict the maximum light intensity and the minimum corneal thickness, which are consistent with measurements.

Based on hospital capacities, facts from past experience with the coronavirus disease 2019 (COVID-19) virus and the number of dark infections during the second wave (DII = 2D2), a reasonable limiting value of 140/D2 for the 7-day incidence per 100,000 persons (MSDIHT) and a second wave herd immunization threshold fraction value of 0.26 in Germany were calculated. If the MSDIHT is held below this limiting value, the German hospital system can cope with the number of new seriously infected persons without any triage decisions. On the basis of the SIRV epidemics model, the classical threshold values for herd immunization were calculated for 18 countries. For these countries, the dates regarding when herd immunization against the second COVID-19 wave will be reached were estimated

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen receptors (ER), progesterone receptors, and HER-2 receptors. Thus, TNBC tumours do not benefit from the current therapies targeting ER or HER-2. Therefore, there is an urgent need to develop novel treatment for this subtype of breast cancer. Marijuana is a common name given to Cannabis plants, a group of plants in the Cannabis genus of the Cannabaceae family. Cannabis plants are among the oldest cultivated crops, traced back at least 12,000 years and are well known for their multi-purpose usage, including medicinal purposes. The main active compounds extracted from Cannabis plants are 21-carbon-containing terpenophenolics, which are referred to as phytocannabinoids. Of these, the tetrahydrocannabinol (THC) group contains highly potent cannabinoids, including delta-9-tetrahydrocannabinol (∆9-THC) and delta-8-tetrahydrocannabinol (∆8-THC), which are the most abundant THCs and are largely responsible for psychological and physiological effects of marijuana. The use of Cannabis plants for medicinal purposes was first recorded in 2337 BC in China, where Cannabis plants were used to treat pains, rheumatism, and gout. Recently, several cannabinoids have been approved for a number of treatments, one of which is the treatment of nausea and vomiting caused by chemotherapy in cancer patients. Furthermore, increasing evidence shows that cannabinoids not only attenuate side effects due to cancer treatment, but might also potentially possess direct antitumor effects in several cancer types, including breast cancer. However, anti-tumour activity of marijuana has been variable in different studies and even promoted tumour growth in some cases. In addition, the mechanisms of cannabinoid action in cancer remain unclear. This review summarizes evidence about the mixed actions of cannabinoids in cancer in general and triple-negative breast cancer in particular.

Introduction: Due to COVID-19 pandemic, performance of many program has been declined and Tuberculosis (TB) program is not an exception. TB case detection and notification has been recognized as one of worst hit area. The objective of this study was to explore the TB notification status of India during this pandemic and explore options to mitigate the issue. Methods: A secondary data analysis was performed on open source TB notification database of India. Relevant literature review was done to find out remedies based on the different initiative taken by different states of India. Results: In 2020, total TB notification decreased in all the states in comparison to 2019. The percentage of loss in the country was 34%. Private TB notification also decreased in 2020 in all the states except in Jharkhand. The percentage of loss in private TB notification in the country was 35%. Notification started declining in the month of February 2020 and it was lowest in the month of April-2020. The trend of notification began to improve since May 2020 when the States started taking innovative initiatives like Integrated TB Covid Case Search. Conclusion: Due to the ongoing COVID-19 pandemic the notifications of TB cases declined noticeably which has a serious implication in terms of silent spread within household and community. But the picture can be improved with integrated approach for TB-COVID case finding and management.

Many inflammatory mechanisms are involved in the pathophysiology of COVID-19 infection. COVID-19 inhibits IFN antiviral responses, so we should expect an out-of-control viral replication. “Cytokine storms” occur due to the over-production of pro-inflammatory cytokines after an influx of neutrophils and monocytes/macrophages and may be responsible for the immunopathology of the lung involvement. Several cascades have been reported in the activation process of NF-κB. In this paper, to find new therapeutic options for COVID-19 infection, we reviewed some natural products that could potentially inhibit the NF-κB pathway. We found that sevoflurane, quercetin, resveratrol, curcumin, KIOM-C, bergenin, garcinia kola, shenfu, piperlongumine, wogonin, oroxylin, plantamajoside, naringin, ginseng, kaempferol, allium sativum L, illicium henryi, isoliquiritigenin, lianhua qingwen, magnoflorine, and ma Huang Tang might be effective in inhibiting the NF-KB pathway. These natural products could be helpful in the control of COVID-19 infections. However, larger clinical trials are needed to ascertain the efficacy of these products fully.

Objectives: To determine the prevalence of controlled systemic hypertension and its associated risk factors among the hypertensive patients who attended the clinic at Mbeya Zonal Referral Hospital in Tanzania. Methods: A descriptive cross-sectional quantitative study was used determine the prevalence of co to 252 hypertensive patients were recruited during clinic visit from September to November 2020 and participant was randomly selected interviews using structured self-administered questionnaires. Data was analyzed using chi square test to find the risk factors associated with controlled hypertension. Results: Among 252 participants, 94(39.7%) individuals with controlled hypertension giving the prevalence of controlled hypertension. The proportion of females with controlled hypertension was slightly higher than male (49 females to 45 males). The prevalence of uncontrolled hypertension was 152(60.3%) participants. The prevalence of controlled hypertension was higher among patients who have regular clinic visit (p< .05) and have daily adherence to their anti-hypertensive medication. A similar trend was observed among participants without financial challenges to attend clinic, short duration of illness, higher level of education and there was no association between age, sex, marital status, smoking, alcohol consumption, having health insurance and having chronic illness. Conclusion: Prevalence of controlled hypertension is higher among patients who have regular clinic visit and have daily adherence to their anti-hypertensive medication. Also, it is higher among participants without financial challenges to attend clinic so they can have regular clinic visit and checkup. Reinforcement on regular drug intake and clinic visit, good nutrition and reduced salt intake and modifying lifestyles of patient with hypertension is important.

There is a growing need for novel in vitro corneal models to replace animal-based ex vivo test in drug permeability studies. In this study we demonstrate a corneal mimetic that models the stromal and epithelial compartments of human cornea. Human corneal epithelial cells (HCE-T) were grown on top of a self-supporting porcine collagen-based hydrogel. Cross sections of the multilayers were characterized by histological staining and immunocytochemistry of zonula occludens-1 protein (ZO-1) and occludin. Furthermore, water content and elastic properties of the synthetized collagen type I-based hydrogels were measured. The apparent permeability coefficient (Papp) values of a representative set of ophthalmic drugs were measured and correlated to rabbit cornea Papp values found in the literature. Multilayered structure of HCE-T cells and expression of ZO-1 and occludin in full thickness of multilayer were observed. The hydrogel-based corneal model exhibited excellent correlation to rabbit corneal permeability (r=0.96), whereas insert-grown HCE-T multilayer was more permeable and the correlation to the rabbit corneal permeability was lower (r=0.89). The hydrogel-based human corneal model predicts the rabbit corneal permeability more reliably in comparison to HCE-T cells grown in inserts. This in vitro human corneal model can be successfully employed for drug permeability tests whilst avoiding ethical issues and reducing costs.

Abstract Aim: To determine the efficacy of health beliefs model –based intervention in changing the belief related to substance use among university student in Mosul city-Iraq. Design: A randomized controlled trial. Methods: A probability (simple random sample) of (N=80) undergraduate student in different specialties would be selected. The study sample will be recruited from (4) colleges in the University of Mosul's Engineering, Sciences, Medicine and Education Colleges. The sample will be randomly assigned into experimental and control groups of (40) undergraduate student for each group. Such chosen is employed of pool of topics that have the criteria contain students who have using on (Smoking, Hookah, Drug abuse and Alcohol).For during from 25of October / 2019 till 1 of February/2021. Data is analyzed using the "Statistical Package for Social Science" (SPSS) software for Windows (V:26). Results: This finding indicated that before the intervention, mean scores for all concepts of HBM, add to Motivation, Control, and behaviors intensions of students they were almost equal. However, after the intervention were significantly different in the study group, while it was not significant in the control group. Conclusion:This study concluded that designing an HBM-based study could affect students' understanding and their behaviors in the field of substance abuse. Considering the positive correlation between construct of HBM, particularly in "perceived benefits and perceived severity" related to students’ beliefs. These beliefs implied a significant correlation with each other and with the attention to the prevention of addiction.