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THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) accounts for about 90% of all head and neck cancers, the prognosis is very poor, and there are no effective targeted therapies. Herein, we isolated Machilin D (Mach), a lignin, from the roots of Saururus chinensis (S. chinensis) and assessed its inhibitory effects on OSCC. Herein, Mach had significant cytotoxicity against human OSCC cells and showed inhibitory effects against cell adhesion, migration, and invasion by inhibiting adhesion molecules, including the FAK/Src pathway. Mach suppressed the PI3K/AKT/mTOR/p70S6K pathway and MAPKs, leading to apoptotic cell death. We investigated other modes of programmed cell death in these cells and found that Mach increased LC3I/II and Beclin1 and decreased p62, leading to autophagosomes, and suppressed the necroptosis-regulatory proteins RIP1 and MLKL. Our findings provide evidence that the inhibitory effects of Mach against human YD-10B OSCC cells are related to the promotion of apoptosis and autophagy and inhibition of necroptosis and are mediated via focal adhesion molecules. [ABSTRACT FROM AUTHOR]

The altered expression of microRNA (miRNA) has been implicated in glioma. Here, the current study aimed to clarify the oncogenic effects of miR-19b-3p on cellular processes of glioma and to elucidate the underlying mechanism associated with SOCS3 and the JAK-STAT signaling pathway. Differentially expressed genes related to glioma were initially identified via microarray analysis. Twenty-five glioma patients were selected for clinical data collection, while additional 12 patients with traumatic brain injuries were selected as controls. Cell senescence was assessed by β-galactosidase staining, proliferation by MTT assay and apoptosis by flow cytometry following gain- and/or loss-of-function of miR-19b-3p or SOCS3. Glioma xenograft mouse model was developed through subcutaneous injection to nude mice to provide evidence in vivo. The glioma patients exhibited overexpressed miR-19b-3p and poorly-expressed SOCS3. SOCS3 was identified as a target gene of miR-19b-3p through dual-luciferase reporter gene assay. miR-19b-3p repressed SOCS3 expression and activated the JAK-STAT signaling pathway. Furthermore, miR-19b-3p inhibition promoted apoptosis and senescence, and suppressed cell proliferation through inactivation of the JAK-STAT signaling pathway and up-regulation of SOCS3. The reported regulatory axis was validated in nude mice as evidenced by suppressed tumor growth. Taken together, this study demonstrates that miR-19b-3p facilitates glioma progression via activation of the JAK-STAT signaling pathway by targeting SOCS3, highlighting a novel therapeutic target for glioma treatment. [ABSTRACT FROM AUTHOR]

Atrazine (ATZ) is part of a group of herbicides called triazines. ATZ is widely used in agricultural areas of Mexico, commonly used for the selective control of weeds in corn and sorghum crops. The exposure to ATZ can have serious human health effects since its use was associated with the development of cutaneous melanoma in an epidemiological study. The aim of this study was to evaluate the expression of maturation and apoptotic markers in primary skin cultures exposed to ATZ. The primary skin cultures were exposed to 0.1, and 10 µM ATZ with or without ultraviolet (UV) radiation and the expression of maturation and apoptotic markers were evaluated by RT-qPCR. We observed a significant increase in all the melanocyte maturation markers in cells exposed to ATZ with or without UV, with SOX-9 and FAK (melanoblast markers) being the highest. Also, the expression of BCL-2 (anti-apoptotic marker) was the most increased gene in cells exposed to ATZ with or without UV. Low concentrations of ATZ and UV radiation induce genetic changes associated with the development of immature melanocytes and activate mechanisms associated with the inhibition of apoptosis characteristics of malignant cell transformation, which will allow proposing new therapeutic targets and generating new restrictions or care in farmers exposed to pesticides such as the ATZ. [ABSTRACT FROM AUTHOR]

Background: Intra-abdominal infections are the second most common cause of sepsis in the intensive care unit. Intestinal epithelial injury due to abdominal sepsis results in a variety of pathological changes, such as intestinal bacteria and toxins entering the blood, leading to persistent systemic inflammation and multiple organ dysfunction. The increased apoptosis of intestinal epithelial cells induced by sepsis further exacerbates the progression of sepsis. Although several studies have revealed that circRNAs are involved in intestinal epithelial injury in sepsis, few studies have identified the roles of circRNAs in intestinal epithelial apoptosis. Methods: We used laser capture microdissection to obtain purified epithelial cells located in intestinal crypts from four patients with abdominal sepsis induced by intestinal perforation and four samples from age and sex-matched non-septic patients. Microarray analysis of circRNAs was conducted to assess differentially expressed circRNAs between patients with and without sepsis. Lastly, in vitro and in vivo assays were performed to study the mechanism of circFLNA in intestinal epithelial apoptosis during sepsis. Results: circFLNA was upregulated in the intestinal epithelium after abdominal sepsis induced by intestinal perforation. Inhibition of miR-766-3p impaired si-circFLNA-mediated inhibition of apoptosis and inflammation factor levels in lipopolysaccharide (LPS)-treated HIEC-6 cells. circFLNA aggravated apoptosis and inflammation through the Fas-mediated apoptosis pathway in both LPS-treated HIEC-6 cells and a mouse cecal ligation and puncture model. Conclusion: Our findings showed that circFLNA promotes intestinal injury in abdominal sepsis through the Fas-mediated apoptosis pathway by sponging miR-766-3p. The circFLNA/miR-766-3p/Fas axis has potential as a novel therapeutic target for treating intestinal injury in sepsis. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of circ_0016788 targeting miR-338-3p on the proliferation, apoptosis, migration and invasion of prostate cancer cells. Methods circ_0016788 and miR-338-3p expressions were detected by RT-qPCR in prostate cancer tissues.si-circ_0016788, si-NC, miR-NC, miR-338-3p mimic, si-circ_0016788+anti-miR-NC, si-circ_0016788+ anti-miR-338-3p were transfected into DU145 cells respectively. CCK-8, Transwell method and flow cytometry were applied to detect DU145 cells growth, migration, invasion and apoptosis rate. The interaction between circ_0016788 and miR-338-3p was confirmed by dual luciferase reporter assay. Results circ_0016788 was highly expressed（P＜0.05） while miR-338-3p was lowly expressed（P＜0.05） in prostate cancer tissues. After inhibiting the expression of circ_0016788, the cell inhibition rate, apoptosis rate and miR-338-3p expression level were increased（P＜0.05）, and the numbers of migration and invasion were decreased（P＜0.05）. After overexpression of circ_0016788, the cell inhibition rate and apoptosis rate were decreased（P＜0.05）, and the numbers of migration and invasion were increased（P＜0.05）. miR-338-3p was a direct target gene of circ_0016788. Inhibition of miR-338-3p expression significantly attenuated the effects of circ_0016788 low expression on DU145 cells inhibition rate, migration and invasion number, and cell apoptosis rate（P＜0.05）. Conclusion Inhibition of circ_0016788 can induce prostate cancer cell apoptosis and inhibit proliferation, migration and invasion by promoting miR-338-3pexpression. [ABSTRACT FROM AUTHOR]

This study aimed to explore the possible cytoprotective effects of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in the testicles of diabetic rats. Exenatide has numerous advantageous properties in addition to its hypoglycemic effect. However, its impact on testicular tissue in diabetes needs more clarification. Therefore, rats were divided into control, exenatide-treated, diabetic and exenatide-treated diabetic groups. Blood glucose and serum levels of insulin, testosterone, pituitary gonadotropins and kisspeptin-1 were measured. Real-time PCR for beclin-1, p62, mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK), were estimated in testicular tissue in addition to markers of oxidative stress, inflammation, and endoplasmic reticulum stress. Also, immuno-expression of protein P53, nuclear erythroid factor2 (Nrf2) and vimentin was conducted. Exenatide was able to attenuate diabetic toxic changes and enhance autophagy in testicular tissue. These results indicate the protective effect of exenatide against diabetic testicular dysfunction. [ABSTRACT FROM AUTHOR]

(1) Background: Ischemia/hypoxia plays an important role in interstitial cystitis/bladder pain syndrome (IC/BPS). Platelet-rich plasma (PRP) has been shown to relieve symptoms of IC/BPS by regulating new inflammatory processes and promoting tissue repair. However, the mechanism of action of PRP on the IC/BPS bladder remains unclear. We hypothesize that PRP might protect the urothelium during ischemia/hypoxia by decreasing apoptosis. (2) Methods: SV-HUC-1 cells were cultured under hypoxia for 3 h and treated with or without 2% PLTGold® human platelet lysate (PL). Cell viability assays using trypan blue cell counts were examined. Molecules involved in the mitochondrial-mediated intrinsic apoptosis pathway, HIF1α, and PCNA were assessed by Western blot analysis. The detection of apoptotic cells and CM-H2DCFDA, an indicator of reactive oxygen species (ROS) in cells, was analyzed by flow cytometry. (3) Results: After 3 h of hypoxia, the viability of SV-HUC-1 cells and expression of PCNA were significantly decreased, and the expression of ROS, HIF1α, Bax, cytochrome c, caspase 3, and early apoptosis rate were significantly increased, all of which were attenuated by PL treatment. The addition of the antioxidant N-acetyl-L-cysteine (NAC) suppressed the levels of ROS induced by hypoxia, leading to inhibition of late apoptosis. (4) Conclusions: PL treatment could potentially protect the urothelium from apoptosis during ischemia/hypoxia by a mechanism that modulates the expression of HIF1α, the mitochondria-mediated intrinsic apoptotic pathway, and reduces ROS. [ABSTRACT FROM AUTHOR]

The present study investigates the effects of resveratrol (RSV) on brain and liver tissues in rats with pembrolizumab (PEMB)‐induced toxicity. Obtained for the study were 28 male Sprague‐Dawley rats (3–4 months old) which were divided into four groups: Group 1: Control. Group 2: Administered PEMB at 5 mg/kg/day i.p. for a week. Group 3: Administered RSV orally at the dose of 20 mg/kg/day for 30 days by gavage. Group 4: Administered PEMB and RSV at 20 and 5 mg/kg/day RSV, respectively, for 30 days. The results of this study revealed that PEMB leads to a significant increase in thiobarbituric acid reactive substance (TBARS) levels and a significant decrease in glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) activities, and glutathione (GSH) levels in the liver and brain tissues. The decreased SOD, CAT, GPx activities, and GSH levels increased significantly following RSV treatment in Group 4. The PEMB treatment showed histopathological alterations associated with strong positive cysteinyl aspartic acid‐protease‐3 (caspase‐3) immunoreactivity, while RSV treatment reduced both the expression of caspase‐3 protein and the histopathological changes. RSV administration prevents the biochemical, immunological, and histological alterations induced by PEMB. It can be suggested that the lower caspase‐3 immunoreactivity in the PEMB + RSV group than in the PEMB group led to an inhibition of RSV on apoptosis. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the underlying mechanism of AS‐IV and CCN1 in PAH and to evaluate whether the protective effect of AS‐IV against PAH is associated with CCN1 and its related signalling pathway. In vivo, male SD rats were intraperitoneally injected with monocrotaline (MCT, 60 mg/kg) or exposed to hypoxia (10% oxygen) and gavaged with AS‐IV (20, 40 and 80 mg/kg/day) to create a PAH model. In vitro, human pulmonary artery endothelial cells (hPAECs) were exposed to hypoxia (3% oxygen) or monocrotaline pyrrole (MCTP, 60 μg/mL) and treated with AS‐IV (10, 20 and 40 μM), EGF (10 nM, ERK agonist), small interfering CCN1 (CCN1 siRNA) and recombinant CCN1 protein (rCCN1, 100 ng/mL). We identified the differences in the expression of genes in the lung tissues of PAH rats by proteomics. At the same time, we dynamically detected the expression of CCN1 by Western blot both in vivo and in vitro. The Western blot experimental results showed that the expression of CCN1 increased in the early stage of PAH and decreased in the advanced stage of PAH. The results showed that compared with the control group, MCT‐ and hypoxia‐induced increased the hemodynamic parameters and apoptosis. AS‐IV can improve PAH, as characterized by decreased hemodynamic parameters, vascular wall area ratio (WA%), vascular wall thickness ratio (WT%) and α‐SMA expression and inhibition of cell apoptosis. Moreover, the improvement of PAH by AS‐IV was accompanied by increased CCN1 expression, which activated the ERK1/2 signalling pathway. Meanwhile, CCN1 and p‐ERK1/2 were inhibited by siCCN1 and promoted by rCCN1. EGF not only activated the ERK1/2 signalling pathway but also induced the expression of CCN1. In conclusion, AS‐IV improves PAH by increasing the expression of CCN1 and activating the ERK1/2 signalling pathway. The results of our study provide a theoretical basis for additional study on the protective effect of AS‐IV against PAH. [ABSTRACT FROM AUTHOR]

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Nocardia seriolae, an intracellular gram-positive pathogen, is prone to infecting immunocompromised and surface-damaged fish, causing serious losses to the aquaculture industry. Although a previous study has demonstrated that N. seriolae infects macrophages, the persistence of this bacterium in macrophages has not been well characterized. To address this gap, we used the macrophage cell line RAW264.7, to investigate the interactions between N. seriolae and macrophages and deciphered the intracellular survival mechanism of N. seriolae. Confocal and light microscopy revealed that N. seriolae entered macrophages 2 hours post-inoculation (hpi), were phagocytosed by macrophages at 4-8 hpi, and induced the formation of multinucleated macrophages by severe fusion at 12 hpi. Flow cytometry, evaluation of mitochondrial membrane potential, release of lactate dehydrogenase, and observation of the ultrastructure of macrophages revealed that apoptosis was induced in the early infection stage and inhibited in the middle and later periods of infection. Additionally, the expression of Bcl-2, Bax, Cyto-C, Caspase-3, Capase-8, and Caspase-9 was induced at 4 hpi, and then decreased at 6-8 hpi, illustrating that N. seriolae infection induces the activation of extrinsic and intrinsic apoptotic pathways in macrophages, followed by the inhibition of apoptosis to survive inside the cells. Furthermore, N. seriolae inhibits the production of reactive oxygen species and releases large amounts of nitric oxide, which persists in macrophages during infection. The present study provides the first comprehensive insight into the intracellular behavior of N. seriolae and its apoptotic effect on macrophages and may be important for understanding the pathogenicity of fish nocardiosis. [ABSTRACT FROM AUTHOR]

With rapid development of liver transplantation technology, the demand for transplants have reached beyond the supply of organs, and thus development of effective strategies to reduce cold ischemia injury in fatty liver is important. Here, we explored the potential effect of SGLT-2 inhibitor in cold ischemia injury, fatty livers from 2 weeks methionine and choline deficient diet (MCD) rats were administered. After one week of intragastric administration of Sodium-dependent glucose transporters (SGLT-2) inhibitor empagliflozin (EMPA) or NaCI, liver were stored for 24 h. The results showed that EMPA could significantly reduce the cold ischemic injury in the mitochondria of fatty liver. To explore the mechanism, signal transducers and activators of transcription 3(STAT3) inhibitor AG490 group was used in a similar manner. We detected the changes in p-signal transducers and activators of transcription 3 (P-STAT3), alcohol-dehydrogenase 2 (ALDH2) and degree of apoptosis in three distinct groups. The results suggested that the protein expression of P-STAT3 and ALDH2 was higher in the EMPA group than in other two groups, whereas extent of apoptosis in the EMPA group was lower than other two groups. The data suggested that SGLT2 inhibitors could alleviate cold ischemia damage of mitochondria in fatty liver, which may be related to the inhibition of apoptosis and the activation of P-STAT3 and ALDH2. • This is the first study of sodium-dependent glucose transporters 2 inhibitor in cold ischemic injury of fatty liver. • SGLT2inhibitor can alleviate cold ischemia damage of mitochondria in fatty liver. • The data suggested that SGLT2 inhibitorcould alleviate cold ischemia damage of mitochondria in fatty liver, which may be related to the inhibition of apoptosis and the activation of p-signal transducers and activators of transcription 3 and alcohol-dehydrogenase 2. [ABSTRACT FROM AUTHOR]

Isorhamnetin (ISO) is a methylated flavonol present in the leaves, flowers, and fruits of many plants with antitumour, anti-inflammatory, antioxidant, and anti-apoptotic properties. ISO has been suggested as the active substance in Vernonia anthelmintica (L.) to treat vitiligo. However, the mechanisms underlying its effects remain unclear. In this study, human keratinocytes (HaCaT cells) were pre-treated with or without ISO and then stimulated with hydrogen peroxide (H2O2) to generate oxidative damage. Pre-treatment with ISO increased HaCaT cell viability, reduced malondialdehyde content, and enhanced superoxide dismutase activity, resulting in a reduction in the loss of mitochondrial membrane potential, improved cell morphological damage, and apoptosis inhibition. Furthermore, we identified 51 significantly dysregulated differentially expressed genes (DEGs) of HaCaT cells treated with ISO using RNA-sequencing. Enrichment analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases indicated that the protective effect of ISO could be related to its effects on the Wnt signalling pathway. Our study provides novel insights into key gene regulation in the progression of oxidative damage and the mechanisms of action of ISO. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLSs), the main pathological cells in rheumatoid arthritis (RA), display tumor-like phenotype, including hyper-proliferation, apoptosis resistance, and aggressive phenotype. Excessive proliferation and insufficient apoptosis of RA-FLSs can lead to hyperplastic synovial pannus tissue, excess production of inflammatory mediators, and destruction of joints. In this article, we investigate the effect of PRIMA-1MET on the apoptosis induction and inhibition of pro-inflammatory cytokines in RA-FLSs. Synovial tissue samples were obtained from 10 patients with RA. The FLSs were treated with different concentrations of PRIMA-1MET. The rate of apoptosis and cell survival was assessed by flow cytometry and MTT assay and Real-time quantitative PCR was performed to evaluate the transcription of p53, IL-6, IL-1β, TNF-α, Noxa, p21, PUMA, Bax, Survivin, and XIAP in treated RA-FLSs. The protein level of p53, IκBα, and phospho-IκBα were measured using Western blotting. The results showed that PRIMA-1MET induced apoptosis in RA-FLSs and increased significantly the expression of Noxa, and decreased significantly IL-6, IL-1β, p53, and phospho-IκBα expression. PRIMA-1MET can induce apoptosis in RA-FLSs through induction of Noxa expression while p53 was downregulated. Furthermore, PRIMA-1MET treatment results in the suppression of pro-inflammatory cytokine production and NF-κB inhibition. Given the role of p53 and NF-κB in RA-FLSs, PRIMA-1MET can be considered as a new therapeutic strategy for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Influenza viruses are responsible for significant morbidity and mortality worldwide in winter seasonal outbreaks and in flu pandemics. Influenza viruses have a high rate of evolution, requiring annual vaccine updates and severely diminishing the effectiveness of the available antivirals. Identifying novel viral targets and developing new effective antivirals is an urgent need. One of the most promising new targets for influenza antiviral therapy is non-structural protein 1 (NS1), a highly conserved protein exclusively expressed in virus-infected cells that mediates essential functions in virus replication and pathogenesis. Interaction of NS1 with the host proteins PI3K and TRIM25 is paramount for NS1's role in infection and pathogenesis by promoting viral replication through the inhibition of apoptosis and suppressing interferon production, respectively. We, therefore, conducted an analysis of the druggability of this viral protein by performing molecular dynamics simulations on full-length NS1 coupled with ligand pocket detection. We identified several druggable pockets that are partially conserved throughout most of the simulation time. Moreover, we found out that some of these druggable pockets co-localize with the most stable binding regions of the protein–protein interaction (PPI) sites of NS1 with PI3K and TRIM25, which suggests that these NS1 druggable pockets are promising new targets for antiviral development. [ABSTRACT FROM AUTHOR]

Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor‐prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell‐permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor‐prognosis cancers. [ABSTRACT FROM AUTHOR]

The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet transplantation. We demonstrated that BMSCs could deliver exosomes containing miR-21-5p into islet cells.Then, we found that miR-21-5p overexpression attenuated apoptosis of islets and rat insulinoma (INS-1) cells, while miR-21-5p inhibition significantly promoted apoptosis.The upregulated miR-21-5p directly binds to the 3'UTR of PDCD4, thereby reducing apoptosis in transplanted islets. This study confirms the results of previous studies, suggesting that miR-21-5p can be used as a therapeutic agent to minimize β-cell apoptosis in the early stage of islet transplantation and thus improve the transplantation outcome. [ABSTRACT FROM AUTHOR]

Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3 -MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity. [Display omitted] • Urolithin A protects against Dox-induced apoptosis and cardiotoxicity. • Urolithin A enhances PINK1-mediated mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. • Urolithin A may serve as a valuable treatment option for addressing Dox-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Thymocyte selection-associated high mobility group box protein (TOX) is regarded as a crucial transcription factor involved in T cell exhaustion in acute myeloid leukemia (AML). Previous studies have identified aberrant TOX expression as a major oncogenic driver in hematologic malignancies, indicating that TOX may potentially be both an immune biomarker and an immunotherapy target. However, due to heterogeneity in the distribution patterns of TOX and its correlation with clinical prognosis, the mechanism underlying TOX-mediated tumor immune responses remains unclear. In this study, we demonstrate that high TOX expression in AML patients is associated with poor prognosis, and TOX overexpression promotes AML cell proliferation and restricts apoptosis. In vitro TOX inhibition promoted the apoptosis of AML cells, suppressed cell viability, and induced cell cycle arrest in the G0/G1 phase. Moreover, TOX knockdown could reduce tumor burden in vivo in immunodeficient mice and prolong their survival. Furthermore, the anti-AML effects of inhibiting TOX may act through activation of the IFN-α signal pathway and upregulating IRF7 expression. In summary, we report for the first time that TOX knockdown exerts powerful anti-tumor effects in AML. These findings will provide a theoretical basis for targeted therapy in AML patients. • TOX overexpression promoted AML cell proliferation and restricted apoptosis. • TOX inhibition promoted the apoptosis of AML cells, suppressed cell viability, and induced cell cycle arrest in the G0/G1 phase. • Knockdown of TOX could reduce the tumor burden in immunodeficient mice and prolong survival time in vivo. • The anti-AML effects of TOX inhibition may work through activation of the IFN-α pathway and upregulation of IRF7 expression. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOXO) is a widely used anti-cancer agent, yet the precise mechanism underlying the induction of tumor cell death remains unclear. This study aimed to elucidate new mechanisms by which doxorubicin induces apoptosis in the EMT6 mouse breast carcinoma cell line. The role of doxorubicin was assessed using the XTT assay. The assessment of oxidative stress markers, alongside the analysis of SIRT2 and NF-κB p65 (RelA) phosphorylation inhibition, was conducted. In silico studies, including density functional theory (DFT) calculations and molecular docking simulations, were employed to characterize the molecular interactions between doxorubicin and SIRT2. Additionally, doxorubicin was assessed for its capacity to modulate gene expression and associated pathways using multiple bioinformatics tools and web-based platforms. Our finding indicates that Doxorubicin induced apoptosis in EMT6 cells with an IC50 of 8,32 μM. At lower concentrations, doxorubicin enhances the oxidative balance and promotes cell viability. At high concentrations, doxorubicin inhibits SIRT2. Furthermore, an experimental investigation revealed that doxorubicin inhibits RelA phosphorylation. The results also showed that doxorubicin modulated the expression of 19 genes involved in different pathways and several transcription factors. The results of implementing the gene set with SIRT2 and RELA consolidated the experimental results. In conclusion, Doxorubicin was observed to induce EMT6 apoptosis through the inhibition of SIRT2 and RelA proteins. The outcomes of both experimental and bioinformatic studies provide a novel perspective on the biological effects of doxorubicin and underscore the potential of inhibiting the SIRT2-RelA axis as a promising biological target for cancer therapy. Legend: Doxorubicin inhibits SIRT2 and NF- k B p65 phosphorylation and induces EMT6 cell death. [Display omitted] • Doxorubicin induces tumor cell death with an IC50 value of 8,32 μM. • Doxorubicin inhibited SIRT2 and the NF- k B p65 (RelA) proteins leading to the carcinoma cell death. • Doxorubicin modulates expression of 19 genes and more. Implementation of the gene set by SIRT2 and RELA consolidates the experimental finding. • I nhibition of the Sirt2-RelA axis appears as a promising target for breast carcinoma treatment. [ABSTRACT FROM AUTHOR]

Iron overload leads to apoptosis and increased expression of receptor activator of nuclear factor kappa‐Β ligand (RANKL) in osteocytes, which in turn accelerates osteoclastogenesis. Since osteocytes are the main RANKL producers, we hypothesized that apoptotic osteocytes increase RANKL expression in osteocytes, which in turn stimulates osteoclastogenesis and bone resorption. In this study, alendronate or IG9402, a bisphosphonate (BP) analog which does not inhibit bone resorption, inhibited iron overload-induced osteocyte apoptosis and increased RANKL expression. Both BPs also prevented osteoblast apoptosis but did not inhibit the increase in osteoblastic RANKL. Alendronate, but not IG9402, prevented the increase in osteoclastogenesis and serum levels of the bone resorption marker C-telopeptide of type I collagen (CTX) in iron-overloaded mice. Alendronate also prevented the iron overload-induced reduction in femoral bone mineral density, disruption of bone microstructure, and weakness of bone strength. Although IG9402 did not prevent bone loss due to iron overload, it partially prevented reduction of strength, suggesting that osteocyte viability contributes to the maintenance of bone strength. In conclusion, although osteocyte apoptosis in the presence of iron overload leads to an increase in osteocytic RANKL production. However, blocking these events was not sufficient to inhibit iron overload-induced osteoclastogenesis and bone loss. • Bisphosphonates inhibit iron overload-induced osteocyte and osteoblast apoptosis. • Blocking osteocyte apoptosis does not decrease excess iron-induced osteoclastogenesis. • Blocking osteocyte apoptosis does not prevent iron overload-induced bone loss. • Blocking osteocyte apoptosis prevents impaired bone strength due to iron overload. [ABSTRACT FROM AUTHOR]

[Display omitted] • The synergistic anti-hepatoma effect of gallic acid combined with exosomes has been observed. • Exosomes are known to modulate inflammatory, oxidative stress, and glycolytic pathways. • The combination therapy of Gallic acid and exosomes affect Selenocompound, Cysteine and methionine metabolism. Clinically, hepatoma patients are more frequently encountered in the intermediate and advanced stages. Consequently, the majority of patients miss out on the chance to undergo liver transplantation or radical surgery. Radiotherapy and chemotherapy often fall short of delivering satisfactory outcomes. The incidence and mortality rates for liver cancer approach nearly 100%. In recent years, both exosomes (Exos) and natural chemical compounds have demonstrated robust anti-cancer properties; however, the synergistic effect of their combination remains unexplored. Exos were extracted from human umbilical cord mesenchymal stem cells (hUC-MSCs). The impact of gallic acid (GA), hUC-MSCs-Exos, and their combined administration on the proliferation inhibition rate and apoptosis of SMMC-7721 hepatoma cells was assessed to ascertain the efficacy differences before and after the combined treatment. A combination of cells metabolomics and network pharmacology techniques was employed to investigate the underlying mechanisms of action. The pivotal targets associated with glycolysis, inflammation, and oxidative stress pathways were confirmed through ELISA assays. The findings elucidate that GA profoundly impedes the proliferation of SMMC-7721 hepatoma cells and instigates apoptotic processes therein. While the impact of hUC-MSCs-Exos alone was inconspicuous, a notable augmentation in effect ensued upon their combined application. Concomitantly, a marked reduction was observed in the expressionlevels of key enzymes including HK, PFK, PK, LDH, TNF-α, IL-1β, CAT, SOD and GSH-Px in the malignant hepatocytes, while IL-6 and MDA exhibited heightened expression. Pathway enrichment analysis underscored selenocompound metabolism and cysteine and methionine metabolism as pivotal pathways. The potentiated efficacy of GA conjunction with hUC-MSCs-Exos may be attributed to their synergistic modulation of anti-inflammatory, antioxidant, and glycolytic functions, thereby influencing selenocompound metabolism and cysteine and methionine metabolism. This study reveals the efficacy and mechanism of Exos and GA combined therapy for hepatoma, providing new methods and ideas for the clinical treatment of hepatoma. [ABSTRACT FROM AUTHOR]

• BspE, a Brucella T4SS effector, promotes bacterial growth, survival in macrophages, and impacts inflammatory factor release. • It interacts with host PCBP1 in the nucleus, influencing P53 signaling, apoptosis inhibition, and Brucella replication. Brucella T4SS secretes numerous effector proteins to disrupt host immune responses and apoptosis, enabling long-term survival. One such effector protein is BspE, whose role remains largely unknown. In this study, we demonstrated that BspE promotes the growth of Brucella , enhances its survival in macrophages, and affects the release of macrophage inflammatory factors. Furthermore, BspE facilitates Brucella colonization and pathological damage in mice. Our findings reveal that BspE can be translated in the host cell nucleus, where it interacts with the host RNA-binding protein PCBP1 to promote Brucella replication in macrophages. Knockdown of PCBP1 affects BspE-mediated proliferation of Brucella in macrophages. Furthermore, the BspE-PCBP1 interaction hinders P53 signaling and inhibits macrophage apoptosis. Although this interaction affects inflammatory cytokines, it does not significantly involve the NF-κB pathway. These findings contribute to a better understanding of how the Brucella effector protein BspE regulates host immune responses and apoptosis to influence its own survival. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is an idiopathic syndrome with painful burdensome symptoms. Radiotherapy is one of the main therapeutic modalities for treating various malignancies and there is a probable association between FM exacerbation and exposure to ionizing radiation. Based on that nanomedicines progressively being explored for their promising applications in medicine, the aim of the current study is to assess the possible therapeutic benefits of nanoform of pregabalin (N-PG) in managing FM symptoms during being exposed to ionizing radiation. Rats were allocated into four groups. First group served as control, the other three groups received gamma radiation (2 Gy/day) after 1 h of reserpine administration (1 ml/kg per day, s.c.) to induce FM for three successive days. On the next day, third and fourth groups received (30 mg/kg, p.o.) of PG and N-PG, respectively once daily for ten consecutive days. Tail flick test was performed and von Frey filaments were used to assess mechanical allodynia/hyperalgesia, and then rats were sacrificed to obtain brains. N-PG effectively replenished reserpine effects and treated both allodynia and hyperalgesia, improved thermal allodynia, effectively recovered all neurotransmitters near to normal baseline, inhibited oxidative stress status via decreasing malondialdehyde (MDA), increasing glutathione (GSH) and superoxide dismutase (SOD), it had strong anti-inflammatory effect as verified by reducing both cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kB) in addition to inhibition of intrinsic apoptosis through caspase-3 (casp-3) decrease and B-cell lymphoma-2 (Bcl-2) increase. Histopathological and immunohistochemical results confirmed the biochemical findings. N-PG could be a promising drug for treating FM especially when there is urgent need to expose patient to ionizing radiation. A Graphical abstract of the experimental design : Rats received gamma radiation (2 Gy/day) after 1 h of reserpine administration (1 ml/kg per day, s.c.) to induce FM for three successive days. On the next day, third and fourth groups received (30 mg/kg, p.o.) of pregabalin (PG) and nano-form of pregabalin (N-PG), respectively once daily for ten consecutive days. Rats were exposed to mechanical allodynia/hyperalgesia and tail flick test, and then were sacrificed to obtain brains for further neurochemical assessment. [Display omitted] • Fibromyalgia is generalized painful syndrome that exacerbated during radiotherapy. • Pregabalin was approved for the treatment of fibromyalgia. • Nanomedicines became of a great application in medicine. • Possible therapeutic benefits of using nanoform of pregabalin were investigated. • New promising drug managing fibromyalgia during exposure to radiation was raised. [ABSTRACT FROM AUTHOR]

• Induced pluripotent stem cells (iPSCs) engineered with FGFR3-TACC3 fusion gene combat osteosarcoma aggressiveness. • Modified CTLs derived from iPSCs effectively target and kill osteosarcoma cells. • In vitro assays demonstrate significant apoptosis induction and inhibition of migration and invasion. • In vivo experiments validate the efficacy of iPSC-derived CTLs against osteosarcoma. • This study highlights the potential of personalized immunotherapy for osteosarcoma utilizing iPSC technology. Osteosarcoma, a highly aggressive bone cancer, poses significant treatment challenges. This study investigates a novel approach utilizing induced pluripotent stem cells (iPSCs) engineered with the FGFR3-TACC3 fusion gene to generate cytotoxic T lymphocytes (CTLs) targeting osteosarcoma. The aim was to assess the efficacy of iPSC-derived CTLs in combating osteosarcoma progression. Abnormal expression of the FGFR3-TACC3 fusion gene was confirmed in osteosarcoma samples. iPSCs were successfully modified to express the fusion gene and were then differentiated into CTLs. In vitro experiments demonstrated that these modified CTLs effectively killed osteosarcoma cells, induced apoptosis, and inhibited migration and invasion. Findings were validated in in vivo experiments. This study suggests that iPSC-derived CTLs targeting FGFR3-TACC3 hold promise for personalized immunotherapy against osteosarcoma. [ABSTRACT FROM AUTHOR]

• Reveals ADAP2 as a potential biomarker for gliomas. • ADAP2 mediates glioma cell apoptosis through the NF-κB and P53 signaling pathway in gliomas. • Established a nomogram related to apoptosis. • The established novel nomogram showed good predictive performance. Apoptosis continues to be a pivotal area of investigation in glioma research. ADAP2 mediates the malignant progression of gliomas through the inhibition of apoptosis and predicts the overall survival(OS) of glioma patients based on prognostic modeling of the apoptotic gene set. Methods: The study encompassed 686 glioma patients, with 413 allocated to the training group and 273 to the validation group. Differential expression of ADAP2 across various glioma subtypes was assessed through bioinformatics analysis and Western blotting. The correlation between ADAP2 and apoptosis was examined using Gene Set Enrichment Analysis (GSEA). Multivariate Cox regression analysis and LASSO dimension reduction analysis were employed to identify apoptosis-related genes with prognostic significance in glioma patients and to construct a nomogram. Biological functions and mechanisms associated with risk scores were explored via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA analyses, with validation through Western blotting, flow cytometry, and AM/PI staining. Results: ADAP2 was found to be enriched in more aggressive glioma subtypes and was closely linked to glioma cell apoptosis, modulating this process via the NF-κB and P53 signaling pathway. A nomogram for OS in glioma patients was constructed using thirteen apoptosis-related genes. Additionally, ROC curves, calibration curves, and C-indices confirmed the robust applicability of the nomogram. Conclusion: ADAP2 functions as a prognostic biomarker for glioma patients, regulating glioma cell apoptosis through the NF-κB and P53 signaling pathway. Moreover, prognostic models based on apoptosis-related genes can accurately predict OS for glioma patients at 1, 2, 3, 5, and 10 years. [ABSTRACT FROM AUTHOR]

• Triptolide and Curcumin synergistically reduce joint and synovial damage in collagen-induced arthritis rat models. • Triptolide and Curcumin may inhibit the IL-17/NF-κB signaling pathway both in vitro and in vivo. • Triptolide and Curcumin improve cell proliferation and induce cell apoptosis in vitro. Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease. While triptolide (TPL) and curcumin (CUR) are known to have multiple beneficial effects on RA, the combined effect of TPL and CUR remains unexplored. This study aimed to investigate their synergistic effect on cell proliferation and apoptosis via the IL-17/NF-κB signaling pathway. The collagen-induced arthritis (CIA) rat model was established, showing severe joint and synovial damage compared to normal rats. Treatment with TPL and CUR reduced the severity of RA in the CIA rat model and alleviated serum inflammatory cytokines, such as rheumatoid factor, IL-17, TNF-α, IL-1β, and IL-6. The elevated levels of IL-17 and NF-κB in CIA rats were also inhibited, and the resistant apoptosis was aggravated by TPL and CUR. In vitro , the improvement of cell proliferation and induction of apoptosis were observed in LPS-stimulated MH7A cells treated with TPL and CUR, associated with the inhibition of the IL-17/NF-κB signaling pathway. Taken together, a synergistic effect of TPL and CUR on RA may involve relieving symptoms, improving excessive proliferation, inducing apoptosis resistance, and inhibiting the IL-17/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Nanoparticles, like graphene oxide (GO), are particles with unique physiochemical properties that enable their wide application in various areas of life. The effects of GO on individual cell organelles like mitochondria and the effects of interactions are worth investigating, as they can activate multiple cellular processes, such as autophagy or apoptosis. Mitochondrial injury plays an essential role in the majority of cell death routines. In the project, we investigated cell health status measured as mitochondrial inner membrane depolarization, autophagy, and apoptosis induction during long-term GO administration in food (0.02 μg g−1 and 0.2 μg g−1 of food). Two unique Acheta domesticus strains that differ in life strategy were used: wild-type and long-lived at three different life stages (larva, young adult, mature adult). The changes in mitochondrial trans -membrane potential were marked in the wild-type strain. The autophagy was lower in all GO-treated groups in both strains, and the apoptosis was lower in both strains in the mature adult crickets. Low GO concentrations treatment for the whole life, despite mitochondrial dysfunction, may lead to inhibition of autophagy and apoptosis by arresting the cell cycle for the duration of repair, and other repair tools are involved in the process of restoring homeostasis. [Display omitted] • Graphene oxide in low concentrations changes mitochondrial trans -membrane potential. • Whole-life graphene oxide treatment leads to inhibition of autophagy and apoptosis. • Graphene oxide intoxication depends on life strategy and age. [ABSTRACT FROM AUTHOR]

[Display omitted] • Docking and MD simulations verified CDK2 as the anticancer target of the designed compounds. • Simple, efficient, and optimized reaction conditions for nucleoside synthesis were developed. • The synthesised compounds displayed significant cytotoxicity in the NCI-60 and MTT assays. • Inhibition of CDK2/cyclin A2 was identified as a selective anticancer mechanism. • Designed compounds promoted apoptosis and G2/M cell cycle arrest. Purine analogues were discovered to be inhibitors of CDK2, suggesting a potential therapeutic scaffold. This paper addresses the design, synthesis, and anticancer evaluation of purine analogues as kinase inhibitors. In the early stages of the investigation, the designed compounds demonstrated a promising docking score and greater protein–ligand stability in MD simulation than the standard, indicating a higher affinity against CDK2. Thus, we synthesised new purine analogues under simple and optimised reaction conditions. Among the studies under NCI-60, 5 g and 5i were the most effective, with a percentage GI of 98.09 and 90 against OVCAR-4 and SNB-75, respectively, at a dose of 10 µM. Additionally, 5 g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC 50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM). In addition, 5 g and 5i showed selective cytotoxicity against PA-1 and MCF-7 than normal cells, with selectivity indexes of 26.40 and 15.45, respectively, as compared to the standard (SI=3.83 and 5.91). In the kinase selectivity assay, both compounds demonstrated greater affinity against CDK2 than other kinases, with IC 50 of 0.21 µM and 0.59 µM, in contrast to the standard (IC 50 = 0.63 µM). Furthermore, 5 g confirmed kinase inhibition in the western blot by lowering CDK2, cyclin A2, and other downstream substrates. Moreover, it triggered cell death by apoptosis and cell cycle arrest in G2/M. Taken together, 5 g merits further investigation in PKPD research to discover a potential therapeutic candidate against cancer. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is the tenth most common cancer with the highest mortality rate. Since the etiological role of viral infection in the development of BC is less known, the aim of the present study was to examine the pooled prevalence and possible relationship between viral infection and BC. A systematic search of major online databases was conducted to investigate relevant studies. We estimated the pooled odds ratio (OR), 95 % confidence interval (CI), and heterogeneity for all studies by using meta-analysis and forest plots. All data were analyzed using Stata Software v.14.1. We analyzed 87 articles (97 datasets), which included 59 case-control and 38 cross-sectional designs. The pooled prevalence of viral infection among BC patients was 17.59 % (95 % CI: 13.09–22.55 %; I2 = 96.34 %). Our subgroup analysis indicated that the pooled prevalence of human herpesvirus (HHV), papillomavirus (HPV), polyomavirus, and adenovirus was 33.67 %, 15.18 %, 7.46 %, and 30.14 %, respectively. We detected a significant relationship between viral infection and BC [summary OR 2.34 (95 % CI 1.56–3.51; I2 = 58.0 %)]. This possible association was exhibited for Epstein–Barr virus (EBV) and HPV. Our finding indicated that HPV and EBV infections with significant associations with BC can be considered as possible risk factors for BC. Although the specific molecular mechanism of the role of viruses in the development of BC has not been identified, persistent viral infection, oncogenic protein expression, apoptosis inhibition, cell cycle promotion, and disruption of signaling pathways in bladder tissue are possible pathways for the role of viruses in the development of BC. [ABSTRACT FROM AUTHOR]

[Display omitted] • Proteasome activators show promising potential in hypoxic cardiomyocyte protection. • A batch of highly active proteasome activators were obtained through virtual screening and structural optimization. • Proteasome activators possessed abilities to alleviate endoplasmic reticulum stress. • Proteasome activators exert their protective function in hypoxic conditions, potentially by inhibiting apoptosis. Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016–8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion. [ABSTRACT FROM AUTHOR]

In order to study the mechanisms of ginsenoside Rb3 (G-Rb3) against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in HT22 cells based on metabolomics and PCR array, HT22 cells were randomly divided into control group, model group, G-Rb3 high-dose group (10 µmol/l) and G-Rb3 low-dose group (5 µmol/l). Except for the control group, which was left untreated, the remaining groups were incubated with 10 mmol/l Na2S2O4 in sugar-free DMEM medium for 2 h and then replaced with serum-free high-sugar DMEM medium for 2 h in order to replicate in vitro OGD/R model. Trypan blue staining was used to detect the cell viability; flow cytometry was used to detect apoptosis; western blotting was used to detect the protein expression levels of Bax, Bcl-2 and caspase-3. The metabolomics were used to analyze the differential metabolites of G-Rb3 affecting OGD/R in order to find the relevant metabolic pathways. PCR array assay was performed to identify the expression of the differential genes. G-Rb3 could inhibit HT22 apoptosis according to the result of cell morphology, trypan blue staining and flow cytometry. The levels of Bax and caspase-3 protein expression were decreased, whereas the level of Bcl-2 protein expression was increased after the treatment of G-Rb3. Metabolomics results showed that a total of 31 differential metabolites between OGD/R group and G-Rb3 group, such as guanosine level, was downregulated, the levels of enalaprilat and sorbitol were upregulated, affecting ABC transporters, galactose metabolism, citrate cycle and other related metabolic pathways; according to the result of PCR array, it was observed that G-Rb3 significantly downregulated Trp63, Trp73, Dapk1, Casp14 and Cd70 pro-apoptotic genes. In conclusion, G-Rb3 has a significant protective effect on the OGD/R model simulated in vitro, and the mechanism may be related to the inhibition of apoptosis by affecting metabolites. [ABSTRACT FROM AUTHOR]

Myocardial infarction is characterized by oxygen deficiency caused by arterial flow restriction. Salidroside (SAL) protects against myocardial damage via antioxidant production and inhibition of apoptosis. The present study aimed to investigate potential rescue mechanism of SAL on hypoxic cardiomyocytes. H9C2 cardiomyocytes were divided into normoxia, hypoxia and hypoxia + SAL groups. The inhibitory rate of hypoxia and the optimal concentration and rescue effect of SAL were determined using Cell Counting Kit-8 assay and flow cytometry. Ca2+ concentration following hypoxia treatment and SAL intervention were detected by Fluo-4/acetoxymethyl. Tandem mass tag (TMT) proteomics was used to analyze the differential expression of hypoxia-associated proteins among the three groups. SAL exerted a protective effect on hypoxia-injured cardiomyocytes by enhancing aerobic metabolism during hypoxia and rescuing cardiomyocytes from hypoxic damage. SAL promoted cell proliferation, decreased apoptosis and increased Ca2+ levels in cell membranes of hypoxic cardiomyocytes. TMT proteomics results showed that the expression levels of intracellular hypoxia inducible factor-1 (HIF)-1α and Egl-9 family HIF 1 (EGLN1) in H9C2 cells were elevated under hypoxic conditions. However, SAL significantly decreased expression levels of HIF-1α and EGLN1. SAL inhibited mitochondrial calcium overload in hypoxic cardiomyocytes and attenuated expression of hypoxia-associated factors. SAL exerted its rescue effect on hypoxic cardiomyocytes through the EGLN1/HIF-1α pathway, thereby suppressing cardiomyocyte apoptosis, improving mitochondrial energy metabolism efficiency and rescuing cardiomyocytes from hypoxic injury. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the leading types of cancer worldwide. CRC development has been associated with the constitutive activation of signal transducer and activator of transcription 3 (STAT3). STAT3 is a master regulator of inflammation during cancer-associated colitis, and becomes upregulated in CRC. In CRC, STAT3 is activated by IL-6, among other pro-inflammatory cytokines, inducing the expression of target genes that stimulate proliferation, angiogenesis and the inhibition of apoptosis. One of the main STAT3-regulated inhibitors of apoptosis is survivin, which is a bifunctional protein that regulates apoptosis and participates in cell mitosis. Survivin expression is normally limited to foetal tissue; however, survivin is also upregulated in tumours. In silico and experimental analyses have shown that the STAT3 interactome is relevant during CRC progression, and the constitutive STAT3-survivin axis participates in development of the tumour microenvironment and response to therapy. The presence of a STAT3-survivin axis has been documented in CRC cohorts, and the expression of these molecules is associated with poor prognosis and a higher mortality rate in patients with CRC. Thus, STAT3, survivin, and the upstream activators IL-6 and IL-6 receptor, are considered therapeutic targets for CRC. Efforts to develop drugs targeting the STAT3-survivin axis include the evaluation of phytochemical compounds, small molecules and monoclonal antibodies. In the present review, the expression, function and participation of the STAT3-survivin axis in the progression of CRC were investigated. In addition, an update on the pre-clinical and clinical trials evaluating potential treatments targeting the STAT3-survivin axis is presented. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in polycystic ovary syndrome (PCOS). A rat model PCOS was constructed by subcutaneous injection with dehydroepiandrosterone (DHEA). Follicular atresia and reduced granular cells (GCs) in ovaries suggested successful modeling. The low expression of TIGAR was observed in ovarian tissue of PCOS rat. To explore the role of TIGAR in PCOS, lentivirus carrying the TIGAR were used to up-regulate TIGAR expression. TIGAR overexpression reduced the DHEA-induced increase of ovarian weight, the levels of estradiol (E2), and the ratio of luteinizing hormone/follicle-stimulating hormone (LH/FSH) in the serum, as well as improved the morphology of the follicle, especially increased the thickness of the GC layer, which attributed to the inhibition of apoptosis by TIGAR. In addition, high expression of TIGAR inhibited oxidative stress in ovaries of PCOS rat, as evidenced by decreased level of malondialdehyde (MDA), and reactive oxygen species (ROS), and enhanced activity of glutathione peroxidase (GPX) and superoxide dismutase (SOD). Mechanically, Nrf2/OH-1 signal pathway was activated by TIGAR. The effect of TIGAR on PCOS were verified in the primary rat GCs treated with dihydrotestosterone, but also the rescue experiment was performed. Downregulation of Nrf2 reversed the effects of TIGAR, indicating that TIGAR suppressed oxidative stress and GC apoptosis by activating Nrf2/OH-1 pathway in PCOS. Finally, non-targeted metabolomics revealed that TIGAR might affect the energy metabolic pathway, thereby altering the metabolic profile of primary rat GCs. This study provided new insights into the prevention and treatment of PCOS. • TIGAR overexpression alleviates polycystic ovary syndrome in rat. • TIGAR prevents oxidative stress by activating the Nrf2/HO-1 signaling pathway. • TIGAR expression affects metabolic processes in granulosa cells. [ABSTRACT FROM AUTHOR]

25-hydroxycholesterol (25HC) is an oxysterol derived from cholesterol and plays a role in various cellular processes, such as lipid metabolism, inflammatory responses, and cell survival. Extravillous trophoblasts (EVTs) are a major cell type found in the placenta, which are highly energetic cells with proliferative and invasive properties. EVT dysfunction can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction. This study investigated the effects and underlying mechanisms of action of 25HC on EVT proliferation. Swan 71 cells, an EVT cell line, were treated with different concentrations of 25HC. Next, cell proliferation was assessed. The mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potentials (MMPs), lipid peroxidation (LPO), and glutathione (GSH) levels were measured. Apoptosis, ferroptosis, and autophagy were evaluated by western blotting and flow cytometry. The results revealed that 25HC significantly inhibited proliferation and decreased the metabolic activity of EVTs. Moreover, 25HC caused oxidative stress by altering mtROS, LPO, MMPs, and GSH levels. Additionally, 25HC induces apoptosis, ferroptosis, and autophagy through the modulation of relevant protein levels. Interestingly, pretreatment with Z-VAD-FMK, an apoptosis inhibitor, and ferrostatin-1, a ferroptosis inhibitor, partially restored the effects of 25HC on cell proliferation, oxidative stress, and cell death. In summary, our findings suggest that 25HC treatment inhibits EVT proliferation and triggers apoptosis, ferroptosis, and autophagy, which are attributable to oxidative stress. [Display omitted] • 25-Hydroxycholesterol (25HC) inhibited proliferation and triggered oxidative stress in Swan 71 cells. • 25HC induced apoptosis by regulating the levels of p53, Bax, cleaved PARP, Bcl2, and caspase-3/7. • 25HC resulted in ferroptosis by elevating Fe2+ level and modulating the levels of NCOA4, FTH1, SLC7A11, and GPX4. • 25HC induced autophagy by increasing the levels of LAMP1 and LC3B-II and regulating the phosphorylation of AMPK and Akt. • Inhibition of apoptosis and ferroptosis partially alleviated 25HC-induced cell death. [ABSTRACT FROM AUTHOR]

This article, titled "[Retracted] Brain cell apoptosis inhibition by butylphthalide in Alzheimer's disease model in rats," was published in the journal Experimental & Therapeutic Medicine in 2017. However, it has since been retracted due to concerns raised by a reader. The TUNEL assay data presented in Figure 1A were found to be strikingly similar to data from other articles published by different authors at different research institutes. The authors were asked for an explanation but did not respond. The editor of the journal apologizes for any inconvenience caused. [Extracted from the article]

Proteasome inhibitors have been employed in the treatment of relapsed multiple myeloma and mantle cell lymphoma. The observed toxicity caused by proteasome inhibitors is a universal phenotype in numerous cancer cells with different sensitivity. In this study, we investigate the conserved mechanisms underlying the toxicity of the proteasome inhibitor bortezomib using gene editing approaches. Our findings utilizing different caspase knocking out cells reveal that bortezomib induces classic intrinsic apoptosis by activating caspase-9 and caspase-3/7, leading to pore-forming protein GSDME cleavage and subsequent lytic cell death or called secondary necrosis, a phenotype also observed in many apoptosis triggers like TNFα plus CHX, DTT and tunicamycin treatment in HeLa cells. Furthermore, through knocking out of nearly all BH3-only proteins including BIM, BAD, BID, BMF and PUMA, we demonstrate that NOXA is the sole BH3-only protein responsible for bortezomib-induced apoptosis. Of note, NOXA is well known for selectively binding to MCL-1 and A1, but our studies utilizing different BH3 mimetics as well as immunoprecipitation assays indicate that, except for the constitutive interaction of NOXA with MCL-1, the accumulation of NOXA after bortezomib treatment allows it to interact with BCL-XL, then simultaneous relieving suppression on apoptosis by both anti-apoptotic proteins BCL-XL and MCL-1. In addition, though bortezomib-induced significant ER stress and JNK activation were observed in the study, further genetic depletion experiments prove that bortezomib-induced apoptosis occurs independently of ER stress-related apoptosis factor CHOP and JNK. In summary, these results provide a solid conclusion about the critical role of NOXA in inactivation of BCL-XL except MCL-1 in bortezomib-induced apoptosis. • Bortezomib induces apoptosis with "blowing bubbles" phenotype mediated by GSDME. • NOXA is the sole BH3-protein responsible for bortezomib-induced apoptosis. • NOXA relieves both BCL-XL and MCL-1 suppression after bortezomib exposure. • CHOP and JNK are not required for bortezomib-induced apoptosis. [ABSTRACT FROM AUTHOR]

Introduction: Accumulating evidence demonstrates that long non-coding RNAs (lncRNAs) are associated with the development of osteoporosis. Methods: This study aimed to investigate the effects of MALAT1 on osteogenic differentiation and cell apoptosis in osteoporosis. MALAT1 level, detected by RT-qPCR, was downregulated in hindlimb unloading (HU) mice and simulated microgravity (MG)-treated MC3T3-E1 cells. Moreover, osteogenic differentiation-related factor (Bmp4, Col1a1, and Spp1) levels were measured by RT-qPCR and Western blot. ALP activity was detected, and ALP staining was performed. Cell apoptosis was assessed by flow cytometry. Results: The results revealed that MALAT1 upregulated the expression of Bmp4, Col1a1, and Spp1, and enhanced ALP activity. Knockdown of MALAT1 suppressed their expression and ALP activity, suggesting that MALAT1 promoted osteogenic differentiation. Additionally, MALAT1 inhibited apoptosis, increased Bax and caspase-3 levels, and decreased Bcl-2 level. However, knockdown of MALAT1 had opposite results. In MG cells, MALAT1 facilitated osteogenic differentiation and suppressed apoptosis. Furthermore, miR-485-5p was identified as a target of MALAT1, and WNT7B was verified as a target of miR-485-5p. Overexpression of miR-485-5p rescued the promotion of osteogenic differentiation and the inhibition of apoptosis induced by MALAT1. Knockdown of WNT7B abolished the facilitation of osteogenic differentiation and the suppression of apoptosis induced by downregulation of miR-485-5p. Discussion: In conclusion, MALAT1 promoted osteogenic differentiation and inhibited cell apoptosis through the miR-485-5p/WNT7B axis, which suggested that MALAT1 is a potential target to alleviate osteoporosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fibronectin type III domain containing 5 (FNDC5) is a protein molecule that regulates glycolipid metabolism, regulates cell apoptosis and participates in the inhibition of atherosclerosis. OBJECTIVE: By constructing a lentiviral vector overexpressing FNDC5 for transfecting human umbilical vein endothelial cells, to verify the effect of FNDC5 in regulating endothelial cell apoptosis. METHODS: The lentiviral vector overexpressing FNDC5 was constructed. Human umbilical vein endothelial cells in logarithmic growth phase were cultured and divided into three groups: blank group was not transfected with lentivirus, control group was transfected with an empty vector lentivirus without FNDC5, and experimental group was transfected with the lentiviral vector overexpressing FNDC5. At 7 days after transfection, RT-PCR and western blot were used to detect the mRNA and protein expression of FNDC5. After 7 days of transfection, oxidized low-density lipoprotein solution was added to the three groups of cells, and the cell viability was determined by cell counting kit-8 method, and cell apoptosis was detected by Hoechst 33342/PI double staining and flow cytometry. RESULTS AND CONCLUSION: The mRNA and protein expressions of FNDC5 in the experimental group were higher than those in the blank and control groups (P < 0.05). Cell counting kit-8 test results showed that the cell viability in the experimental group was higher than that in the blank and control group at 1 and 2 hours after addition of oxidized low-density lipoprotein (P < 0.05). However, there was no significant difference in the cell viability between the three groups at 4 hours after addition of oxidized low-density lipoprotein (P > 0.05). Flow cytometric results showed that the apoptotic rate was lower in the experimental group than the blank and control group at 24 hours after addition of oxidized low-density lipoprotein (P < 0.05). Hoechst 33342/PI double staining results showed that the number of apoptotic cells in experimental group was less than that in the blank and control groups. To conclude, overexpression of FNDC5 could inhibit the apoptosis of human umbilical vein endothelial cells. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify the role of HOXB9 and associated molecular mechanism in acquiring chemoresistance to ovarian cancer cells. After establishing HOXB9-overexpressing cells (HOXB9-OE/SKOV3), cisplatin resistance-induced cells (Cis-R/SKOV3), and an ovarian cancer xenograft mouse model, the effects of HOXB9 were evaluated in vitro and in vivo. Expression levels of ERCC-1, MRP-2, XIAP, and Bax/Bcl-2 were assessed as putative mechanisms mediating chemoresistance. Cisplatin-induced apoptosis was significantly decreased in HOXB9-OE/SKOV3 compared to SKOV3. Cisplatin treatment of SKOV3 strongly induced ERCC-1, MRP-2, and XIAP, and apoptosis was strongly induced through the inhibition of Bcl-2 and activation of Bax. ERCC-1, MRP-2, XIAP, and Bcl-2 were also strongly induced in HOXB9 OE/SKOV3. In contrast to SKOV3, cisplatin treatment alone of HOXB9 OE/SKOV3 did not affect the expression of Bcl-2 and Bax, and consequently, there was no increase in apoptosis. HOXB9 knockdown suppressed the expression of ERCC-1 and XIAP, but did not affect MRP-2 and Bcl-2/Bax expression in HOXB9 OE/SKOV3 and Cis-R/SKOV3, and caused a small increase in apoptosis. Treatment of SKOV3 with both cisplatin and siRNA_HOXB9 led to complete suppression of ERCC-1, MRP-2, and XIAP, and significantly increased apoptosis through inhibition of Bcl-2 expression and activation of Bax. The results observed in Cis-R/SKOV3 were similar to that in HOXB9 OE/SKOV3. Our data suggest that HOXB9 overexpression may cause chemoresistance in ovarian cancer cells by differential induction of ERCC-1, MRP-2, and XIAP depending on the strength of HOXB9 expression through inhibition of the mitochondrial pathway of apoptosis, including Bax/Bcl-2. [ABSTRACT FROM AUTHOR]

The present study investigated 3,3′‐dimethoxy‐4,4′‐dihydroxy‐stilbene triazole (DMDHSB) in vitro for alleviation of β‐amyloid mediated damage to the PC12 neuronal cells. Exposure of PC12 cells to DMDHSB significantly (P<0.05) reversed β‐amyloid induced loss of viability of PC12 cells in dose‐dependent manner. Moreover, DMDHSB exposure significantly (P<0.05) inhibited over production of PGE2 activated by β‐amyloid in PC12 cells. The β‐amyloid promoted higher levels of COX‐2 and NO were also down‐regulated in PC12 cells on exposure to DMDHSB. The exposure to DMDHSB led to a significant (P<0.05) inhibition of β‐amyloid promoted higher expression of iNOS. The β‐amyloid promoted higher release of iNOS was effectively alleviated by DMDHSB exposure in PC12 cells. In DMDHSB exposed PC12 cells, the β‐amyloid promoted elevation of NF‐κB nuclear translocation was effectively prevented compared to the control. It was observed from the docking studies that one‐pose of DMDHSB interacted with COX‐2 protein at binding affinity of −9.6 kcal/mol at 0‐rmsd. Thus, β‐amyloid promoted loss of PC12 cell viability is prevented on DMDHSB exposure through targeting inflammatory response. Therefore, DMDHSB may be developed as therapeutic candidate for investigation in detail against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Apoptosis of macrophages infected by Mycobacterium tuberculosis via Fas-FasL is an important immune mechanism against infection. This study investigated the association of tuberculosis (TB) with the presence of the polymorphisms FAS -670A/G and FASL -124A/G, the levels of sFas and sFasL, and the gene expression of FASL and cytokines. Samples of 200 individuals diagnosed with TB and 200 healthy controls were evaluated. Real-time PCR (genotyping and gene expression) and ELISA (dosages of sFas, sFasL, IFN-γ, and IL-10) tests were performed. There was no association of FAS -670A/G and FASL -124A/G polymorphisms with TB. The TB group exhibited high plasma levels of sFas and reduced plasma levels of sFasL (p < 0.05). The correlation analysis between these markers revealed a positive correlation between the levels of sFas and sFasL, sFasL and FASL expression, and between sFas and FASL expression (p < 0.05). In the TB group, there was a positive correlation between FASL expression and IFN-γ levels and higher levels of IL-10 compared to IFN-γ (p < 0.05). High levels of sFas and reduced levels of sFasL and FASL expression may contribute to the inhibition of apoptosis in infected cells and represent a possible bacterial resistance resource to maintain the infection. [ABSTRACT FROM AUTHOR]

The brain is the most sensitive organ to hypoxia in the human body. Hypoxia in the brain will lead to damage to local brain tissue. When the blood supply of ischemic brain tissue is restored, the damage will worsen, that is, cerebral ischemia–reperfusion injury. Hydrogen sulfide (H2S) is a gaseous signal molecule and a novel endogenous neuroregulator. Indeed, different concentrations of H2S have different effects on neurons. Low concentration of H2S can play an important protective role in cerebral ischemia–reperfusion injury by inducing anti-oxidative stress injury, inhibition of inflammatory response, inhibition of cell apoptosis, reduction of cerebrovascular endothelial cell injury, regulation of autophagy, and other ways, which provides a new idea for clinical diagnosis and treatment of related diseases. This review aims to report the recent research progress on the dual effect of H2S on brain tissue during cerebral ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Graphic 1. Schematic illustration of anti-dysfunctional activities exerted by non-split HDL and proatherosclerotic effects induced by OxHDL. [Display omitted] Numerous studies have demonstrated that dysfunctional high-density lipoprotein (HDL), especially oxidized HDL (OxHDL), could generate multifaceted in vivo proatherogenic effects that run counter to the antiatherogenic activities of HDL. It thereby reminded us that the in vitro reconstituted HDL (rHDL) might encountered with oxidation-induced dysfunction. Accordingly, a green-inspired method was employed to recycle non-split HDL from human plasma fraction IV. Then it was compared with rHDL formulated by an ethanol-injection method in terms of physicochemical properties and anti-dysfunctional activities. Results exhibited that rHDL oxidation extent exceeded that of non-split HDL evidenced by higher malondialdehy content, weaker inhibition on low-density lipoprotein (LDL) oxidation and more superoxide anion. The reserved paraoxonase-1 activity on non-split HDL could partially explain for above experimental results. In the targeted transport mechanism experiment, upon SR-BI receptor inhibition and/or CD36 receptor blockage, the almost unchanged non-split HDL uptake in lipid-laden macrophage indicated its negligible oxidation modification profile with regard to rHDL again. Furthermore, compared to rHDL, better macrophage biofunctions were observed for non-split HDL as illustrated by accelerated cholesterol efflux, inhibited oxidized LDL uptake and lessened cellular lipid accumulation. Along with decreased ROS secretion, obviously weakened oxidative stress damage was also detected under treatment with non-split HDL. More importantly, foam cells with non-split HDL-intervention inspired an enhanced inflammation repression and apoptosis inhibition effect. Collectively, the anti-dysfunctional activities of non-split HDL make it suitable as a potential nanocarrier platform for cardiovascular drug payload and delivery. [ABSTRACT FROM AUTHOR]