A Traumatic brain injury (TBI) is among the main causes of sudden death after head trauma. These injuries can result in severe degeneration and neuronal cell death in the CNS, including the retina which is a crucial part of the brain responsible for perceiving and transmitting visual information. The long-term effects of mild-repetitive TBI (rmTBI) are far less studied thus far, even though damages induced by repetitive injuries occurring in the brain are more common, especially amongst athletes. rmTBI can also have a detrimental effect on the retina and the pathophysiology of these injuries are likely to differ from the severe TBI (sTBI) retinal injury.Here we showed how rmTBI and sTBI can dissimilarly affect the retina. Our results indicate an increase in the number of activated microglial cells and Caspase3-positive cells in the retina in both traumatic models, suggesting a rise in the level of inflammation and cell death after TBI. The pattern of microglial activation appears evenly distributed and widespread but differs amongst the various retinal layers. sTBI induced microgial activation in both the superficial and deep retinal layers. In contrast to sTBI, no significant change occurred following the repetitive mild injury in the superficial layer, only the deep layer (spanning from the inner nuclear layer to the outer plexiform layer) shows microglial activation. This difference suggests that alternate response mechanisms play a role in the case of the different TBI incidents. The Caspase3 activation pattern showed a uniform increase in both the superficial and deep layers of the retina. This suggests a different action in the course of the disease in sTBI and rmTBI models and points to the need for new diagnostic procedures.Our present results suggest that the retina might serve as such a model of head injuries since the retinal tissue reacts to both forms of TBI and is the most accessible part of the human brain.

Cancer is one of the world's most serious health problems and the top cause of mortality today. S. variolaris is a valuable sea creature that has long been used as a folk medicine to cure and prevent ailments. A subcritical water extraction was used method to obtain crude extract from spikes of S. variolaris. The extract had shown antiproliferative effect in HeLa cells with an IC50 of 723.1 ± 9.73 µg/ml, but no toxicity in HEK293. Westernblot was used to detect protein expression; Bax, caspase-8, and IκBα were increased, whereas IKKα and p-NFκB-65(Ser 536) were downregulated. RNA/mRNA expression was revealed by RT-qPCR, and fold changes of caspase-3, cytochrome-c, Bax, Apaf-1, caspase-9, and Bak genes’ expression were raised. Using gel electrophoresis, the treatment groups showed more DNA fragmentation than the control group. GC-MS was used to identify the components in the crude extract; anticancer activity could be attributed to dodecanoic acid, hexadecanoic acid, and tetradecanoic acid content. In conclusion, these results showed the potential use of the crude extract of a spike from S. variolaris with anticancer activity against cervical cancer.

Here we draw insights from the latest serendipitous findings made on the opposing roles of a validated drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell-survival- vs. cell-death-promoting behaviors. In the process, we convey how understanding reactive chemical-signal regulation at a single-protein-specific level is an enabling necessity in deconstructing otherwise intricate reactive-small-molecule-responsive cellular pathways. We hope this opinion piece further spurs the broader interests of basic and pharmaceutical research communities toward better understanding of molecular mechanisms underpinning reactive small-molecule-regulated signaling subsystems.

White Spot Syndrome Virus (WSSV) has emerged as one of the most prevalent and lethal viruses globally, and infects both shrimps and crabs in the aquatic environment. This study aimed to investigate the occurrence of WSSV in different ghers of Bangladesh and the virulence of the circulating phylotypes. We collected 360 shrimp (Penaeus monodon) and 120 crab (Scylla sp.) samples from the South-East (Cox’s Bazar) and South-West (Satkhira) coastal regions of Bangladesh. The VP28 gene-specific PCR assays and sequencing revealed statistically significant (p < 0.05, Kruskal Wallis test) differences in the prevalence of WSSV in shrimps and crabs between the study areas (Cox’s Bazar and Satkhira), and over the study periods (2017-2019). The mean Log load of WSSV varied from 8.40 (Cox’s Bazar) to 10.48 (Satkhira) per gram of tissue. The mean values for salinity, dissolved oxygen, temperature and pH were 14.71±0.76 ppt, 3.7±0.1 ppm, 34.11±0.38˚C and 8.23±0.38, respectively in the WSSV-positive ghers. The VP28 gene-based phylogenetic analysis showed an amino-acid substitution (E→G) at 167th position in the isolates from Cox’s Bazar (referred to as phylotype BD2) compared to the globally circulating one (BD1). Shrimp PL artificially challenged with BD1 and BD2 phylotypes with filtrates of tissue containing 0.423 X 109 copies of WSSV per mL resulted a median LT50 value of 73 hrs and 75 hrs, respectively. The in-vivo trial showed higher mean Log WSSV copies (6.47±2.07 per mg tissue) in BD1 challenged shrimp PL compared to BD2 (4.75±0.35 per mg tissue). Crabs infected with BD1 and BD2 showed 100% mortality within 48 hrs and 62 hrs of challenge, respectively with mean Log WSSV copies of 12.06±0.48 and 9.95±0.37 per gram tissue, respectively. Moreover, shrimp antimicrobial peptides (AMPs) penaeidin and lysozyme expression was lower in BD1 challenged group compared to BD2 challenged shrimps. These results collectively demonstrated that relative virulence properties of WSSV based on mortality rate, viral load and expression of host immune genes in artificially infected shrimp PL could be affected by single aa substitution in VP28.

Diabetes mellitus is a heterogeneous disease of complex etiology and pathogenesis. Hyperglycemia leads to many serious complications, but also directly initiates the process of β cell apoptosis. A potential strategy for the preservation of pancreatic β cells in diabetes may be to inhibit the implementation of pro-apoptotic pathways or to enhance the action of pancreatic protective factors. The HIPPO signaling pathway is proposed and selected as a target to manipulate the activity of its core proteins in therapy - basic research. MST1 and LATS2 as major upstream signaling kinases of the Hippo pathway are considered as target candidates for pharmacologically induced tissue regeneration and inhibition of apoptosis. Manipulating the activity of components of the HiPPO pathway offers a wide range of possibilities, and thus is a potential tool in the treatment of diabetes and the regeneration of β cells. Therefore, it is important to fully understand the processes involved in apoptosis in diabetic states and to fully characterize the role of this pathway in diabetes. Therapy consisting in slowing down or stopping the mechanisms of apoptosis may be an important direction of diabetes treatment shortly.

We aimed to evaluate the protective effects of acetyl-xylogalactan on the activity of RAW264.7 macrophages against heat stress. To this end, we assessed cell survival, phagocytic activity, in-tracellular Ca2+ level, mitochondria potential exchange, apoptotic assay findings, galactosidase activity and the RNA-seq by NGS and real-time polymerase chain reaction (PCR) expression. In our evaluation of macrophage morphology at 37°C and 41°C, the macrophages showed an oval shape at 41°C , unlike the spindle shape at 37°C. Therefore, 41°C was chosen as the heat stress condition. Subsequently, we designed an experiment to evaluate changes in the RAW264.7 macrophages after acetyl-xylogalactan treatment under heat stress. The survival of RAW264.7 macrophages treated with acetyl-xylogalactan was higher than that of controls that were not treated with acetyl-xylogalactan. Moreover, on the basis of the results of the annexin-V detection assay, the apoptotic activity of macrophages appeared to have reduced after treatment with ac-etyl-xylogalactan. Moreover, treatment with acetyl-xylogalactan resulted in a stronger recovery trend in the intracellular Ca2+ and mitochondrial membrane potential after heat stress. RNA sequencing and real-time polymerase chain reaction (PCR) illustrated that Sarcodia suieae acetyl-xylogalactan could upregulate the expression of the anti-apoptosis Cflar gene and down-regulate the expression of the apoptosis factors Ddit3, and Hyou1 to protect macrophages under heat stress.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma is possibly derived from nodal T-cell/histiocyte-rich large B-cell lymphoma; however, a transition between the nodal and splenic micronodular forms has not been described to date. Of note, the only lymph nodes to be involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes, and that, with partial involvement only. Kan et al, in their series of articles, have raised the possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations (apoptosis, necrosis, tissue shrinkage), which modify or even obscure the diagnostic morphological features. The indications for glucocorticoid therapy are either related to the suspected lymphoma, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic, rather than nodal subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved tissue, causing disparate morphologies in the spleen. Apoptosis, as induced by corticosteroids, is hypothesized as the major mechanism initiating the histopa-thological and functional changes in the splenic micronodular variant of our patients.

Calcineurin plays a key role in cardiovascular pathogenesis by exerting pro-apoptotic effects in cardiomyocytes; however, its involvement in the regulation of cardiomyocyte autophagy under chronic intermittent hypoxia (CIH) remains largely unknown. Here we showed that CIH induced calcineurin activity in H9C2 cells, resulting in the attenuation of adenosine monophos-phate-activated protein kinase (AMPK) signaling and inhibition of H9C2 cell autophagy. Au-tophagy, LC3-II levels, and AMPK phosphorylation were significantly elevated in response to CIH in H9C2 cells by day 3; however, these effects were reversed, and calcineurin activity and apoptosis were significantly increased by day 5. The calcineurin inhibitor, FK506, restored AMPK activation and LC3 protein levels, and reduced CIH-induced H9C2 cell apoptosis, while calcineurin overexpression significantly attenuated the increase in LC3 levels and enhanced H9C2 cell apop-tosis. Calcineurin inhibition failed to induce autophagy or alleviate apoptosis in H9C2 cells ex-pressing a dominant negative K45R AMPK mutant. Autophagy downregulation abrogated the protective effects of FK506-mediated calcineurin inhibition. These results indicated that calcineurin suppressed adaptive autophagy during CIH by downregulating AMPK activation. Our findings showed the underlying mechanisms of calcineurin and autophagy regulation during H9C2 cell survival in response to CIH, and suggested a new strategy for preventing CIH-induced cardiomyocyte damage.

Ischemic Stroke precedes depression . Post Stroke Depression (PSD) is a major driver for poor recovery, negative quality of life, poor rehabilitation outcomes and poor functional ability. This systematic reviews confirmed the post stroke depression as the norm as complex ischemic cascade involve the bioenergetic failure, deranged iron homeostasis ( calcium influx, Na influx, potassium efflux etc) excitotoxicity, acidotoxicity,disruption of the blood brain barrier, cytokine mediated cytotoxicity, reactive oxygen mediated toxicity , activation of cyclooxygenase pathway and generation of toxic products, infiltration of immune mediated cells resulting the cell death and deranged neuronal networks in mood related brain regions. This review focus on the pathobiology of stroke in the context and make the argument that PSD is the norm after a stroke rather than the exception.

Background and Aim: Pancreatic cancer (PC) is a highly aggressive malignancy associated with low survival rates. Many chemotherapeutic regimens have been investigated for advanced unresectable and metastatic PC, but with only minimal improvement in survival and prognosis. The present study aimed to investigate the anti-cancer function of free and nano-encapsulated hydroxytyrosol (Hyd) and curcumin (Cur), and its combinations (Hyd-Cur) on the PANC-1 cell line.Methods: The poly lactide-co-glycolide-co-polyacrylic acid (PLGA-co-PAA) nano-encapsulated Hyd and Cur were synthesized, and MTT assay was performed to evaluate cytotoxic effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur. Moreover, effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur were evaluated on viability, migration, morphological alterations, colony formation, and apoptosis on PANC-1 cell line. The mRNA expression levels of MMP2, MMP9, BAX, BCL-2, and Cas9 genes were assessed after treated PANC-1 cells with free and nano-encapsulated Hyd, Cur, and Hyd-Cur.Results: The obtained results showed that free and nano-encapsulated Hyd, Cur, and Hyd-Cur treatments significantly decreased the viability, migration, and colony formation in the PANC-1 cells. Furthermore, apoptosis rates in PANC-1 cells were increased in a concentration and time dependent manner in all of the treatment groups. Moreover, anti-proliferative activity of nano-encapsulated Hyd-Cur was significantly more than other treatments.Conclusion: According to our results, Hyd-Cur combination and nano-encapsulation therapy exerts more profound apoptotic and anti-proliferative effects on PANC-1 cell line than free Hyd or Hyd monotherapy.

The natural products and conventional chemotherapeutic drugs are believed to increase the cure rates of anti-cancer treatment while reducing their toxicity. The current study investigates the cytotoxic and apoptogenic effects of bioactive compounds from Monotheca buxifolia on Hep G2 cell lines. The effect on the viability of Hep G2 cells was evaluated by MTT assay; Morphological changes were studied, the apoptotic activity was demonstrated through Annexin-V-FITC/ PI, a molecular dynamics simulation study was conducted to explore the binding pattern of the compounds in the active site of the PPRAδ protein. The isolated compounds lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate inhibited the growth of hepatocellular cancer cells, as determined by MTT assay and annexin V-FITC/PI. The IC50 value for lauric acid was 56.4584 ± 1.20 µg/ml, that for oleanolic acid was 31.9421 ± 1.03 µg/ml, and that for bis(2-ethylhexyl) phthalate was 83.8019 ± 2.18 µg/ml. After 24 h of treatment, 29.5% of Hep G2 cells treated with lauric acid, 52.1% of those treated with oleanolic acid, and 22.4% of those treated with bis(2-ethylhexyl) phthalate were apoptotic. Morphological assay and Hoechst staining microscopy revealed the morphological alterations of cell membrane accompanied by nuclear condensation after treatment. The high fluctuation indicates the high potency and adopting various interactions, and vice versa, the oleanolic acid showed highly residues fluctuation, which remains stable in the active site of PPARδ protein and involved in various interactions while remaining locally fluctuated in the binding site the other two compounds. In conclusion, a significant apoptogenic effect was exhibited by lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate against HepG2 cells in inducing apoptosis. Our findings indicate that these bioactive compounds hold promise as potential therapeutic for hepatocellular carcinoma.

To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact on normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed to restore proteostasis, allowing cells to survival the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress and this condition could be exploited in a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

Breast cancer is the most common malignancies in women and the second leading cause of cancer death in women. Triple negative breast cancer (TNBC) subtype is a breast cancer subset without ER, PR and HER2 expression, limiting treatment options and presenting a poorer survival rate. Thus, we investigated whether HDACi would be used as potential anti-cancer therapy on breast cancer cells. In this study, we found TNBC and HER2-enrich breast cancers are extremely sensitive to Panobinostat, Belinostat of HDACi via experiments of cell viability assay, apoptotic marker identification and flow cytometry measurement. On the other hand, we developed a bioluminescence based live cell non-invasive apoptosis detection sensor (IADS) detection system to evaluate the quantitative and kinetic analyses of apoptotic cell death by HDAC treatment on breast cancer cells. In addition, the use of HDACi may also be accompanied with chemotherapeutic agent such as doxorubicin to synergic drug sensitivity on TNBC cell (MDA-MB-231), but not in breast normal epithelia cells (MCF-10A), providing therapeutic benefits against breast tumor in clinic.

Toll-like receptor 4 (TLR4) is a member of the TLR family. Members of the TLR family play an important role in innate immune responses and are induced by recognition of pathogen-associated molecular patterns. They are also involved in cell proliferation and apoptosis in cancer. We investigated the role of TLR4 in apoptotic cell death in gynecological cancer cells; gynecological cancer is associated with infertility and spontaneous abortion. To examine the effect of TLR4 activation on apoptotic signaling in cancer cells, cultured primary cancer cells were treated with the TLR4 agonist lipopolysaccharide (LPS). The morphology of cancer cells was compared with normal myometrial cells. Enhanced growth rate and loss of contact inhibition with cellular overlap was observed in the cancer cells. The molecular mechanism analysis revealed differential expression of tumor suppressor genes in LPS-treated cancer cells. The expression of apoptosis-related caspase-3 was increased significantly in cancer cells with TLR4 activation after exposure to LPS. Taken together, these results suggest the pro-apoptotic activity of TLR4 as a potential therapeutic target for the treatment of gynecological cancers.

: Since the COVID-19 pandemic, people have become aware that materials (products) can transmit infection and have begun to focus on questions such as how bacteria and germs, the sources of in-fection, maintain their infectivity on material surfaces, and the extent to which materials can or cannot prevent this. and to what extent materials can and cannot prevent it. The SIAA, a non-profit organization of many Japanese companies, had created an entirely separate interna-tional standard for materials' antibacterial, antiviral, and antibiofilm properties (products). The authors have studied the academic basis for the operation of the standards and were deeply in-volved as researchers in establishing one of the standards. This paper describes the interna-tional standards and some representative examples of the authors' actual use of these standards and explains the current status and future problems.

Abstract: In the last decade, gypsogenin has widely grabbed the attention of medicinal chemists by virtue of its prominent anti-cancer potential. Despite its late identification, gypsogenin proved itself as a new an-ti-proliferative player battling for a front position among other classic pentacyclic triterpenes such as oleanolic acid, glycyrrhetinic acid, ursolic acid, betulinic acid, and celastrol. Herein, we present insights into the anti-cancer activity of gypsogenin and its semisynthetic derivatives and go further by introducing our perspective to judiciously guide the prospect rational design. The present article opens a new venue for better exploitation of gypsogenin chemical entity as a lead compound in cancer chemotherapy. To the best of our knowledge, this is the first review article exploring the anti-cancer activity of gypsogenin derivatives.

The synthesis of the presented benzo[d]thiazol-2-amine derivatives was performed by condensing-(4-chlorobenzylidene) benzo[d]thiazol-2-amine with a number of substituted phenols in the presence of potassium iodide and anhydrous potassium carbonate in dry acetone. IR spectroscopy, 1HNMRspectroscopy and spectroscopy methods were used to characterize the structural properties of newly synthesized derivatives. In order to observe the attributes of drug-like candidates of these derivatives, the number of their molecular properties was estimated. Benzo[d]thiazol-2-amine derivatives were molecularly docked with selective enzymes COX-1 and COX-2. Findings suggested that Compounds G3, G4, G6, G8 and G11 possess higher binding affinity than diclofenac sodium, when docking was performed with enzyme COX-1. Compounds G1, G3, G6, G8and G10 showed lower binding affinity than Indomethacin when docking performed with enzyme COX-2.In vitro evaluation of the COX-1 and COX-2 enzyme inhibitory activities were performed for synthesized compounds. Compounds 10 and 11 exhibited significant COX-1 and COX- enzyme inhibitory action with IC50 values of 5.0 and 10 µM, respectively. Using the hot plate method and the carrageenan-induced rat paw edema model, the synthesized compounds were screened for their biological activities, including analgesic and anti-inflammatory activities. The highest analgesic action was exhibited by derivative G11and the compound G10 showed the highest anti-inflammatory response.

Polyacetylene phytochemicals are emerging as potentially responsible for the chemoprotective effects of consuming apiaceous vegetables. There is some evidence suggesting that polyacetylenes impact carcinogenesis by influencing a wide variety of signalling pathways, which are important in regulating inflammation, apoptosis, cell cycle regulation, etc. Studies have shown a correlation between human dietary intake of polyacetylene-rich vegetables with reduced risk of inflammation and cancer. Polyacetylene supplementation can influence cell growth, gene expression, and immunological responses, and reduce tumour number in rat and mouse models. Cancer chemoprevention by dietary polyacetylenes involves several mechanisms, including effects on inflammatory cytokines, the NF-κB pathway, antioxidant response elements, UPR pathway, growth factor signalling, cell cycle progression, and apoptosis. This review summarises the published research on falcarinol-type polyacetylene compounds and their mechanisms of action regarding cancer chemoprevention and treatment, and also identifies some gaps in our current understanding of the health benefits of these polyacetylenes.

： Anti-MDA5 antibody bearing (anti-MDA5+)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) &amp;/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD especially with regards to the mortality rate are unknown. We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Thirty-nine (55%) patients presented with DM/PM but 32 (45%) didn’t. Twenty-two of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among 32 patients who didn’t have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio [OR]=1.816, P=0.032), presence of anti-Ro-52 antibody (OR=1.676, P=0.018), elevated C-reactive protein (CRP, OR= 4.354, P&lt;0.001) and carcinoembryonic antigen (CEA, OR=2.625, P=0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p=0.009), CRP (p=0.001), CEA (p=0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR=0.245, P=0.017) and multivariate (OR= 0.058, P=0.036) regressions, indicating that they may be a protective factor from RPILD (OR= 0.543, P=0.008) or fatality (OR= 0.707, P=0.012), which was also demonstrated in subgroup analyses. In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might be conversely a protective factor in anti-MDA5+ patients.

Background: Antiphospholipid antibodies (aPL) are a laboratory criterion for the classification of antiphospholipid syndrome (APS), and are known to cause clinical symptoms: vascular thrombosis or obstetric complications. It is suggested that aPL may be associated with thromboembolism in severe COVID-19 cases. Aim: to combine clinical data with aPL findings at 4 time points (admission, worsening, discharge, 3-month follow-up) in patients hospitalized with COVID-19 pneumonia. Methods: current and past history of thrombosis and obstetric complications; aPL determined at 4 time points: anticardiolipin (aCL), anti-β2-glycoprotein I (anti- β2GPI) and antiphosphatidylserine/prothrombin (aPS/PT) of the IgM, IgG or IgA isotypes. Results: 111 patients with COVID-19 pneumonia were enrolled. During hospitalization, 7 patients died, 3 of them due to pulmonary artery thromboembolism (none was aPL positive). Only one of the five who developed pulmonary artery thrombosis was aPL positive. Of 9/101 patients with a history of thrombosis, 5 had arterial thrombosis and none was aPL positive at admission and follow-up; 4 had venous thrombosis and one was aPL positive at all time points (newly diagnosed APS). Of these 9/101 patients, 55.6% were transiently aPL positive at discharge only, compared to 26.1% without history of thrombosis (p=0.05). Conclusions: aPL were not associated with fatal outcomes and vascular thrombosis; aPL were transiently positive in more than half of patients with a history of thrombosis.

Cisplatin is a widely used anticancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas increased Bcl-2 expression. Moreover, in cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor interacting protein kinase (RIPK) and mixed lineage kinase domain like (MLKL) were identified. In vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted by co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anticancer adjuvant.

Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitates the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. Increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID downregulated and HRK upregulated on days 2 and 7, respectively. The data suggests that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide.

Ovarian cancer poses a significant therapeutic challenge owing to the lack of specific targets for treatment. New treatment strategies are needed to improve patient outcomes and reduce the toxicity of existing therapies. This study aimed to investigate the synergistic effects of recombi-nant human apurinic/apyrimidinic endonuclease 1/redox factor 1 (rhAPE1/Ref-1) and aspirin on PEO14 and CAOV-3 ovarian cancer cells and human umbilical vein endothelial cells (HUVECs). Specifically, this study examined the mechanisms underlying the effect of rhAPE1/Ref-1 and as-pirin on cell death and the associated pathways. Cell viability was assessed using the MTT assay, and flow cytometry analysis and caspase-3/7 activity assays were conducted to determine apop-tosis. Western blotting was performed to evaluate the cleavage of poly(ADP-ribose) polymerase (PARP). Exposure to aspirin (3 mM) for 24 h did not affect cell viability in PEO14. Co-incubation of aspirin with rhAPE1/Ref-1 in PEO14 cells led to rhAPE1/Ref-1 acetylation and intracellular hyperacetylation. Co-treatment with aspirin (3 mM) and rhAPE1/Ref-1 induced a rhAPE1/Ref-1 concentration-dependent increase in cell death, particularly in PEO14 cells, as well as apoptosis, caspase-3/7 activation, and PARP cleavage. Furthermore, this combination treatment significantly increased paclitaxel-induced PEO14 cell death. Therefore, co-administration with rhAPE1/Ref-1 and aspirin is a potential strategy for ovarian cancer treatment.

There is an urgent need to develop new therapies for cancer treatment due to high rates of resistance and tumor relapse. Moreover, chemotherapy and radiation weaken the immune system and leave patients susceptible to sudden death from infections and organ failure since antineoplastic drugs lack specificity. Hence, scientists worldwide continue the search for natural alternatives with anticancer activities and fewer side effects. In this regard, traditional medicine offers strategies for preventing and treating numerous diseases and nowadays scientific studies worldwide highlight some of the mechanisms underlying their potential as an effective alternative for the management of cancer. In Mexico, Mayan healers have been prescribed mainly medicinal plants for more than 2,000 years. Furthermore, their ethnomedical knowledge has led to drug discovery or the development of herbal remedies. Medicinal plants from the genus of Cissus remain an important element of all indigenous medical systems in Mexico including the Mayan tribes in Yucatan, particularly for the management of gastrointestinal illnesses, sores, cutaneous diseases, and tumors. In this review, we present the reported bioactivities against cancer cells of the extract and compounds from the species of Cissus with a particular focus on recent studies on the phytochemistry of C. trifoliata which is widely distributed in Mexican territory and used for tumor management in traditional medicine.

High-temperature cooking process like frying, baking, smoking, or drying can induce chemical transformations in conventional food ingredients, causing deteriorative modifications. These reactions, including hydrolytic, oxidative, and thermal changes, are a common occurrence and can result in alterations to the food's chemical composition. In this study, a combination of sucrose and histidine (Su-Hi) was transformed through a process of charring or pyrolysis. The GC-MS profiling study showed that when sucrose and histidine (Su-Hi) are exposed to high temperatures (≈240°C), they produce carbonyl and aromatic compounds including beta-D-Glucopyranose, 1,6-anhydro (10.11 %), 2-Butanone, 4,4-dimethoxy- (12.89 %), 2(1H)-Quinolinone-hydrazine (5.73%), Benzenamine (6.35%), 2,5-Pyrrolidinedione, 1-[(3,4-dimethylbenzoyl)oxy]- (5.82%), Benzene-(1-ethyl-1-propenyl) (5.62%), and 4-Pyridinamine-2,6-dimethyl (5.52%). The compounds mentioned have the ability to permeate the cell membrane and contribute to the development of cell death by necrosis in human immune cells. The evidence available suggests that a specific set of pyrolytic compounds may pose a risk to immune cells. This investigation reveals the complex relationship between high-temperature cooking-induced transformations, compound permeation inside the cells, and downstream cellular responses, emphasizing the significance of considering the broader health implications of food chemical contaminants.

Chrysin, a flavonoid compound, has attracted interest as a therapeutic agent due to its anti-inflammatory, antidiabetic, antidepressant, and particularly its anticancer properties. Although studies have presented findings regarding the anticancer properties of chrysin, research on its molecular mechanisms of action remains largely insufficient. This research aimed to deeply investigate chrysin's effects on the breast cancer cell line, MDA-MB-231, in terms of proliferation, invasion, colony formation, and apoptosis. The XTT test results confirmed chrysin's cytotoxic effect on MDA-MB-231 cells, indicating a 48-hour IC50 value of 115.77 µM. Chrysin induced apoptosis in cells, as evidenced by Annexin V assay, and also reduced their colony-forming and invasion. Gene expression analyses showed elevated levels of APC, AXIN1, AXIN2, GSK3A, GSK3B, CK1α, CTNNB1, as well as apoptosis-related genes CASP3, -7, -9, and BAX. This increase was corroborated by the observed rise in protein levels of caspase 3/7 and GSK3B. Moreover, molecular docking results showed that chrysin interacted with genes in the WNT/β-catenin pathway and exhibited drug-like ADME properties. In conclusion, chrysin exhibits potential anticancer effects against MDA-MB-231 cells. It is hoped that these findings will advance preclinical and clinical studies on chrysin's potential in breast cancer treatment.

Licochalcone H (LCH), a regioisomer of licochalcone C derived from the root of Glycyrrhiza inflata. CRC treatment has always been challenged by the development of resistance. We investigated the antiproliferative activity of LCH in oxaliplatin (Ox)-sensitive and -resistant CRC cells. LCH significantly inhibited cell viability and colony growth in both Ox-sensitive and Ox-resistant CRC cells. We found that LCH decreased epidermal growth factor receptor (EGFR) and AKT kinase activities and related activating signaling proteins including phospho (p)-EGFR and pAKT. A computational docking model indicated that LCH may interact with EGFR, AKT1, and AKT2 at the ATP-binding sites. LCH induced ROS generation, as verified by N-acetyl-L-cysteine (NAC) treatment, and increased the expression of the ER stress markers. LCH treatment of CRC cells induced depolarization of MMP and increased. Multi-caspase activity was induced by LCH treatment and confirmed by Z-VAD-FMK treatment. LCH increased the number of subG1 cells and arrested the cell cycle at the G1 phase. LCH inhibits the growth of Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, and inducing ROS generation and ER stress-mediated apoptosis. Therefore, LCH could be a potential therapeutic agent for improving not only Ox-sensitive but also Ox-resistant CRC treatment.

Background: In trials using normofractionated regimen, the radiation-induced lymphocyte apoptosis (RILA) and the chromosomal damage assays (CDA) have shown prognostic roles of radiation-induced adverse events. The main objectives here were to validate RILA and CDA in extreme and moderate hypofractionation regimens for breast (FAST) and prostate (CHHiP) cancers. Methods: Blood samples were collected from 400 volunteers included in FAST and CHHiP trials. The primary endpoints (PE) were first change in photographic breast appearance and first grade ≥2 RTOG bladder or bowel toxicity (BBT) in FAST and CHHiP, respectively. The secondary endpoints was first grade ≥2 breast clinical changes (BCC) in FAST and BBT using different scales in CHHiP. Results: 103 FAST and 297 CHHiP patients with lab and clinical data were included. In FAST trial, no significant association of RILA with the primary endpoint was observed. A significant association of higher RILA levels with lower risk of any RIAE was found. The risk of developing grade ≥2 RIAE decreased significantly for patients with RILA≥24% compared to those with RILA≤16% with a HR of 0.50 (95%CI 0.25-1.00, p=0.012). Concerning chromosomic aberrations, no significant associations were found with change in photographic breast appearance nor with the secondary endpoint of any RIAE. In CHHiP trial, a decreased risk of grade≥2 RTOG bladder or bowel RIAE was observed for increasing values of RILA (HR 0.97, 95%CI 0.94-1.01, p=0.11) but did not reach statistical significance. Concerning chromosomic aberrations, we found significant association of higher levels of micronuclei per cell with lower risk of gr2+ RTOGAE (p=0.021 for trend test across tertiles; p=0.023 for upper vs lower tertile). Conclusions: This study is the first to evaluate RILA and CDA as predictors of late effects after breast and prostate RT in the “hypofractionation” era. Development of toxicity biomarkers whatever the RT fractionation are urgently needed.

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.

The voltage-gated potassium channel KV1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of KV1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency, and selectivity of the new KV1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective KV1.3 inhibitor 44 in the series with an IC50 value of 470 nM in oocytes and 950 nM in Ltk cells. Kv1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an an-ti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP had an anti-cancer effect against the CRC cell lines HCT116, and DLD-1, SW480 and COLO320DM with IC50 values of 7.88 nM, and 8.22 nM, 9.84 nM and 7.757 nM, respec-tively induction of DNA damage. Colonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either alone, suggesting that APP sensitizes CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Apoptosis is associated with numerous phenotypical characteristics, and is thus studied with many tools. In this study, we compared two broadly used apoptotic assays: TUNEL and staining with an antibody targeting the activated form of an effector caspase. To compare them, we developed a protocol based on commonly used tools such as filters, zprojection and thresholding. Even though it is commonly used in imageprocessing protocols, thresholding remains a recurring problem. Here we analyzed the impact of processing parameters and readout choice on the accuracy of apoptotic signal quantification. Our results show that TUNEL is quite robust, even if image processing parameters can allow or not to detect subtle differences of the apoptotic rate. On the contrary, images from anticleaved caspase staining are more sensitive to handle and proved to necessitate to be processed more carefully. We then developed an open source Fiji macro automatizing most steps of the image processing and quantification protocol. It is noteworthy that the field of application of this macro is wider than apoptosis as it can perfectly be used to treat and quantify other kind of images.

Diffuse large B cell lymphoma (DLBCL), the most frequent type of non-Hodgkin lymphoma in adulthood, remains challenging clinical issues. Despite enhanced remission rates can be achieved, there are one-third of patients who will not respond to current treatment or will relapse with resistant disease, necessitating ongoing efforts on effective treatment strategies and agents. The vacuole H+-ATPase inhibitor bafilomycin A1 is broadly used to block late stage of autophagy flux at high concentration. In this study, we show that, to our surprise, bafilomycin A1 effectively inhibited and killed DLBCL cells at nanomolar concentrations (5nM). Bafilomycin A1 targeted cell cycle regulators cyclin D1 and cyclin E2 to induce cell cycle arrest in G0/G1 phase. Meanwhile, it induced caspase-dependent apoptosis with concomitant cleaved caspase-3 and Parp. Furthermore, we found that bafilomycin A1 inhibited autophagy flux at both early and late stages of the autophagy flux through activating ERK and mammalian target of rapamycin signaling, as well as by inhibiting the degradation of autolysosomes. We speculated that bafilomycin A1 as autophagy inhibitor might enhance the effect of DLBCL chemotherapeutic drug rituximab. Accordingly, our results provided evidence that the combination of bafilomycin A1 with rituximab enhanced the inhibition of DLBCL cells notably. Taken together, our data suggest that bafilomycin A1 may be a promising candidate drug in the therapy of diffuse large B cell lymphoma.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus considered as a threat to human health due to large epidemics and serious clinical outcomes such as microcephaly in newborns. Like all flaviviruses, ZIKV relies on the cellular machinery to complete its viral cycle, with the endoplasmic reticulum (ER) being the critical site of viral replication factories. The sudden high protein load in the ER induces an ER stress to which the cell responds with an appropriate unfolded protein response (UPR) in an attempt to restore its disturbed homeostasis. When the restoration fails, the cell signaling leads to a programmed cell death by apoptosis with the upregulation of the UPR-induced C/EBP homologous protein (CHOP) which acts as the main trigger for this fatal outcome. Our previous studies have shown the ability of ZIKV to manipulate various cellular responses in order to optimize virus production. ZIKV is able to delay apoptosis to its benefit and although ER stress is induced, the UPR is not complete. Here we discovered that ZIKV impairs the expression of CHOP/DDIT3, the main factor responsible of ER-stress driven apoptosis. Surprisingly, the mechanism does not take place at the transcriptional level but at the translational level.

Ovarian cancer is the common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, the frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic roles remain unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on autophagic and apoptotic pathway regulation in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using the MTT and colony formation assay in SK-OV-3. The results of tissue microarray showed that PKM2 expression positively correlated with the severity of the tumor. Moreover, the expression of pro-apoptotic proteins increased in SK-OV-3 following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by the inhibition of mTOR. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation in SK-OV-3. Compound 3K treatment suppressed tumor progression in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected Warburg effects and induced autophagic cell death. Therefore, the use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.

7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural origin (Tussilago farfara)has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. Neuropathic pain was induced in mice by PSNL surgery performed on day 1 and ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose dependent manner. ECN significantly reversed the severity of neuropathic pain by improving distress symptoms and survival rate. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, anti-neuropathic potential of ECN might be due to inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.

Parkinson’s disease (PD) is a neurodegenerative disease that progresses with increasing age and some of its major symptoms include tremor, postural and movement related difficulties. Till date, the treatment of PD remains a challenge because available drugs only treat the symptoms of the disease or possess serious side effects. In light of this, new treatment options are needed, hence this study investigates the neuroprotective effects of an organic Boophone haemanthoides extract (BHE) and its bioactive compounds using an in vitro model of PD involving the toxin 1-methyl-4-phenylpyridinium (MPP+) and SH-SY5Y neuroblastoma cells. A total of seven compounds were isolated from BHE viz: distichamine (1), 1α,3α-diacetylnerbowdine (2), hippadine (3), stigmast-4-ene-3, 6-dione (4), cholest-4-en-3-one (5), tyrosol (6), and 3-hydroxy-1-(4`-hydroxyphenyl)-1-propanone (7). Six compounds (1, 2, 4, 5, 6, 7) were investigated and five showed neuroprotection alongside the BHE. This study gives insight into the bioactivity of the non-alkaloidal constituents of Amaryllidaceae since the isolated compounds and the BHE showed improved cell viability, increased ATP generation in the cells as well as inhibition of MPP+-induced apoptosis. Together, these findings support the claim that the Amaryllidaceae plant family could be a potential reserve of bioactive compounds for the discovery of neuroprotective agents.

Hizikia fusiformis is a common, edible marine alga found in Asia. Although the anticancer activity of its extracts has previously been investigated, its active compounds have not been identified. In this study, saringosterol acetate (SA) was isolated from H. fusiformis extracts by centrifugal partition chromatography (CPC) system (two phase solvents condition: n-hexane:ethyl acetate/methanol:water = 5:3:7:1, v/v), exhibited anticancer effects in the human lung adenocarcinoma epithelial cell line, A549, by inducing apoptosis and sub-G1 phase cell cycle arrest. In addition, SA increased the expression of the pro-apoptotic proteins, Bax and cleaved caspase 3, and decreased that of the anti-apoptotic protein Bcl-xL. Although, SA did not affect the expression of p53, induces expression of Bid and caspase 8. In conclusion, we suggested that SA induces apoptosis against A549 cells via Bid and caspase 8 dependent pathway.

Helicobacter pylori is a common human pathogen that causes gastroduodenal diseases. H. pylori genome consists of numerous restriction-modification (R-M) genes. It is established that N6-adenine methylation plays a crucial role in bacterial gene regulation and virulence, but not much is known about the role of C5-cytosine methylation. In this study, we examined the influence of an orphan cytosine methyltransferase, hpyAVIBM on gastric infection in mice and cultured cells. Histopathological staining showed that the deletion of hpyAVIBM in H. pylori strain SS1 had increased damaging hemorrhagic effects on the mice stomach. The gelatin-zymography result demonstrated that the mice infected with mutant SS1ΔhpyAVIBM had significantly up-regulated pro-MMP-9 than those infected with SS1. Additionally, ELISA results of pro-inflammatory cytokines proved that mutant strain caused significantly more inflammatory effect on mice stomach than its wild-type counterpart. The immunohistochemistry data showed that mutant strain caused attenuated epithelial cell damage. Co-culture studies of H. pylori with AGS (Human Gastric Adenocarcinoma cell line) cells revealed that SS1ΔhpyAVIBM instigated significantly more apoptotic death in the AGS cells compared to the wild-type strain. Our results indicated that DNA methylation by hpyAVIBM plays a crucial role in modulating virulence factors in bacterial cells and their interaction with the host cells.

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S-phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the transformation of ribonucleotides into deoxyribonucleotides, a rate limiting step in DNA synthesis. HU is listed as an essential medicine by the World Health Organization. Several studies have indicated that HU is well tolerated and safe in pregnant women and very young pediatric patients. To our knowledge, only a few controlled studies about the adverse effects of HU therapy have been done in humans. Despite this, the prevalence of central nervous system abnormalities, including ischemic lesions and stenosis have been reported. This review will summarize and present the effects of HU-exposure on the prenatal and perinatal development of the rat cerebellar cortex and deep cerebellar nuclei neurons. Our results call for the necessity to better understand HU effects and define the administration of this drug to gestating women and young pediatric patients.

As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl- 2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silybin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, a 17- to 52-fold improvement in potency as compared with silybin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

The toxic effects of 4-octylphenol (4-OP) have been studied in species such as mouse and fish; however, the toxic effects of 4-OP in male specific niche cells has not been researched. In this study, we investigated the molecular mechanism of toxicity of 4-OP in mouse TM4 Sertoli cells. TM4 cells were treated with four concentrations (0, 10, 30, and 50 µM/mL) of 4-OP at time points 24, 48, and 72 h. Cell viability and apoptosis assay was conducted following exposure. 4-OP significantly decreased cell viability in a concentration- and time-dependent manner, and increased apoptosis. Quantitative PCR analysis showed that Bad, Bax, and Bak mRNA expression levels were higher in exposed cells than in the control, but Bcl-2 expression was decreased. Western blotting revealed that 4-OP induced activities of caspase-3 and phosphorylation of Bad in a concentration- and time-dependent manner. Additionally, cytochrome C protein did not colocalize with mitochondria marker dye by 24 h. Cytochrome c protein expression increased in a time-dependent manner with 50 µM/mL. These results suggest that 4-OP induces mitochondria-mediated apoptosis by regulation of Bcl-2 family proteins and caspase-3 activation in male Sertoli cells.

Hepatitis C virus (HCV) represents a challenging global health threat in ~200 million infected individuals. Clinical data suggests that only ~10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts a myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence that includes, but not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here, we discussed a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.

Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhiza bunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and a reduction in angiogenesis. We further investigated the anti-cancer effects of CTT in A549 and H460 which are NSCLC cell lines. CTT treatment in NSCLC cells reduced cell growth through PI3K/Akt/GSK3β pathway inhibition, G0 / G1 cell cycle arrest, and the activation of apoptosis. CTT induced increase of Bax and cleavage of apoptosis-related signaling such as caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of anti-apoptosis related signaling such as Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. In addition, CTT reduced the protein expression of the PI3K/Akt/GSK3β signaling pathway related to cell proliferation. These results highlight the latent potential of CTT as natural therapeutic agent for NSCLC.

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

Background and Objectives: Age-related macular degeneration (AMD) is one of the major causes of central vision loss in the older age group and its dry form accounts for the majority of cases. Although several causes and mechanisms for the development and progression of AMD have previously been identified, the pathogenesis of this complex disease is still not entirely understood. As the inflammation and involvement of the immune system are strongly suggested to have a central role to promote the degenerative process and to stimulate the onset of complications, we aimed to analyze the prevalence of serum anti-retinal (ARA) and anti-endothelial cell antibodies (AECA) in patients with dry AMD and to determine their relationship with the clinical features of the disease, notably area of geographic atrophy (GA). Materials and Methods: We enrolled 41 patients with dry AMD and 50 sex- and age-matched healthy controls without AMD. The presence of ARA was determined by indirect immunofluorescence using monkey retina as an antigen substrate, while the presence of AECA was determined using cultivated human umbilical vein endothelial cells and primate skeletal muscle. Results: ARA were detected 36 (87.8%) AMD patients (titers range from 1:20 to 1:320) and in 16 (39.0%) (titers range from 1:10 to 1:40) of controls (p=0.0000). Twenty of the 41 patients (48.8%) were positive for AECA, while in a control group AECA were present only in 5 sera (10.0%). The titers of AECA in AMD patients ranged from 1:100 to 1:1000 and in the control group the AECA titers were 1:100 (p=0.0001). There were no significant correlations between the presence of AECA and disease activity. Conclusions: This study provides evidence for the possible involvement of an autoimmune process against retina and retinal vessel antigens in the pathogenesis of geographic atrophy associated with dry AMD.

The West-African variety of Sorghum bicolor leaf sheath (SBLS) Jobelyn® is a natural remedy, which has gained international recognition for its anti-anemic effect and energy boosting qualities in debilitating diseases. The widespread use of traditional medicine in the region usually confirms its safety, but not its efficacy or deep assessment of their pharmacological properties. The other major issue for herbal-based treatments is the lack of definite and complete information about the composition of the extracts. Despite limitations, efforts have been made in isolation and characterisation of active compounds in this specie of sorghum showing various subclasses of flavonoids including apigeninidin, a stable 3-deoxyanthocyanidin and potential fungal growth inhibitor, which accounts for 84% of the total extract. Non-clinical in vitro and in vivo studies support previous indications that this variety of Sorghum bicolor possesses several biologically active compounds with potent antioxidant, anti-inflammatory, anti-aging and neuro-protective properties. Clinical studies show that SBLS has the ability to boost hemoglobin concentrations in anemic conditions and most remarkably to increase CD4 count in HIV-positive patients. The multiple effects and high safety profiles of this extract may encourage its development as a therapeutic agent for the treatment of anemia, chronic inflammatory conditions or in the symptomatic management of HIV infections. This review describes the potential therapeutic aspects of SBLS extract and its potential benefits.

Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declined responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Here we review evidence from animal models and clinical studies that supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing macrophage activation are critically involved in arteriolar CNV formation and anti-VEGF resistance. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.

Background The evolution of treatment patterns in neovascular age-related macular degeneration (nAMD) warrants investigation into the impact of patients’ adherence to anti-vascular endothelial growth factor (VEGF) treatment on visual outcomes. This retrospective, non-randomized, non-comparative study aimed to investigate real-world adherence to anti-VEGF treatment. Methods Patients (eyes) (≥ 50 years) with a diagnosis of nAMD who had a first injection of aflibercept or ranibizumab between January 2016 and December 2018 and 12 months of follow-up were included. Visual acuity (VA; logarithm of the minimum angle of resolution letters) and duration of injection intervals were recorded. Adherence was defined as < 20% of visits deviating from the schedule by ≥ 14 days. Results Overall, 133 patient eyes were included: 129 adherent, 4 non-adherent. Mean (± standard deviation) baseline VA was 57.0 (± 23.6) and 53.8 (± 35.3) letters in adherent and non-adherent patient eyes, respectively. Mean change in VA by month 12 was higher in adherent (6.3 letters) than non-adherent patient eyes (−11 letters). In non-adherent patient eyes, no improvement in VA was recorded following completion of the loading period (month 3). Compared with the previous visit, adherent visits were associated with a mean increase in VA of 0.67 letters and non-adherent visits with a decrease of 2.30 letters. Conclusions These results emphasize the importance of adherence to appropriate dosing regimens to optimize visual outcomes in patients with nAMD.

Bangladeshi medicinal plants (BMP) have been used as traditional medicinal plants to treat chronic inflammatory diseases, but the antioxidant and anti-inflammatory effects of the bark of BMP are not yet known. The objective of this study was to determine antioxidant and anti-inflammatory activities using methanolic extracts of bark obtained from 15 medicinal spices of Bangladesh plants. The bark methanol extracts of BMP evaluated the total antioxidant activity and anti-inflammatory effect of lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages. Among the 15 bark extracts of BMP, Albizia odoratissima (A. odoratissima), Engelhardia spicata (E. spicata), and Shorea robusta (S. robusta) showed the highest total phenolic contents and total antioxidant capacity by reducing free radicals scavenging activity. In particular, the three bark extracts significantly reduced the mRNA expression of LPS-induced inflammatory cytokines and inflammation-inducible enzymes in macrophages. Also, the mRNA expression of NADPH oxidase 2 was significantly suppressed by three bark extracts in LPS-induced RAW 264.7 macrophages. The results suggest that among the 15 bark extracts obtained from medicinal plant in Bangladesh, three bark extracts of A. odoratissima, E. spicata, and S. robusta exert total antioxidant capacity by reducing free radicals scavenging activity and inhibitory effects on LPS-stimulated inflammation in macrophages.

Two-dimensional (2D) ice I is an atomic-level ice that is composed of two interlocked atom-ic layers saturated with hydrogen bonds. It has recently been experimentally observed but its properties have yet to be clarified. Accordingly, we theoretically studied the hydrophobic properties of 2D ice I. On the contrary, simulation of a hydrogen fluoride molecule on a 2D ice surface manifested that it destroyed the 2d ice structure and connected new hydrogen bonds with water molecules. Investigations of the interfacial effect between 2D and three-dimensional (3D) ice films indicated that the network structure of 2D ice was not de-stroyed by a 3D ice surface, as the former was saturated with hydrogen bonds. However, the surface of 3D ice reorganized to form as many hydrogen bonds as possible. Thus, the 2D ice film was hydrophobic and inhibited the growth of 3D ice. This shows that if 2D ice can be produced on an industrial scale, it could be used as an anti-3D-icing agent under low tem-perature.

This work is based on identifying the analysis techniques used to evaluate the antioxidant and anti-inflammatory effects using the zebrafish model. In this context, a literature review was performed with the Web of Science database. We used the terms zebra fish, antioxidant, anti-inflammatory, model, and Danio rerio. Fifty articles were reviewed, of which thirty-three were chosen to perform this review and were classified according to the source of plant extracts, compounds extracted from plants, chemical compounds, and other sources. This paper is an effort to provide a literature review on zebrafish models and elucidate their pros and cons to evaluate anti-inflamatory and antioxidant activity.

The purpose of this scoping review was to examine the literature on the use of anti-gravity treadmill and its effects on lower limb motor functions in children and adolescents with locomotor impairments. Four databases (MEDLINE, CINAHL, Embase, Web of Science) were searched for articles from inception to August 2021. Inclusion criteria were: (1) experimental or quasi-experimental studies using the anti-gravity training as the primary intervention; (2) studies conducted in paediatricpediatric participants; (3) articles reporting outcomes related to the lower limb functions; and (4) studies published in French or English. Fifteen articles were included in the review. Studies included children and adolescents aged 4–18 years with locomotor impairments. The intervention duration was ranged from 2 and to 12 weeks, with 2-5 sessions per week. Included studies showed reported that anti-gravity training induces improvements in muscle strength, balance, spatiotemporal gait parameters, and walking endurance in children with locomotor impairments. This review provides relevant information about the modalities, outcomes and limits associated with the anti-gravity training protocol reported in the literature. Overall, the anti-gravity treadmill training could be viewed as a valuable training modality for children with cerebral palsy. However, more precise, and comprehensive description of anti-gravity rehabilitation protocols would be useful.

Acquired Immunodeficiency Syndrome (AIDS) which is chiefly originated by a retrovirus named Human Immunodeficiency Virus (HIV), has influenced about 70 million populations worldwide. Even though several advancements have been invented in the field of antiretroviral combination therapy, still HIV has become the dominant reason for death in South Africa, for example. The current antiretroviral therapies have achieved success in providing instant HIV suppression but with countless undesirable adverse effects. In the present day, the biodiversity of the plant kingdom is being explored by several researchers for the discovery of potent anti-HIV drugs with different mechanisms of action. The primary challenge is to afford a treatment that is free from any sort of risk of drug resistance and serious side effects. Hence, there is a strong demand to evaluate the drugs obtained from natural plants as well as the synthetic derivatives that have been derived from the natural compounds by various chemical reactions. Several plants such as Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia and others have displayed significant anti-HIV activity showing more potent anti-HIV activity along with their structures, SARs & important key findings.

As the time passes the modification in technology world lead to the evaluation in mobile application as well. With evaluation in mobile industry it is an open challenge for software quality researcher that how to enhance software quality to meet the needs of changes? Quality assurance play a key role in differentiating good application from bed application. With the continuous evaluation of mobile application developing process should be quick and efficient to comply with user requirements and satisfaction. While the listed requirement leads to bad design choices known as antipatterns, which in turn affect the reliability of the code. A tool based method PAPRIKA is used in the proposed re-search to identify and monitor these antipatterns together with a two-step assessment model for software quality assurance and object oriented software quality matrix.

The iridoids of H. diffusa play an important role in the anti-inflammatory process, but the specific iridoid with anti-inflammatory effect and its mechanism is lack of study. An iridoid compound named scandoside (SCA) was isolated from H. diffusa and its anti-inflammatory effect was investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Its anti-inflammatory mechanism was confirmed by in intro experiment and molecular docking analysis. As results, SCA significantly decreased the productions of nitric oxide (NO), prostaglandin E₂ (PGE₂), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and inhibited the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 mRNA expression in LPS-induced RAW 264.7 cells. SCA treatment suppressed the phosphorylation of inhibitor of nuclear transcription factor kappa-B alpaha (IκB-α), p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). The docking data suggested that SCA had great binding abilities to COX-2, iNOS and IκB. Taken together, the results indicated that the anti-inflammatory effect of SCA is due to inhibition of pro-inflammatory cytokines and mediators via suppressing the nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, which provided useful information for its application and development.

In vitro studies show that diclofenac inhibits enzymatic steroid glucuronidation. This study was designed to investigate the influence of diclofenac on the excretion of stanozolol and 3'-hydroxystanozolol via analyses in hair, blood and urine in vivo in a rat study. Brown Norway rats were administered with stanozolol (weeks 1-3) and diclofenac (weeks 1-6). Weekly assessment of steroid levels in hair was complemented with spot urine and serum tests. Levels of both stanozolol and 3'-hydroxystanozolol steadily increased in hair during stanozolol treatment and decreased post-treatment, but remained readily detectable for 6 weeks. In contrast, compared to control rats, diclofenac significantly reduced urinary excretion of 3’-hydroxystanozolol which was undetectable in most samples. This is the first report of diclofenac altering steroid metabolism in vivo, detrimentally affecting detection in urine, but not in hair which holds considerable advantages over urinalysis for anti-doping tests.

Background and Objectives: In the current Covid-19 pandemic, children below the age of 12 could manifest Covid-19 symptoms and serve as a reservoir for the virus in the community. The present study was conducted to evaluate the reactogenicity, and immunogenicity of BBIBP-CorV, prior to involving this age group in the vaccination program in the kingdom of Bahrain. Subjects and Methods: The study included 582 children from 3 to 12 years old of Bahraini and non-Bahraini nationality, all of which contributed to the reactogenicity study. Of those, 401 contributed to the immunogenicity study. All children received 2 doses of BBIBP-CorV inactivated virus 3 weeks apart. To assess reactogenicity, children were followed up for 5 weeks to evaluate any vaccine-related adverse events (AE). To assess immunogenicity, blood was collected on day 0 and day 35 to assess antibody titer against S, N, and neutralizing antibody. Results: Of the 582 participants, (45.4%) were female, (54.61%) were male, with 49% in 9-12 age group. Of the 401 children contributing to the immunogenicity study, 274 (68.3%) had no prior exposure to Covid-19. The overall incidence of AE was 27.7%. No significant difference was found among different age groups. The most frequent AE was local (at the injection site) and occurred in 16% of children, followed by fever in 9.3%. No serious adverse events were reported. The Seroconversion rate was 100% among children with no prior exposure to Covid-19. Children with previous Covid-19 exposure had higher averages of anti-S (2379 U/ml compared to 409.1), anti-N (177.6 U/ml compared to 30.9) and neutralizing antibody (93.7 U/ml compared to 77.1) than children with no prior exposure at day 35. Conclusions: Two doses of COVID-19 BBIBP-CorV on the subjects aged between 3 to 12 has good safety and tolerance and can induce an effective immune response and neutralizing antibody titer.

The simplistic morphological characteristics of the Carica papaya, papaya or ‘pawpaw’ should not be the cause for underestimating its potential as a nutraceutical. The market for papaya has been expanding at a staggering rate, partly due to its applicability as a biofortified product, but mostly for its phytochemical properties and traditional health benefits. Recent characterization studies have showed that the entirety of papaya or using a formulation of fermented papaya promotion (FPP) displays effective free radical scavenging abilities, thought to be influenced by its phenolic, carotenoids, flavonoid or amino acid profile. Aiming at reducing the impact of free radical-induced oxidative damage in the human system, the antioxidant properties of FPP have been found to potently target a broad spectrum of diseases ranging from neurological impairments such as senile dementia to systemic diseases, to its interference at the cellular level and support of normal biological ageing processes. FPP has thus been extensively investigated for its ability to exert cellular protective effects and reduce oxidative stress via mitigation of genetic damage, lipid peroxidation and enzymatic inactivation in diseases. Oxidative stress reduction strategies using FPP and its holistic approach in disease prevention and management, with a focus on diabetes, cancer and cognitive health, contributes unequivocally to wellness in an aging population.

To investigate the associated mechanisms concerning collagen and the expression of apoptosis-related proteins in porcine skin injuries induced by laser exposure, pig skin was treated with a 1064 nm laser. The healing process of the laser-treated areas, alterations in collagen structure, and changes in apoptosis were continuously observed and analyzed from 6 hours to 28 days post-irradiation. On the 28th day following exposure, wound contraction and recovery were notably sluggish in the medium-high dose groups, displaying more premature and delicate type III collagen within the newly regenerated tissues. The collagen density in these groups was roughly 37-58% of that in the normal group. Between days 14 and 28 after irradiation, there was a substantial rise in apoptotic cell count in the forming epidermis and granulation tissue of the medium-high dose group, in contrast to the normal group. Notably, the expression of proapoptotic proteins bax, caspase-3, and caspase-9 surged significantly 14 days after irradiation in the medium-high dose groups and persisted at elevated levels on the 28th day. During the later stage of wound healing, the augmented apoptotic cell population and insufficient collagen generation in the newborn skin tissue of the medium-high dose groups were closely associated with delayed wound recovery.

This theoretical study presents a novel perspective on the potential anti-inflammatory properties of Bromelain, a natural agent extracted from pineapple stems. The investigation explores the binding capabilities of Bromelain to Apoptosis-associated speck-like containing CARD (ASC), a crucial adapter molecule known for its involvement in inflammatory processes and inflammasome formation. For the first time, these findings suggest that Bromelain exhibits a notable affinity for ASC, indicating its promising role as a natural anti-inflammatory agent. This study sheds light on the molecular interactions that may contribute to Bromelain's therapeutic potential in modulating inflammatory responses.

The Fas associated Death Domain (FADD) is an adaptor protein that predominantly transduces apoptosis signal from death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator in inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of cellular dynamics of FADD in regulating of programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

Serelaxin (RLX), the recombinant form of human Relaxin-2 hormone, protects the heart from the ischemia/reperfusion (I/R)-induced damage due to its anti-inflammatory, anti-apoptotic and antioxidant properties. RLX exerts its actions by binding to its specific RXFP1 receptor whereby it regulates multiple cellular transduction pathways. In this in vitro study we offer first evidence for the involvement of AMP kinase/Sirtuin1 (AMPK/SIRT1) pathway in the protection afforded by RLX against H/R-induced damage in H9c2 cells. Treatment of the H/R-exposed cells with RLX (17 nmol L−1) enhanced SIRT1 expression and activity. Inhibition of SIRT1 signaling with EX527 (10 µmol L-1) reduced the beneficial effect of the hormone on mitochondrial efficiency and cell apoptosis. Moreover, RLX upregulated AMPK pathway, as shown by the increase in the expression of phospho-AMPK active protein. Finally, AMPK pathway inhibition by Compound C (10 and 20 μmol L−1) abrogated the increase in SIRT1 expression induced by RLX, thus suggesting the involvement of AMPK pathway in this effect of RLX. The results of this study strengthen the concept that RLX exerts its cardioprotective effects against H/R-induced injury by multiple pathways which also include AMPK/SIRT1.

Abstract Background: Gastric cancer, particularly adenocarcinoma, is a significant global health concern. Environmental risk factors, such as Helicobacter pylori infection and diet, play a role in its development. Purpose: This study aimed to characterize the chemical composition and evaluate the in vitro antibacterial and antitumor activities of AOME. Additionally, morphological changes in gastric cancer cell lines were analyzed. Study design: AOME was analyzed using HPLC-MS/MS and its antibacterial activity against H. pylori was assessed using the broth microdilution method. MIC and MBC values were determined, and positive and negative controls were included in the evaluation. Methods: Anticancer effects were assessed through in vitro experiments using AGS, KATO-III, and SNU-1 cancer cell lines. The morphological changes were examined through SEM and TEM analyses. Results: AOME contained several compounds, including caffeic acid, rutin, and hyperoside. The extract displayed significant antimicrobial effects against H. pylori, with consistent MIC and MBC values of 3.70 ± 0.09 mg/mL. AOME reduced cell viability in all gastric cancer cell in a dose and time-dependent manner. Morphological analyses revealed significant ultrastructural changes in all tumor cells lines, suggesting the occurrence of cellular apoptosis. Conclusions: This study demonstrated that AOME possesses antimicrobial activity against H. pylori and potent antineoplastic properties in gastric cancer cell lines. AOME holds promise as a natural resource for innovative nutraceutical approaches in gastric cancer management. Further research and in vivo studies are warranted to validate its potential clinical applications.

Metabolic bone diseases cover a broad spectrum of disorders that share alterations of bone metabolism leading to a defective skeleton, associated with increasing morbidity, disability, and mortality. There is a close connection between the etiology of metabolic bone diseases and genetic factors, being TP53 one of the genes associated therewith. The single nucleotide polymorphism (SNP) Arg72Pro of TP53 is a genetic factor associated with several pathologies, including cancer, stroke and osteoporosis. Here, we aim to analyze the influence of the TP53 Arg72Pro SNP on bone mass in the humanized Tp53 Arg72Pro knock-in mice. This work reported on the influence of TP53 Arg72Pro polymorphism in bone microarchitecture, OPG gene expression and apoptosis bone status. The results showed that the proline variant of TP53 Arg72Pro polymorphism (Pro72-p53) was associated with deteriorated bone tissue, lower OPG/RANK ratio and lower apoptosis in bone tissue. In conclusion, the TP53 Arg72Pro polymorphism modulates bone microarchitecture and may be a genetic biomarker to identify individuals with an increased risk of suffering metabolic bone alterations

This review provides information on acne transcriptomics allowing deeper insights into acne pathogenesis and isotretinoin´s mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). Western diet (hyperglycemic carbohydrates, milk/dairy products) as well co-stimulate AKT/mTORC1 signaling. AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch, which enhances the transactivation of lipogenic and proinflammatory transcription factors including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ), and signal transducer and activator of transcription 3 (STAT3) but reduces FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor of infundibular keratinocyte homeostasis. AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in sebaceous glands of acne patients. Overexpression of these proapoptotic transcription factors explains isotretinoin´s desired sebum-suppressive effect via induction of sebocyte apoptosis but also its adverse effects including teratogenicity (neural crest cell apoptosis), reduced ovarian reserve (granulosa cell apoptosis), risk of depression (apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.

The prevalent pathogens associated with bovine uterine infections are bacteria that appear to increase the host's susceptibility to secondary infections with other bacteria or viruses, among which BoHV-4 is the most frequently found. In this work, the study of the pathways of apoptosis induction was carried out on an experimental model of primary culture of endometrial cells, in order to know the implication of BoHV-4 and the presence of bacterial LPS in the pathogenesis of the bovine reproductive tract. For this, different staining techniques and molecular analysis by RT-PCR were used. The results obtained allowed us to conclude that the level of cell death observed in the proposed primary culture is directly related to the time of viral infection and the presence of LPS in BoHV-4 infection. The apoptosis indices in cells infected with BoHV-4, BoHV-4 + LPS presented a maximum that correlates with the appearance of the cytopathic effect, and the maximum viral titers in the model studied. However, morphological, biochemical and molecular changes were evident during both early and late stages of apoptosis. These findings provide information on the factors that may influence the pathogenesis of BoHV-4 and help to better understand the mechanisms involved in virus infection.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models, and in vitro 3-dimensional bioengineering models of Rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Epithelial cells can undergo apoptosis by manipulating the balance between pro-survival and apoptotic signals. In this work, we show that TRAIL-induced apoptosis can be differentially regulated by the expression of α(1,6)fucosyltransferase (FucT-8), the only enzyme in mammals that transfers the (1,6)fucose residue to the pentasaccharide core of complex N-glycans. Specifically, in the cellular model of colorectal cancer (CRC) progression formed using the human syngeneic lines SW480 and SW620, knockdown of the FucT-8-encoding FUT8 gene significantly enhanced TRAIL-induced apoptosis in SW480 cells. However, FUT8 repression did not affect SW620 cells, which suggests that core fucosylation differentiates TRAIL-sensitive premetastatic SW480 cells from TRAIL-resistant metastatic SW620 cells. In this regard, we provide evidence that phosphorylation of ERK1/2 kinases can dynamically regulate TRAIL-dependent apoptosis and that core fucosylation can control the ERK/MAPK pro-survival pathway in which SW480 and SW620 cells participate. Moreover, the depletion of core fucosylation sensitises primary tumour SW480 cells to the combination of TRAIL and low doses of 5-FU, oxaliplatin, irinotecan or mitomycin C. In contrast, combination of TRAIL and oxaliplatin, irinotecan or bevacizumab reinforces resistance of FUT8-knockdown metastatic SW620 cells to apoptosis. Consequently, FucT-8 could be a plausible target for increasing apoptosis and drug response in early CRC.

The induction of macrophage death is regarded as a potential mechanism by which components secreted by Clostridium septicum are used to evade the innate immune response and cause tissue damage. This study aimed to determine the effect of partially purified fractions of extracellular proteins secreted by C. septicum on the death of mouse peritoneal macrophages. Elicited mouse peritoneal macrophages were incubated with partially purified fractions of proteins secreted by C. septicum into culture medium. After incubation, we found that the protein fraction with a molecular weight ≥ 100 kDa caused significant cell death in macrophages, changed cell morphology, increased markers of apoptosis and autophagy, and increased the expression (protein and mRNA) of IL-1 and TNFα. Our data suggest that the proteins secreted by C. septicum (MW ≥100kDa) induce cell death in macrophages by promoting autophagy-triggered apoptosis. This may contribute to our understanding of the molecular mechanism of immune evasion by C. septicum at the infection site.

Chickpea is an essential legume, a staple food in many cultures and contains nutrients with potential health benefits. The chickpea water (CPW) leached out after cooking is usually discarded, which may potentially have significant anti-cancer and other health beneficial properties. This study compared the in-vitro bioactivity of CPW with chickpea polyphenol extract (CPPE) to evaluate its impact on pathways of colorectal cancer progression and development. Morphological observation by APOPercentage, cell viability detection using a cytotoxic assay and cell migration-scratch assay points to measure rate of metastasis were employed. Overall antioxidant activity of CPW and CPPE were measured using ABTS and DPPH free-radical assays. At 50 µg/mL concentration and above, both CPW and CPPE extracts significantly reduce cell viability in HT-29 colon cancer cell lines (p < 0.05). Moreover, a quantitative analysis of the extent of apoptosis demonstrated that at 250 and 500 μg/mL concentrations, both extracts induced significant apoptosis compared to the untreated control. Meanwhile, the cell migration scratch area decreases by 34.42% and 15.27% when treated with CPW and CPPE, respectively. In summary, CPW demonstrated comparable in vitro anti-cancer properties and antioxidant activity in colorectal cancer cells to CPPE. Further, in vivo studies are warranted to evaluate the physiological bioactivity of CPW and CPPE in targeting pathways of cancer development and progression

Ovarian cancer (OC) is the most lethal gynecologic malignancy. Cannabis sativa is being used to treat different medical conditions. We sought to examine the effectiveness of combinations of cannabis compounds against OC. Cytotoxic activity was determined by XTT assay on HTB75 and HTB161 cell lines. Apoptosis and cell cycle were determined by fluorescence-activated cell sorting (FACS). Gene expression was determined by quantitative PCR. The two most active fractions, F5 and F7, from a high Δ9–tetrahydrocannabinol (THC) cannabis strain extract and their standard mix (SM) showed cytotoxic activity against OC cells. The most effective phytocannabinoid combination was THC+cannabichromene (CBC)+cannabigerol (CBG). F5, F7 and SM affected cell cycle, led to cell apoptosis and to a marked reduction in cell migration. Moreover, these fractions act in synergy with niraparib, and were ~50 fold more cytotoxic to OC cells than to normal keratenocytes. Niraparib+F7 treatment was effective on OC patient's cells. F7 and the niraparin+fraction (F5 and F7) treatments reduced Mitogen-Activated Protein Kinase 4 (MAPK4) gene expression; this reduction may act in synergy with the niraparib inhibition of Poly (ADP-ribose) polymerase 1 (PARP1) activity. Combinations of cannabis compounds and niraparib should be examined for efficacy in pre-clinical studies and clinical trials.

Vision is our primary sense as the human eye is the gateway for more than 65% of information reaching the human brain. Today’s increased exposure to different wavelengths and intensities of light from Light Emitting Diodes (LEDs) sources could induce retinal degeneration and accompanying neuronal cell death. Damage induced by chronic phototoxic reactions occurring in the retina accumulates over years and it has been suggested to be responsible for the etiology of many debilitating ocular conditions. In this work, we examined how LED stimulation affects vision by monitoring changes in the expression of death and survival factors as well as microglial activation in LED-induced damage (LID) of the retinal tissue. We found an LED exposure-induced increase in the mRNA levels of major apoptosis-related markers -BAX, Bcl-2, and Caspase-3 and an accompanying wide-spread microglial and Caspase-3 activation. Everyday LED light exposure was accounted for all the described changes in the retinal tissue of mice in this study, indicating that overuse of non-filtered direct LED light can have detrimental effects on the human retina as well.

Gastric cancer, also known as stomach cancer, is a cancer which develops from the lining of the stomach. Accumulated evidences and epidemiological studies have been indicated that natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action did not elucidate yet. Particularly, experimental studies have been showed that natural products displayed a protective effect against gastric cancer via numerous molecular mechanisms such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Although chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy and immunotherapy, but its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. Additionally, intake of naturally occurring phytochemicals could increase the efficacy of gastric chemotherapy and chemotherapeutics resistance. However, natural product structural stability and powerful bioactivity are important to develop novel treatments for gastric cancer that may minimize such adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural products on prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

GPR4, a member of proton activated GPCRs group. Previously we have reported that GPR4 is constitutively active at physiological pH and knockout of GPR4 has shown to protect dopaminergic neuronal cells from caspase-dependent mitochondrial apoptotic cell death. In this study we have investigated the role of GPR4 in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treated mice model of Parkinson’s disease. Subchronic administration of MPTP in mice produces oxidative stress induced apoptotic cell death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and motor deficits. Treatment with NE52-QQ57, a selective antagonist of GPR4 reduced dopaminergic neuronal loss MPTP-intoxicated C57BL6/J mice and improved motor deficit and memory impairment. Co-treatment with NE52-QQ57 significantly decreases the protein level of proapoptotic marker (Bax), and increases the antiapoptotic marker (Bcl-2) in the SNpc and striatum tissue collected from the brain of MPTP inflicted mice. Further, MPTP induced activation of caspase 3 and cleavage of poly (ADP-ribose) polymerase (PARP) was significantly decreased in the SNpc and striatum tissue of NE52-QQ57 cotreated mice. Further mice receiving both MPTP and NE52-QQ57 mice showed significantly higher TH positive cells in the SNpc and striatum than MPTP treated mice alone. Moreover, NE52-QQ57 cotreatment improved the motor activity in the rotarod test and pole test and also improved spatial memory in Y maze test. Our findings suggest GPR4 as a potential therapeutic target for PD whereas the activation GPR4 is involved in the caspase mediated apoptotic cell death in SNpc and striatum of MPTP-intoxicated mice.

Background: Interleukin (IL)-33 is a member of interleukin (IL)-1 family of cytokines which has been linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has direct effect on human gastric epithelial cells (GES-1) and on human gastric adenocarcinoma cell line (AGS) and gastric carcinoma cell line (NCI-N87), assessing its role in regulation of cell proliferation and cell cycle, apoptosis and necrosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Methods: cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assay, we also evaluated apoptosis by Caspase 3/8 Activity assay and Annexin V assays. Cell cycle were analyzed by means of Propidium Iodine assay and gene expression regulation was assessed by RT-PCR Profiling. Results: we found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell line, while it can stimulate proliferation and reduce apoptosis in normal epithelial cell line. These effects are also confirmed by the analysis of cell cycle gene expression which showed a reduced expression of proproliferative genes in cancer cells, in particular genes involved in G0/G1 and G2/M checkpoint. These results are confirmed by the gene expression analysis on surgical and bioptic specimens. Conclusions: the aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell type-dependent fashion.

The aim of this study was to investigate the possible role of 99mTc-sestamibi in the regulation of cancer cell proliferation and apoptosis. To this end, Te in vivo values of 99mTc-sestamibi uptake have been associated to the in-situ expression of both Ki67 and caspase-3. For in vitro investiga-tions BT-474 cells were incubated with three different concentration of 99mTc-sestamibi: 10µg/ml –1µg/ml – 0,1µg/ml. Expression of caspase-3 and Ki67, as well as the ultrastructure of cancer cells, were evaluated at T0 and after 24, 48, 72 and 120 hours after 99mTc-sestamibi incubation. Ex vivo data strengthened the known association between the sestamibi uptake and the Ki67 expression. Linear regression analysis showed a significant association between the sestamibi uptake and the number of apoptotic cells evaluated as caspase-3 positive breast cancer cells. As concern the in vitro data, a significant decrease of the proliferation index was observed in breast cancer cells incubated with high concentration of 99mTc-sestamibi (10µg/ml). Amazingly, a significant increase in caspase-3 positive cells in cultures incubated with 10µg/ml 99mTc-sestamibi was observed. This study suggested the possible role of sestamibi in the regulation of pathophysiological process involved in breast cancer.

: Annona squamosa L. is an important medicinal plant used in traditional medicine for the treatment of various diseases. Different parts of A. squamosa L. have various therapeutic effects; however, the anticancer activity of the leaves has not yet been identified. In vitro, MTT, nuclear staining, and LDH assays were used to evaluate cell survival and proliferation in cells exposed to the extracts. The effect of the extracts on cell migration was investigated using a monolayer wound repair assay, and the apoptotic effects were evaluated using flow cytometry. A breast cancer model was used to study the effect of the extract on the tumor size, and the expression of different proliferative and apoptotic markers was evaluated by immunohistochemical analysis. At a concentration of 100 µg/mL, A. squamosa leaf extracts exerted strong antiproliferative and cytotoxic effects against various cell lines. The extracts reduced wound closure and strongly induced apoptosis. In vivo study, rats were sacrificed 24 h after the last injection, and tumor size, as well as the expression of proliferative and apoptotic markers, were observed to be greatly affected by treatment with the extracts. Therefore, A. squamosa leaf extract may be developed as a potential novel drug to treat breast cancer in the future

The probiotic bacterial strain Lactobacillus plantarum ZS2058 has been proved to manifest comprehensive functions, which were due to ability to synthesise conjugated fatty acids (CFAs). To investigate the specific functions of CFAs produced by this probiotic bacterium, α-linolenic acid was isomerized by Lactobacillus plantarum strain ZS2058, and two different conjugated α-linolenic acid (CLNA) isomers were successfully isolated. These isoforms, CLNA1 (c9, t11, c15-CLNA, purity 97.48%) and CLNA2 (c9, t11, t15-CLNA, purity 99.00%), both showed the ability to inhibit the growth of three types of colon cancer cells in a time- and concentration-dependent manner. In addition, the expression of MDA in Caco-2 cells was increased by CLNA1 or CLNA2, which indicated lipid peroxidation was related to the antiproliferation activity of CLNAs. Examination of the key protein of pyroptosis showed that CLNA1 induced the cleavage of caspase-1 and gasdermin-D, while CLNA2 induced the cleavage of caspase-4, 5 and gasdermin-D. The addition of relative inhibitors could alleviate the pyroptosis by CLNAs. CLNA1 and CLNA2 showed no effect on caspase-3, 7, 9 and PARP-1, which were key proteins associated with apoptosis. And no sub-diploid apoptotic peak appeared in the result of PI single staining test. In conclusion, CLNA1 activated caspase-1 and induced Caco-2 cell pyroptosis, whereas CLNA2 induced pyroptosis through the caspase-4/5-mediated pathway. The inhibition of Caco-2 cells by the two isomers was not related to apoptosis. This is the first report showing the ability of CLNAs to activate antioxidant defenses resulting in pyroptosis.

Relapsed leukemia following initial therapeutic response and remission is difficult to treat and causes high patient mortality. Leukemia relapse is due to residual quiescent leukemia cells that escape conventional therapies and later reemerge. Eliminating not only growing but quiescent leukemia cells is critical to effectively treating leukemia and preventing its recurrence. Such therapeutic agents, however, are lacking in the clinic. Here we report that a 4-arylmethyl derivative of the natural anticancer compound curcumin demonstrates a dual effect in eliminating both growing and quiescent leukemia cells. This curcumin derivative, C212, on the one hand, inhibits growing leukemia cells at a higher efficacy than curcumin by inducing apoptosis and cell cycle arrest; it, on the other hand, kills quiescent leukemia cells that are resistant to conventional chemotherapy drugs. Furthermore, C212 drives leukemia cells into and kills them at deep quiescence, avoiding the potential risk associated with awaking therapy-resistant subpopulation of quiescent leukemia cells. Lastly, we show that C212 induces apoptosis and drives cells into deep dormancy at least partially by binding to and inhibiting Hsp90, leading to client protein degradation and protein aggregation. Further elucidating the molecular mechanisms underlying the dual function of C212 in eliminating both growing and quiescent leukemia cells will aid the development of novel therapies against leukemia relapse.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

In this study, bioactive compounds present in chestnut shells (CS) - derived from the industrial peeling processing - were extracted through different procedures. The aqueous extracts were characterized and the highest extraction yield and total phenolic content was obtained by Conventional Liquid Extraction (CLE). Gallic and protocatechuic acids were the main simple phenols in the extract with 86.97 and 11.20 mg/g chestnut shells dry extract (CSDE), respectively. Six tumor cell lines (DU 145, PC-3, LNCaP, MDA-MB-231, MCF-7 and Hep G2) and one normal prostate epithelial cell line (PNT2) were exposed to increasing concentration of CSDE (1-100 µg/mL) for 24 h and cell viability was evaluated using MTT assay. A reduced rate in cell viability was observed in DU 145, PC-3, LNCaP and MCF-7 cells while viability of MDA-MB-231 and Hep G2 cells was not affected except for PNT2 cells at a concentration of 100 µg/mL. Furthermore, CSDE-at concentrations of 55.5 and 100 µg/mL- lead to a significant increase of apoptotic cells in DU 145 cells of 28.2% and 61%, respectively. In conclusion, our findings showed that CS might be used for the extraction of several polyphenols that may represent good candidates for alternative therapies or in combination with current chemotherapeutics.

Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

Natural product especially secondary metabolites that produced by plants under the stressed condition shown to have a different pharmacological impact. Aeluropus lagopoides is one of the typical halophyte plants survivals under stressed conditions. It has been used for wound healing and as a painkiller. The bioactivity and the chemical composition of this plant have poorly investigated. Consequently, chemical components of A. lagopoides leaves were extracted using hexane (nonpolar), ethyl acetate (semi-polar), n-butanol (polar) to extract the most extensive variety of metabolites. The cytotoxicity and anticancer impact of extracted secondary metabolites evaluated against breast (MCF-7), colon (HCT-116), and liver (HepG2) cancer cell lines using SRB test. The mechanism of action verified by observing the appearance of apoptotic bodies using the fluorescent microscope while their antiproliferative impact had been evaluated using flow cytometer. Results revealed that secondary metabolites extracted using hexane and ethyl acetate were having the highest cytotoxicity and thus anticancer activity effect on HepG2 with IC₅₀ (24.29 ± 0.85, 11.22 ± 0.679 µg/mL) respectively. Where apoptotic bodies observed, flow cytometer results exhibited that secondary metabolites can inhibit cell cycle in G0/G1 phase. Accordingly, A. lagopoides hexane and ethyl acetate extracts may consider as a candidate anti-cancer drug.

Though Moracin D derived from Morus alba was known to have anti-inflammatory and antioxidant activities, the underlying antitumor mechanism of Moracin D was never unveiled so far. Thus, in the recent study, the apoptotic mechanism of Moracin D was elucidated in breast cancer cells. Herein, Moracin D exerted significant cytotoxicity in MDA-MB231 and MCF7 cells. Also, Moracin D increased sub G1 population, cleaved poly (ADP-ribose) polymerase (PARP) and attenuated the expression of pro-cysteine aspartyl-specific protease (procaspase 3), c-Myc, cyclin D1, B-cell lymphoma 2 (Bcl-2),and X-linked inhibitor of apoptosis protein (XIAP) in MDA-MB231 cells. Of note, Moracin D reduced expression of Forkhead box M1 (FOXM1), β-catenin, Wnt3a, and upregulated glycogen synthase kinase 3 beta (GSK 3β) on Tyr216 along with disturbed binding of FOXM1 with β-catenin in MDA-MB-231 cells. Conversely, GSK3β inhibitor SB216763 reversed the apoptotic ability of Moracin D to reduce expression of FOXM1, β-catenin, pro-caspase3 and pro-PARP in MDA-MB-231 cells. Overall, these findings provide novel insight that Moracin D inhibits proliferation and induces apoptosis via suppression of Wnt3a/FOXM1/β-catenin signaling and activation of caspase and GSK3β

Aims TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employing combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. Method A549 and HCC-15 cells were used in experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay were carried out to evaluate the autophagy. MTP and ROS activity were evaluated by JC-1 and H₂DCFDA staining. Findings Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. Significance Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

Both fibrosis and cirrhosis of the liver are the end results of most kinds of chronic liver damage and present a common but difficult clinical challenge throughout the world. The inhibition of the fibrogenic, proliferative, and migratory effects of hepatic stellate cells (HSCs) has become an experimental therapy for preventing and even reversing hepatic fibrosis. Furthermore, a complete understanding of the function of non-coding RNA-mediated epigenetic mechanisms in HSC activation may improve our perception of liver fibrosis pathogenesis. This review focuses on an evolving view of molecular mechanisms in which HSC activation by miR-29a signaling may moderate their profibrogenic phenotype, thus supporting the use of miR-29a agonists as a potential therapy for treating liver fibrosis in the future.

Research into the causes of neurotoxicity in Alzheimer’s Dementia (AD) has focused on neurofibrillary tangles and beta amyloid (Aβ) plaques. This paper proposes the heterodox theory that these hallmarks of AD are the visible effects, not direct causes of neuronal necrosis. Rather AD results from a combination of age-induced, disproportional decline in physiological support for aerobic metabolism, and dysregulation of the sleep cycle processes. The hypothesis is that the decimation of neurons in AD results from a combination of neurotoxicity and increased apoptosis caused by: 1. direct damage from toxic waste products of anaerobic glycolysis due to a progressive decline in the capacity of neurons to perform oxidative phosphorylation (OXPHOS) and an increased reliance on anaerobic glycolysis to meet metabolic needs; 2. impaired cellular repair and effluent release due to dysregulation of non-rapid eye movement (NREM) sleep allowing damage to cell membranes and synaptic junctions to accumulate inducing a chronic inflammatory response; 3. indirect damage from products produced by inflammatory reaction to toxic metabolites; 4. neuronal apoptosis from the AβPP-mediated pathway due to the age-induced decline of growth hormone (GH), GH-releasing hormone (GHRH) and insulin-like growth factor (IGF).

Traumatic brain injury (TBI) can result in persistent sensorimotor and cognitive deficits, which occur through a cascade of deleterious pathophysiological events over time. In this study, we investigated the hypothesis that neurodegeneration caused by TBI leads to impairments in sensorimotor function. TBI induces the activation of the caspase-3 enzyme, which triggers cell apoptosis in an in vivo model of fluid percussion injury (FPI). We analyzed caspase-3 mediated apoptosis by TUNEL staining and PARP and annexin V western blotting. We correlated the neurodegeneration with sensorimotor deficits by conducting the animal behavioral tests including grid walk, balance beam, inverted screen test, and climb test. Our study demonstrated that the excess cell death or neurodegeneration correlated with the neuronal dysfunction and sensorimotor impairments associated with TBI.

We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), and U87 (human glioblastoma) cells. The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA (at 100 µg/mL) increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87 cells, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, and Bax expression. OA-treated DU145 cells were arrested in G2 because of the activation of p-ERK and p21, and the decrease in cyclin B1 and cyclin E expression. Furthermore, OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin E, and CDK2. U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p21, and p27, and the decrease in CDK2. Thus, OA arrests the cell cycle in different phases, and increases apoptosis in cancer cells. These results suggest that OA may alter the expression of cell cycle regulatory proteins in a cancer type-dependent manner.

The plethora of bio-functional compounds present in fermented alcoholic beverages like wine, as well as the valorization of bioactives from their wineries/breweries by-products like grape pomace and grape seed, has gained significant interest in the functional foods sector. Wine has always accompanied humanity, for religion or for health. For example, Christians are using wine in the “Holy Communion”, following what Jesus Christ himself did and said during the Last Supper, while the benefits of the wine consumption in moderation was embedded in all Mediterranean civilizations, as it is mentioned by the wise King-Prophet David in his psalms, but also by Hip-pocrates and other wise men, in a Greek-based philosophy of “All things in Moderation” (Cleobulus of Lindos; 6th century BC). In modern times, and after the outbreak of research on wine benefits since the 90’s, when the term “French Paradox” was introduced in the US public during a CBS show, recent evidence has outlined that these benefits are derived by the synergisms of its bio-functional compounds and their digestion-derived metabolites. Within this article, the proposed health benefits of moderate wine consumption, as a functional component of a balanced diet (i.e. the Mediterra-nean Diet), against inflammation-related chronic disorders, is thoroughly reviewed. The various bio-functional compounds of both wine and wineries’ by-products, such as their bioactive phe-nolics, unsaturated fatty acids, polar lipids, and dietary fibers, and their functional antioxidant, anti-inflammatory and antithrombotic health promoting properties are also thoroughly evaluated. The mechanisms of actions and synergism, by which the health benefits are elicited, are also ex-plored. Functional properties of non-alcoholic wine products are also introduced. Emphasis is also given to applications of wineries’ by-products bioactives, as ingredients of bio-functional foods, supplements and nutraceuticals. Limitations and future perspectives for this popular functional alcoholic beverage (wine) ant its rich in bioactives by-products are also addressed. .

Lactococcus lactis subsp. cremoris C60 is a probiotic strain of lactic acid bacteria (LAB) which induces various immune modifications in myeloid lineage cells. These modifications subsequently reg-ulate T cell function, resulting in enhanced immunity both locally and systemically. Here, we report that C60 suppresses tumor growth by enhancing macrophage function via metabolic al-terations, thereby increasing adenosine triphosphate (ATP) production in a murine melanoma model. Intragastric (i.g.) administration of C60 significantly reduced tumor volume compared to saline administration in mice. The anti-tumor function of intratumor (IT) macrophage was up-regulated in mice administered with C60, as evidenced by an increased inflammatory phenotype (M1) rather than an anti-inflammatory/reparative (M2) phenotype, along with enhanced anti-gen-presenting ability, resulting in increased tumor antigen-specific CD8+ T cells. Through this functional modification, we identified that C60 establishes a glycolysis-dominant metabolism, rather than fatty acid oxidation (FAO), in IT macrophages, leading to increased intracellular ATP levels. To address the question of why orally supplemented C60 exhibits functions in distal places, we found a possibility that bacterial cell wall components, which could be distributed throughout the body from the gut, may induce stimulatory signals in peripheral macrophages via Toll-like receptors (TLRs) signaling activation. Thus, C60 strengthens macrophage anti-tumor immunity by promoting a predominant metabolic shift towards glycolysis upon TLR-mediated stimulation, thereby increasing substantial energy production.

Abstract Background: Periodontitis is associated with systemic chronic inflammatory diseases. There is limited evidence on the influence of anti-cytokine therapies on the periodontal condition and microbiome in the tooth pocket of such patients, so the aim of this study was to elucidate this issue. Methods: In this observational trial, the periodontal status and the gingival crevicular fluid of 13 patients with different chronic inflammatory diseases were obtained before initiation of anti-cytokine treatment and 14 weeks after. Gingival crevicular fluid was collected for 16S rRNA gene sequencing from a clinically healthy tooth and the deepest measured pocket. Results: In participants with advanced attachment loss at baseline, the clinical attachment level significantly decreased from 2.9 (2.3-3.4) to 2.4 (1.3-3.0) mm (p = 0.04), and the bleeding- on-probing index dropped from 19.4 (10.0-21.0) to 7.3 (6.9-9.9) mm (p = 0.02) without any further periodontal treatment. Shannon’s diversity index significantly increased in the deepest pockets of patients (p = 0.039). Conclusion: The data showed alterations in diversity of the subgingival microbiome and improvement of periodontal parameters over the course of the study, implying a shift towards a healthier condition after starting anti-cytokine therapy. Additional investigations are needed to analyze whether the administration of selective biologicals can improve periodontal conditions in patients with or without chronic inflammatory diseases.

A rare neurological condition known as Dyke-Davidoff-Masson syndrome (DDMS) is characterized by cerebral hemiatrophy, facial asymmetry, contralateral motor impairment, and seizures. Cerebral hypoplasia, ventriculomegaly, paranasal sinus hyper-pneumatization, and compensatory osseous expansion are classic imaging findings. The relationship between clinical and neuroimaging findings provides the basis for the diagnosis of DDMS. DDMS is treated with anticonvulsant medication and physical therapy. This is the case of a 26-year-old male, with a known case of cerebral palsy and on antiepileptics for 15 years, who presented with complaints of generalized weakness, vomiting, difficulty walking, recurrent convulsions, and a recent episode of generalized tonic-clonic seizures. Neuroimaging revealed findings significant of Dyke Davidoff Masson Syndrome. Understanding its imaging and clinical characteristics facilitates prompt and precise diagnosis, permitting appropriate management.

Since ancient times, various scientists and doctors have utilized different herbs to heal diseases. Due to the rise in drug resistance and the negative effects of chemosynthetic drugs, researchers and the general public around the world have become more interested in medicinal herbs and plant metabolites/extracts. This is due to its non-toxicity and several health benefits when used to treat diseases in clinical and medical settings. Ocimum basilicum is one such plant, possessing a wide range of bioactive phytochemicals including alkaloids, phenolics, flavonoids, tannins, saponins, reducing sugars, cardiac glycosides, steroids and glycosides, as well as complex pharmacological activities including anti-inflammatory, antifungal, antibacterial, antioxidant, wound healing and antiviral properties. The results of many studies on Ocimum basilicum plant extracts are collected and presented in this review. The plant extracts have an excellent potential to be used as medicinal raw materials and exhibit an extensive variety of therapeutic capacities, including antibacterial, antioxidant, wound healing, anti-inflammatory, antifungal, and antiviral properties.

Inflammation is natural protective response of the body tissue caused by various stimuli. Macrophages start and control the inflammatory response. Microalgae have high value of ingredients including carotenoids which are well known for anti-inflammatory properties and used for various products in functional food industries. A green microalgal, Tetraselmis species contains a various type of carotenoids such as lutein, violaxanthin, astaxanthin, fucoxanthin, α-carotene and β-carotene. Therefore, we studied whether carotenoids isolated from Tetraselmis sp. with different culture conditions in Raw 264.7 cells and zebrafish (Danio rerio) have an anti -inflammatory effect. Carotenoid extracts of natural seawater (NS) and magma seawater (MS) showed inhibitory activity of nitric oxide (NO) overproduction without toxicity. In addition, carotenoid extracts of NS and MS inhibited pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)- 1β and IL-6. Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, which are inflammatory mediators also decreased by pretreatment of NS and MS. Carotenoid extracts of NS and MS pretreatment also reduced phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kB (NF-kB). In conclusion, the carotenoid extract of Tetraselmis sp. has an anti -inflammatory effect and can be potential industrial ingredient.

A series of pyrazolopyrimidines derivatives 4– 11 were synthesized using 1-(6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)-1H-pyrazolo [3,4-d] pyrimidin-4-amine 3 as a starting material. The detailed synthesis, structure assignments of the novel compounds based on chemical and spectroscopic evidence, spectroscopic data, pharmacological properties and molecular docking are reported. The pharmacological evaluation illustrated that many of these compounds have good analgesic, anti-inflammatory and antimicrobial activities.

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 may to some extent exacerbate every other kind of age-related damage. 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 a method of removing it from single cells in vitro.