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Excessive apoptosis of intestinal epithelial cells leads to intestinal barrier dysfunction, which is not only one of the pathological features of inflammatory bowel disease (IBD) but also a therapeutic target. A natural plant extract, Ginkgetin (GK), has been reported to have anti-apoptotic activity, but its role in IBD is unknown. This study aimed to explore whether GK has anti-colitis effects and related mechanisms. An experimental colitis model induced by dextran sulfate sodium (DSS) was established, and GK was found to relieve colitis in DSS-induced mice as evidenced by improvements in weight loss, colon shortening, Disease Activity Index (DAI), macroscopic and tissue scores, and proinflammatory mediators. In addition, in DSS mice and TNF-α-induced colonic organoids, GK protected the intestinal barrier and inhibited intestinal epithelial cell apoptosis, by improving permeability and inhibiting the number of apoptotic cells and the expression of key apoptotic regulators (cleaved caspase 3, Bax and Bcl-2). The underlying mechanism of GK's protective effect was explored by bioinformatics, rescue experiments and molecular docking, and it was found that GK might directly target and activate EGFR, thereby interfering with PI3K/AKT signaling to inhibit apoptosis of intestinal epithelial cells in vivo and in vitro. In conclusion, GK inhibited intestinal epithelial apoptosis in mice with experimental colitis, at least in part, by activating EGFR and interfering with PI3K/AKT activation, explaining the underlying mechanism for ameliorating colitis, which may provide new options for the treatment of IBD., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background and Aims: Impaired intestinal barrier function is key in maintaining intestinal inflammation in Crohn's disease (CD). However, no targeted treatment in clinical practice has been developed. Peiminine (Pm) strongly protects the epithelial barrier, the purpose of this study is to investigate whether Pm affects CD-like colitis and potential mechanisms for its action., Methods: Trinitro-benzene-sulfonic acid (TNBS)-induced mice and Il-10 -/- mice were used as CD animal models. Colitis symptoms, histological analysis, and intestinal barrier permeability were used to assess the Pm's therapeutic effect on CD-like colitis. The colon organoids were induced by TNF-α to evaluate the direct role of Pm in inhibiting apoptosis of the intestinal epithelial cells. Western blotting and small molecule inhibitors were used to investigate further the potential mechanism of Pm in inhibiting apoptosis of intestinal epithelial cells., Results: Pm treatment reduced body weight loss, disease activity index (DAI) score, and inflammatory score, demonstrating that colonic inflammation in mice were alleviated. Pm decreased the intestinal epithelial apoptosis, improved the intestinal barrier function, and prevented the loss of tight junction proteins (ZO1 and claudin-1) in the colon of CD mice and TNF-α-induced colonic organoids. Pm activated Nrf2/HO1 signaling, which may protect intestinal barrier function., Conclusions: Pm inhibits intestinal epithelial apoptosis in CD mice by activating Nrf2/HO1 pathway. This partially explains the potential mechanism of Pm in ameliorating intestinal barrier function in mice and provides a new approach to treating CD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Severe respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC., Purpose: Our study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection., Study Design and Methods: A murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD 50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed., Results: PTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner., Conclusion: In conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background and Aims: Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved., Methods: Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis., Results: The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro., Conclusions: MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo . Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To investigate the effects of the serine/threonine kinase family member 1 ( PIM1 ) gene on the proliferation and apoptosis of acute myeloid leukemia (AML) U937 cells, and the regulation effect on Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway., Methods: Bone marrow mononuclear cells from newly diagnosed adult AML patients and patients with iron deficiency anemia were collected and PIM1 mRNA expression was detected by RT-qPCR. AML cell line U937 cells were divided into U937 group (U937 cells were cultured normally), Si-PIM1 group (U937 cells were transfected with low expression adenovirus vector containing PIM1 mRNA), Si-NC group (U937 cells were transfected with low expression adenovirus vector without PIM1 mRNA), coumermycin A1 (CoA1) group (JAK2 activator CoA1 was added to U937 cells at a concentration of 20 μmol/L), and Si-PIM1+CoA1 group (U937 cells were transfected with adenoviral vector containing low expression of PIM1 mRNA and added with CoA1 at a concentration of 20 μmol/L). After culture for 24 h, the expressions of PIM1 mRNA and protein, JAK2/STAT3 pathway, cell cycle and apoptosis-related proteins in U937 cells were detected by RT-qPCR and Western blot, the cell proliferation activity was detected by MTT assay, and flow cytometry was used to detect cell cycle changes and apoptosis rate., Results: The PIM1 mRNA expression level in bone marrow mononuclear cells in AML patients was higher than that in patients with iron deficiency anemia ( P < 0.05). Compared with U937 group, PIM1 mRNA and protein, phosphorylated JAK2 (p-JAK2)/JAK2, phosphorylated STAT3 (p-STAT3)/STAT3, Cyclin D1, cyclin-dependent kinase 2 (CDK2) protein, cell proliferation activity, S phase and G 2 /M phase proportions were decreased in Si-PIM1 group (all P < 0.05), while p27, Caspase-3 protein, G 0 /G 1 phase proportion and apoptosis rate were increased (all P < 0.05). However, the changes of above indicators in CoA1 group were just opposite to those in Si-PIM1 group, indicating that CoA1 could reverse the effect of Si-PIM1 on U937 cells. There were no significant differences in above indexes of U937 cells between U937 group, Si-PIM1+CoA1 group and Si-NC group ( P >0.05)., Conclusion: Knockdown of PIM1 gene expression can inhibit U937 cell proliferation and promote apoptosis, in order to alleviate ALM process, which may be related to the inhibition of JAK2/STAT3 pathway activation.

Two new quinoline alkaloids with an α, β-unsaturated amide side chain, xylarinines A and B (1 and 2), were isolated from the ethyl acetate extracts of Xylaria longipes solid fermentation. The structures of these were primarily determined though NMR and HRESIMS data analysis. The absolute configuration of compound 1 was assigned using experimental and calculated ECD data. The neuroprotective effects of compounds 1 and 2 against glutamate-induced damage in PC12 cells were evaluated in vitro bioassay. The results demonstrated that both compounds significantly improved cell viability, inhibited apoptosis, decreased malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione (GSH) levels, and reduced intracellular reactive oxygen species (ROS) accumulation. These findings suggested that these mechanisms contribute to the neuroprotective effects of the compounds., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

The restoration of the function of p53 in tumors is a therapeutic strategy for the highly frequent mutation of the TP53 tumor suppressor gene. P460 is a wild-type peptide derived from the p53 C-terminus and has been proven to be capable of restoring the tumor suppressor function of p53. The poor accumulation of drugs in tumors is a serious hindrance to tumor treatment. For enhancing the activity of P460, the tumor-targeting sequence Arg-Gly-Asp-Arg (RGDR, C-end rule peptide) was introduced into the C-terminus of P460 to generate the new peptide P462. P462 presented better activity than P460 in inhibiting the proliferation of cancer cells and increasing the number of tumor cells undergoing apoptosis. Cell adhesion analysis and tumor imaging results revealed that P462 showed more specific and extensive binding with tumor cells and greater accumulation in tumors than the wild-type peptide. Importantly, treatment with P462 was more efficacious than that with P460 in vivo and was associated with considerably improved tumor-homing activity. This study highlights the importance of the roles of the tumor-homing sequence RGDR in the enhancement in cell attachment and tumor accumulation. The results of this work indicate that P462 could be a novel drug candidate for tumor treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nucleus pulposus (NP) cell apoptosis is a significant indication of accelerated intervertebral disc degeneration; however, the precise mechanism is unelucidated as of yet. Ephrin B2 (EFNB2), the only gene down-regulated in the three degraded intervertebral disc tissue microarray groups (GSE70362, GSE147383 and GSE56081), was screened for examination in this study. Subsequently, EFNB2 was verified to be down-regulated in degraded NP tissue samples. Interleukin-1 (IL-1β) treatment of NP cells to simulate the IDD environment indicated that IL-1β treatment decreased EFNB2 expression. In degenerative NP cells stimulated by IL-1β, EFNB2 knockdown significantly increased the rate of apoptosis as well as the apoptosis-related molecules cleaved-caspase-3 and the Bax to Bcl-2 ratio. EFNB2 was found to promote AKT, PI3K, and mTOR phosphorylation; the PI3K/AKT signaling role was investigated using the PI3K inhibitor LY294002. EFNB2 overexpression significantly increased PI3K/AKT pathway activity in IL-1β-stimulated NP cells than the normal control. Moreover, EFNB2 partially alleviated NP cell apoptosis induced by IL-1β, reduced the cleaved-cas3 level, and decreased the Bax/Bcl-2 ratio after the addition of the inhibitor LY294002. Additionally, EFNB2 overexpression inhibited the ERK1/2 phosphorylation; the effects of EFNB2 overexpression on ERK1/2 phosphorylation, degenerative NP cell viability, and cell apoptosis were partially reversed by ERK signaling activator Ceramide C6. EFNB2 comprehensively inhibited the apoptosis of NP cells by activating the PI3K/AKT signaling and inhibiting the ERK signaling, obviating the exacerbation of IDD. EFNB2 could be a potential target to protect against degenerative disc changes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

20(S)-Ginsenoside Rh2 has significant anti-tumor effects in various types of cancers, including human hepatocellular carcinoma (HCC). However, its molecular targets and mechanisms of action remain largely unknown. Here, we aim to elucidate the potential mechanisms by which Rh2 suppresses HCC growth. We first demonstrate the role of Rh2 in inhibiting angiogenesis. We observe that Rh2 effectively suppresses cell proliferation and induces apoptosis in HUVECs. Furthermore, Rh2 significantly inhibits HepG2-stimulated HUVEC proliferation, migration and tube formation, accompanied by the downregulation of VEGF and MMP-2 expressions. We also reveal that Rh2 inhibits HCC growth through the downregulation of glypican-3-mediated activation of the Wnt/β-catenin pathway. We observe a dose-dependent inhibition of proliferation and induction of apoptosis in HepG2 cells upon Rh2 treatment, which is mediated by the inhibition of glypican-3/Wnt/β-catenin signaling. Moreover, downregulation of glypican-3 expression enhances the effects of Rh2 on the glypican-3/Wnt/β-catenin signaling pathway, resulting in greater suppression of tumor growth in HepG2 cells. Collectively, our findings shed light on the molecular mechanisms through which Rh2 modulates HCC growth, which involve the regulation of angiogenesis and the glypican-3/Wnt/β-catenin pathway. These insights may pave the way for the development of novel therapeutic strategies targeting these pathways for the treatment of HCC.

Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme-mediated tumor apoptosis and enzyme-promoted metabolic clearance is proposed and achieved using GOx-functionalized rhenium nanoclusters-doped polypyrrole (Re@ReP-G). Re@ReP-G reduces ATP production while increasing H 2 O 2 concentrations in the tumor microenvironment through GOx-induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti-apoptotic Bcl-2 proteins, the upregulation of pro-apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser-induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H 2 O 2 catalyzes the conversion of rhenium nanoclusters in Re@ReP-G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP-G-based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Myocardial ischemia-reperfusion injury (MIRI) is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction. It has been shown that cocaine and amphetamine-regulated transcript (CART) can ameliorate cerebral ischemia-reperfusion (I/R) injury, but the effect of CART on MIRI has not been studied yet. Here, we revealed that CART protected the heart during I/R process by inhibiting apoptosis and excessive autophagy, indicating that CART would be a potential drug candidate for the treatment of MIRI. Further analysis showed that CART upregulated the activation of phospho-AKT, leading to downregulation of lactate dehydrogenase (LDH) release, apoptosis, oxidative stress and excessive autophagy after I/R, which was inhibited by PI3K inhibitor, LY294002. Collectively, CART attenuated MIRI through inhibition of cardiomyocytes apoptosis and excessive autophagy, and the protective effect was dependent on PI3K/AKT signalling pathway., (© 2024 John Wiley & Sons Australia, Ltd.)

In recent years, the physical phenomenon of liquid-liquid phase separation has been widely introduced into biological research. Membrane-free organelles have been found to exist in cells that were driven by liquid-liquid phase separation. Intermolecular multivalent interactions can drive liquid-liquid phase separation to form condensates that are independent of other substances in the environment and thus can play an effective role in regulating multiple biological processes in the cell. The way of cell death has also long been a focus in multiple research. In the face of various stresses, cell death-related mechanisms are crucial for maintaining cellular homeostasis and regulating cell fate. With the in-depth study of cell death pathways, it has been found that the process of cell death was also accompanied by the regulation of liquid-liquid phase separation and played a key role. Therefore, this review summarized the roles of liquid-liquid phase separation in various cell death pathways, and explored the regulation of cell fate by liquid-liquid phase separation, with the expectation that the exploration of the mechanism of liquid-liquid phase separation would provide new insights into the treatment of diseases caused by regulated cell death., Competing Interests: Declaration of competing interest The authors have no personal, financial, or other conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pristimerin (Pris), a bioactive triterpenoid compound extracted from the Celastraceae and Hippocrateaceae families, has been reported to exhibit an anti-cancer property on various cancers. However, the effects of Pris on esophageal cancer are poorly investigated. This current study sought to explore the activity and underlying mechanism of Pris against human esophageal squamous cell carcinoma (ESCC) cells. We demonstrated that Pris showed cytotoxicity in TE-1 and TE-10 ESCC cell lines, and significantly inhibited cell viability in a concentration dependent manner. Pris induced G0/G1 phase arrest and triggered apoptosis. It was also observed that the intracellular ROS level was remarkedly increased by Pris treatment. Besides, the function of Pris mediating the activation of ER stress and the inhibition of AKT/GSK3β signaling pathway in TE-1 and TE-10 cells was further confirmed, which resulted in cell growth inhibition. And moreover, we revealed that all of the above pathways were regulated through ROS generation. In conclusion, our findings suggested that Pris might be considered as a novel natural compound for the developing anti-cancer drug candidate for human esophageal cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In SARS-CoV-2 infection, it has been observed that viral replication lasts longer in the nasal mucosa than in the lungs, despite the presence of a high viral load at both sites. In hamsters, we found that the nasal mucosa exhibited a mild inflammatory response and minimal pathological injuries, whereas the lungs displayed a significant inflammatory response and severe injuries. The underlying cellular events may be induced by viral infection in three types of cell death: apoptosis, pyroptosis, and necroptosis. Our findings indicate that apoptosis was consistently activated during infection in the nasal mucosa, and the levels of apoptosis were consistent with the viral load. On the other hand, pyroptosis and a few instances of necroptosis were observed only on 7 dpi in the nasal mucosa. In the lungs, however, both pyroptosis and apoptosis were prominently activated on 3 dpi, with lower levels of apoptosis compared to the nasal mucosa. Interestingly, in reinfection, obvious viral load and apoptosis in the nasal mucosa were detected on 3 dpi, while no other forms of cell death were detected. We noted that the inflammatory reactions and pathological injuries in the nasal mucosa were milder, indicating that apoptosis may play a role in promoting lower inflammatory reactions and milder pathological injuries and contribute to the generation of long-term viral replication in the nasal mucosa. Our study provides valuable insights into the differences in cellular mechanisms during SARS-CoV-2 infection and highlights the potential significance of apoptosis regulation in the respiratory mucosa for controlling viral replication., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Carbon black nanoparticles (CBNPs) are widely distributed in the environment and are increasingly recognized as a contributor in the development of cardiovascular disease. A variety of cardiac injuries and diseases result from structural and functional damage to cardiomyocytes. This study explored the mechanisms of CBNPs-mediated myocardial toxicity. CBNPs were given to mice through intra-tracheal instillation and it was demonstrated that the particles can be taken up into the cardiac tissue. Exposure to CBNPs induced cardiomyocyte inflammation and apoptosis. In combination with in vitro experiments, we showed that CBNPs increased the ROS and induced mitochondria fragmentation. Functionally, CBNPs-exposed cardiomyocyte exhibited depolarization of the mitochondrial membrane potential, release of cytochrome c, and activation of pro-apoptotic BAX, thereby initiating programmed cell death. On the other hand, CBNPs impaired autophagy, leading to the inadequate removal of dysfunctional mitochondria. The excess accumulation of damaged mitochondria further stimulated NF-κB activation and triggered the NLRP3 inflammasome pathway. Both the antioxidant N-acetylcysteine and the autophagy activator rapamycin were effective to attenuate the damage of CBNPs on cardiomyocytes. Taken together, this study elucidated the potential mechanism underlying CBNPs-induced myocardial injury and provided a scientific reference for the evaluation and prevention of the CBNPs-related heart risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dendritic cells (DCs), the most efficient antigen-presenting cells (APCs), bridge the innate and adaptive immune systems. As such, the turn-over of DCs is critical during autoimmune responses, and the dysregulation of DC apoptosis could cause severe immune destruction in the host. For example, reduction of immunogenic DCs by increased apoptosis could lead to immune tolerance to pathogen infection that might allow exposure of nuclear autoantigens, whereas reduced apoptosis could result in long-term lymphocyte activation to break the immune tolerance for the development of autoimmune disease. Thus, keeping a balance between survival and apoptosis of DCs is crucial to maintain immune homeostasis. In this review, we summarize the recent development on the factors inducing DC apoptosis and their underlying mechanisms to provide insights into the immunopathogenesis of some autoimmune diseases, which could lead to effective therapeutic interventions in the clinics., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Objective: To investigate the effects and mechanisms of zinc finger E-box binding homeobox transcription factor-2 ( ZEB 2) on the proliferation, colony formation, migration, and invasion abilities and the epithelial-mesenchymal transition (EMT) of PANC-1 cells, a human pancreatic cancer cell line., Methods: Data on the expression of ZEB 2 in pancreatic cancer tissues and paracancerous tissues from The Cancer Genome Atlas (TCGA) database were analyzed. PANC-1 pancreatic cancer cells were divided into si-NC group, si- ZEB 2 group, pcDNA3.1 group, and pcDNA3.1- ZEB 2 group. qRT-PCR and Western blot were conducted to confirm the effectiveness of ZEB 2 knockdown or overexpression. CCK-8, colony formation, wound healing, and Transwell assays were conducted to examine the effects of ZEB 2 on the proliferation, colony formation, migration, and invasion of PANC-1 cells. qRT-PCR and immunofluorescence assays were performed to examine the expression of E-cadherin and vimentin, the EMT markers, in the cells. Prediction of proteins interacting with ZEB2 was made through the STRING database., Results: TCGA database analysis showed that the expression level of ZEB 2 in pancreatic cancer tissues was significantly higher than that in adjacent tissues ( P <0.05). Compared with those of cells in the control group, the proliferation, colony formation, migration, and invasion of cells in the si- ZEB 2 group were decreased ( P <0.05). Compared with those of cells in the pcDNA3.1 group, the proliferation, colony formation, migration and invasion of cells in the pcDNA3.1- ZEB 2 group were increased (all P <0.05). According to the results of qRT-PCR and immunofluorescence assays, compared with those of the si-NC group, the expression of E-cadherin mRNA, an epithelial marker, in the si- ZEB 2 group increased, while the expression of vimentin mRNA, an mesenchymal marker, and the protein decreased. Compared with those of the pcDNA3.1 group, the expression of E-cadherin mRNA in the PANC-1 cells of the pcDNA3.1- ZEB 2 group decreased, while the expression of vimentin mRNA and the protein increased (all P <0.05). Analysis with the STRING database predicted that 10 proteins had close interaction with ZEB2., Conclusion: Overexpression of ZEB 2 promotes the migration, invasion, and the EMT process of PANC-1 pancreatic cancer cells., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

In this study, a double resonator piezoelectric cytometry (DRPC) technology based on quartz crystal microbalance (QCM) was first employed to identify HeLa cell pyroptosis and apoptosis by monitoring cells' mechanical properties in a real-time and non-invasive manner. AT and BT cut quartz crystals with the same frequency and surface conditions were used concurrently to quantify the cells-exerted surface stress (Δ S ). It is the first time that cells-exerted surface stress (Δ S ) and cell viscoelasticity have been monitored simultaneously during pyroptosis and apoptosis. The results showed that HeLa pyroptotic cells exerted a tensile stress on quartz crystal along with an increase in the elastic modulus ( G '), viscous modulus ( G ″), and a decrease of the loss tangent ( G ″/ G '), whereas apoptotic cells exerted increasing compressive stress on quartz crystal along with a decrease in G ', G ″ and an increase in G ″/ G '. Furthermore, engineered GSDMD -/- -DEVD- HeLa cells were used to investigate drug-induced disturbance and testify the mechanical responses during the processes of pyroptosis and non-pyroptosis. These findings demonstrated that the DRPC technology can serve as a precise cytomechanical sensor capable of identifying pyroptosis and apoptosis, providing a novel method in cell death detection and paving the road for pyroptosis and apoptosis related drug evaluation and screening.

Background: Copper (Cu) metabolism is strongly associated with liver disease. Cuproptosis is a novel format of cell death, and cuproptosis-related genes (CRGs) were identified. However, the role of CRGs in Hepatocellular Carcinoma (HCC) remains unknown., Method: The mRNA transcriptome profiling data, somatic mutation data, and copy number gene level data of The Cancer Genome Atlas-Liver Hepatocellular Carcinoma project (TCGA-LIHC) were downloaded for subsequent analysis. Molecular characterization analysis of CRGs, including differential gene expression analysis, mutation analysis, copy number variation (CNV) analysis, Kaplan-Meier analysis, and immune regulator prioritization analysis, was implemented. The nonnegative matrix factorization (NMF) approach was used to identify the CRG-related molecular subtypes. Principal component analysis was adopted to verify the robustness and reliability of the molecular subtype. The least absolute shrinkage and selection operator regression analysis was performed to construct the prognostic signature based on differentially expressed genes between molecular subtypes. The survival characteristics of the molecular subtype and the signature were analyzed. The Gene Set Variation Analysis was performed for functional annotation. The immune landscape analysis, including immune checkpoint gene analysis, single sample gene set enrichment analysis, tumor immune dysfunction and exclusion (TIDE) analysis, immune infiltration cell, and tumor mutation burden analysis (TMB), was conducted. The ability of the signature to predict conventional anti-HCC agent responses was evaluated. The signature was validated in the LIRI-JP cohort and the IMvigor210 cohort., Result: A total of 13 CRGs are differentially expressed between the tumor and normal samples, while the mutation of CRGs in HCC is infrequent. The expression of CRGs is associated with the CNV level. Fourteen CRGs are associated with the prognosis of HCC. Two clusters were identified and HCC patients were divided into 2 groups with a cutoff risk score value of 1.570. HCC patients in the C1 cluster and high-risk have a worse prognosis. The area under the receiver operating characteristic curve for predicting 1-, 2-, and 3-year overall survival is 0.775, 0.768, and 0.757 in the TCGA-LIHC cohort, and 0.811, 0.741, and 0.775 in the LIRI-JP cohort. Multivariate Cox regression analysis indicates that the signature is an independent prognostic factor. Pathways involved in metabolism and gene stability and immune infiltration cells are significantly enriched. Immune checkpoint genes are highly expressed in the C1 cluster. TMB is positively correlated with the risk score. HCC patients in the high-risk group are more likely to benefit from conventional anti-HCC agents and immune checkpoint inhibitor therapies., Conclusion: The molecular characterization of CRGs in HCC is presented in this study, and a successful prognostic signature for HCC based on the cuproptosis-related molecular subtype was constructed., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Xiangjun Qi et al.)

Rhein, one of the main active components of rhubarb (Dahuang) and Polygonum multiflorum (Heshouwu), has a wide range of effective pharmacological effects. Recently, increasing studies have focused on its potential hepatorenal toxicity, but the cardiotoxicity is unknown. In this study, we found that the IC 50 of rhein to H9c2 cells at 24 h and 48 h were 94.5 and 45.9μmol/L, respectively, with positive correlation of dose-toxicity and time-toxicity. After the treatment of rhein (106, 124 and 132μmol/L), the number of H9c2 cells decreased significantly, and the morphology of H9c2 cells showed atrophy, round shape and wall detachment. Moreover, the proportion of apoptotic cells in H9c2 cells treated with rhein was significantly increased in a dose-dependent manner. And rhein induced S phase arrest of H9c2 cells and inhibited cell proliferation. Rhein up-regulated ROS, LDH levels and low MMP but down-regulated SOD content in H9c2 cells. Additionally, the results showed that the cardiac function LVEF and LVFS of rhein high-medium-low dose groups (350, 175, 87.5 mg/kg) were significantly reduced. And the contents of Ca 2+ , cTnT, CK and LDH in serum of KM mice were significantly up-regulated by rhein. Furthermore, western blot results suggested that rhein the above effects via promoting Fas-induced apoptosis pathway in vitro and in vivo. In general, rhein may cause cardiotoxicity via Fas-induced apoptosis pathway in vivo and in vitro, which provides reference for the safe use of medicinal plant containing rhein and its preparations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.

Helicobacter pylori infection is an essential factor in the development of human gastric diseases, but its pathogenic mechanism is still unclear. In this work we have showed that, the LC3II levels were increased and β1-integrin levels were decreased in H. pylori-positive human gastric tissue samples and H. pylori co-cultured GES-1 cells. There was significant upregulation of LC3II levels and downregulation of P62 levels in GES-1 cells after β1-integrin knockdown co-cultured with H. pylori. This indicated that β1-integrin downregulation promoted autophagy in GES-1 cells after H. pylori infection. The cell apoptosis rate and poly ADP-ribose polymerase (PARP) and caspase-3 activities were increased in GES-1 cells pretreated with 3-methyladenine (3-MA ) after H. pylori infection. Furthermore, there was a significant decrease in apoptosis of β1-integrin knockdown GES-1 cells co-cultured with H. pylori; apoptosis was also downregulated in β1-integrin knockdown- and 3-MA-treated GES-1 cells co-cultured with H. pylori. Correspondingly, PARP and caspase-3 activities were decreased in β1-integrin knockdown cells co-cultured with H. pylori and β1-integrin knockdown-3-MA-treated-1 cells with H. pylori infection. Thus, β1-integrin is a novel autophagy and apoptosis regulator during H. pylori infection. However, inhibition of autophagy did not reverse the decrease in apoptosis caused by downregulation of β1-integrin., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnT R141W transgenic mice, which developed typical DCM phenotypes, were used. Following treatment with DAS for 6 weeks, echocardiography, histological analysis and molecular marker detection were conducted to investigate the DAS‑induced improvement on myocardial function and morphology. Biochemical analysis, western blotting and TUNEL assays were used to detected ROS production and myocyte apoptosis. It was found that DAS improved the typical DCM phenotypes, including chamber dilation, wall thinning, fibrosis, poor myofibril organization and decreased ventricular blood ejection, as determined using echocardiographic and histopathological analyses. Furthermore, the regulatory mechanisms, including inhibition both of the oxidative stress levels and the mitochondria‑dependent apoptosis pathways, were involved in the effects of DAS. In particular, DAS showed advantages in terms of improved chamber dilation and dysfunction in model mice, and the improvement occurred in the early stage of the treatment compared with enalaprilat, an angiotensin‑converting enzyme inhibitor that has been widely used in the clinical treatment of DCM and HF. The current results demonstrated that DAS could protect against DCM via inhibition of oxidative stress and apoptosis. These findings also suggest that inhibition of CYP2E1 may be a valuable therapeutic strategy to control the development of heart diseases, especially those associated with CYP2E1 upregulation. Moreover, the development of DAS analogues with lower cytotoxicity and metabolic rate for CYP2E1 may be beneficial.

Programmed cell death (PCD) plays crucial roles in plant development and defence response. Reactive oxygen species (ROS) are produced during normal plant growth, and high ROS concentrations can change the antioxidant status of cells, leading to spontaneous cell death. In addition, ROS function as signalling molecules to improve plant stress tolerance, and they induce PCD under different conditions. This review describes the mechanisms underlying plant PCD, the key functions of mitochondria and chloroplasts in PCD, and the relationship between mitochondria and chloroplasts during PCD. Additionally, the review discusses the factors that regulate PCD. Most importantly, in this review, we summarise the sites of production of ROS and discuss the roles of ROS that not only trigger multiple signalling pathways leading to PCD but also participate in the execution of PCD, highlighting the importance of ROS in PCD.

The present study aimed to investigate the mechanism(s) through which endoplasmic reticulum stress (ERS)-induced apoptosis, in the role of periodontitis, affects vascular calcification. Rat models of periodontitis, vascular calcification, periodontitis-vascular calcification, and a normal group were established. Cardiovascular tissues were obtained, and hematoxylin-eosin staining was applied to demonstrate the morphological changes in vascular tissues. Immunohistochemical staining was applied to analyze apoptosis in cardiovascular tissues. The expression levels of apoptotic factor cysteinyl aspartate specific proteinase 3 (Caspase-3), ERS-induced apoptotic factors glucose-regulated protein 78 (GRP78), 94 (GRP94), and ERS-induced apoptosis pathways Caspase-12, C/EBP homologous protein (CHOP), and c-Jun N-terminal kinase (JNK) were analyzed and compared. Hematoxylin-eosin staining revealed that the arterial layers in the normal group were structurally intact. The structural damage to the aortic wall gradually aggravated from the periodontitis group to the vascular calcification group to the combined group. The immunohistochemistry results showed Caspase-3, GRP78, GRP94, and ERS-induced apoptosis pathways in the cardiovascular tissues cells in the periodontitis group, vascular calcification group, and combined group. The Caspase-3, GRP78, GRP94, and CHOP expression levels in the combined group were significantly higher than that in the normal group (P < 0.05); however, the Capase-12 and JNK expression levels in the four groups exhibited no significant differences (P > 0.05). Apoptosis induced by ERS is involved in the effect of periodontitis on vascular calcification and might be mainly achieved through the activation of the CHOP transcription pathway., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Chromosomal instability (CIN) is a hallmark of cancer 1 . Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably 'silent' genomes with minimal CIN 2 . Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe.Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials., (© 2021. The Author(s).)

Background: Various circular RNAs (circRNAs) are dysregulated in the placenta of fetal growth restriction (FGR) fetuses, but their roles and regulatory mechanisms have not been fully elucidated. Herein, we aimed to elucidate the role of hsa&#95;circ&#95;0081343 in regulating the migration, invasion, and apoptosis of human extravillous trophoblast HTR-8 cells., Methods: CircRNA and miRNA levels were examined by quantitative reverse transcription PCR (qRT-PCR). Overexpression plasmid constructs and siRNAs were used to overexpress and knockdown hsa&#95;circ&#95;0081343, respectively. Transwell assays and flow cytometry analyses were performed to evaluate the effects of hsa&#95;circ&#95;0081343 or miR-210-5p on migration, invasion, and apoptosis. Protein levels were analyzed by western blotting. Dual luciferase activity and anti-AGO2 RNA immunoprecipitation (RIP) assays were performed to identify the relationship between miR-210-5p and hsa&#95;circ&#95;0081343., Results: Hsa&#95;circ&#95;0081343 expression was significantly downregulated in 37 FGR placental tissues compared to healthy placental control tissues. Hsa&#95;circ&#95;0081343 overexpression may inhibit apoptosis by downregulating the expression of cleaved caspase 3 and caspase 9 and alleviating the migration and invasion of HTR-8 cells by inducing the expression of MMP2 and MMP9. The dual luciferase activity and anti-AGO2 RIP assay results showed that hsa&#95;circ&#95;0081343 binds to miR-210-5p. miR-210-5p overexpression eliminated the effect of hsa&#95;circ&#95;0081343 overexpression in HTR-8 cells. Finally, DLX3 was identified as a direct target of miR-210-5p., Conclusions: hsa&#95;circ&#95;0081343 expression levels are significantly downregulated in FGR placental tissues. Hsa&#95;circ&#95;0081343 regulates the migration, invasion, and apoptosis of HTR-8 cells via the hsa-miR-210-5p/DLX3 axis., (© 2021. The Author(s).)

Background: Emerging evidence has indicated that exosomes serve as key regulators in acute myocardial infarction (AMI). This study was determined to investigate the effect of M2 macrophage-derived exosomes (M2-Exos) in AMI and the further mechanism., Methods: M2 macrophages were induced and M2-exos were isolated and verified. The AMI mouse model was prepared by ligation of the left anterior descending coronary artery (LAD) and then intravenously injected with the isolated M2-exos. The mouse cardiac function was assessed by echocardiography. Hematoxylin and eosin (HE) staining and TUNEL assay were conducted to examine myocardial lesion and apoptosis in cardiac tissues. The expressions of associated molecules were detected by quantitative real time-PCR (qRT-PCR) and western blot. MTT assay, Flow cytometry and Dual-luciferase reporter assay were carried out to detect cell viability, apoptosis and the interaction of miRNA and the target., Result: M2-Exos could promote cardiac repair in AMI mice. M2-Exos suppressed apoptosis and enhanced viability of hypoxia-induced cardiomyocytes through delivery of miR-1271-5p. SOX6 is a direct target of miR-1271-5p. miR-1271-5p decreased cardiomyocyte apoptosis induced by hypoxia and alleviated cardiac injury in AMI via down-regulating SOX6 expression., Conclusion: We identified that M2-Exos could carry miR-1271-5p to reduce apoptosis of cardiomyocytes and promote cardiac repair via down-regulating SOX6., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sepsis is one of the primary causes of death in intensive care units. Recently, increasing evidence has identified lncRNA HOTAIR is involved in septic cardiomyopathy. However, the potential mechanism underlying HOTAIR on septic cardiomyopathy is still unknown. H9C2 cells were treated with lipopolysaccharide (LPS) after transfection with sh-HOTAIR, sh-Lin28, pcDNA3.1-HOTAIR, and pcDNA3.1-PDCD4. qRT-PCR was used to examine the level of HOTAIR, Lin28, PDCD4, and sepsis-related inflammatory cytokines. Flow cytometric analysis was applied to detect cell apoptosis. The interaction between Lin28 and HOTAIR or PDCD4 was verified by RNA pull-down and RIP assay. HOTAIR levels were interfered by AAV9-sh-HOTAIR in LPS-induced septic cardiomyopathy mice. ELISA analysis was used to evaluate TNF-α, IL-6, and IL-1β level. Western blot was used to detect the expression of LIN28 and PDCD4 in mouse cardiomyocytes. Echocardiography was used to evaluate the cardiac function. In our study, knockdown of HOTAIR inhibited LPS-induced inflammation and H9C2 cells apoptosis. HOTAIR promoted LPS-induced inflammatory response and apoptosis of H9C2 cells by enhancing PDCD4 stability. RNA pull-down and RIP assay exhibited that Lin28, a highly conserved RNA-binding protein, was combined with HOTAIR and PDCD4. The in vivo experiments verified that the HOTAIR knockdown alleviated the cardiac function injury and secretion of inflammatory factors caused by sepsis. In conclusion, our findings supported that the HOTAIR/Lin28/PDCD4 axis serves as a critical regulator of sepsis, which may open a new direction for the development of sepsis therapeutic., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Microchromosome maintenance protein 7 (MCM7), a DNA replication permitting factor, plays an essential role in initiating DNA replication. MCM7 is reported to be involved in tumor formation and progression, whereas the expression profile and molecular function of MCM7 in colorectal cancer (CRC) remain unknown. In this study, we aimed to evaluate the clinical significance and biological function of MCM7 in CRC and investigated whether MCM7 can be used for a differential diagnosis in CRC and whether it may serve as a more sensitive proliferation marker for CRC evaluation. Moreover, immunohistochemical analysis of MCM7 was performed in a total of 89 specimens, and high MCM7 expression levels were associated with worse overall survival (OS) in CRC patients. Furthermore, the cell functional test suggested that lentivirus-mediated silencing of MCM7 with shRNA in CRC cells significantly inhibited cellular proliferation and promoted apoptosis in vitro and inhibited tumor growth in vivo. Additionally, mechanistic studies further demonstrated that P21-activated protein kinase 2 (PAK2) was regulated by MCM7 via microarray analysis and cell functional recovery tests, and miR-107 played a role in regulating expression MCM7 via miRNA microarray analysis and 3'UTR reporter assays. Taken together, our results suggest that the miR-107/MCM7/PAK2 pathway may participate in cancer progression and that MCM7 may serve as a prognostic biomarker in CRC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Glycine is a well-known free radical scavenger in the cellular antioxidant system that prevents oxidative damage and apoptosis. Excessive fluoride exposure is associated with multiple types of cellular damage in humans and animals. The objective of the present study was to investigate the protective effects of glycine on sodium fluoride (NaF) exposure and the possible underlying mechanisms in a porcine testicular Sertoli cell line model. Cellular viability and proliferation were examined following NaF exposure and glycine supplementation, and glycine dramatically ameliorated the decreases in NaF-induced porcine testicular Sertoli cell viability and proliferation. Further investigations revealed that glycine decreased NaF-induced intracellular reactive oxygen species production, DNA fragment accumulation and the apoptosis incidence in the porcine testicular Sertoli cell line; in addition, glycine improved mitochondrial function and ATP production. Notably, results of the SPiDER-β-Gal analysis suggested that glycine alleviated NaF-induced cellular senescence and downregulated P53, P21, HMGA2 and P16INK4a gene expression in the porcine testicular Sertoli cell line. Collectively, the beneficial effects of glycine alleviate NaF-induced oxidative stress, apoptosis and senescence, and together with our previous findings, support the hypothesis that glycine plays an important role in protecting against NaF exposure-induced impairments in the porcine testicular Sertoli cell line., (© 2021 Wiley-VCH GmbH.)

N- trans -Feruloyloctopamine (FO), a natural compound, was reported in our previous study to inhibit a tumor cell malignant phenotype by AKT- and EMT-related signals and might be used as a promising drug for HCC treatment. However, the specific targets and detailed mechanisms still need to be clarified. Screening with RNA-Seq in Huh7 cells treated with FO revealed that 317 genes were modulated, of which 188 genes were upregulated and 129 genes were downregulated. Real-time cell analyzer and flow cytometry data reveal that tumor cell proliferation and apoptosis were impacted by FO. DAVID bioinformatic data showed that most of the biological process GO terms are related to proliferation and apoptosis. KEGG enrichment analysis showed that FO mainly regulates PI3K-AKT- and apoptosis-related signals, in which BBC3, DDIT3, NOXA, and CDKN1A on the surface serve as the novel targets of FO inducing HCC cell apoptosis. The result implied that FO might exacerbate HCC cell apoptosis by regulating BBC3, DDIT3, CDKN1A, and NOXA signals. The obstacle effect of FO can provide new targets and new credibility for the treatment of liver cancer., Competing Interests: All authors declare that they have no conflicts of interest., (Copyright © 2021 Bin Ma et al.)

Heat Shock Protein 90 (Hsp90) is frequently upregulated in many cancers, and its inhibition simultaneously blocks multiple signaling pathways, resulting in cell differentiation or apoptosis. However, the complexity of Hsp90 in differentiation and its relation with apoptosis have remained unsettled. In this study, we demonstrated that HDN-1, a C-terminal inhibitor of Hsp90, induced the differentiation of HL-60 cells toward apoptosis. HDN-1 induced the differentiation of cells containing mutant AML1-ETO into mature granulocytes, which was related to its selective effect on client proteins of Hsp90. HDN-1 destabilized AML1-ETO and preserved C/EBPβ at the same time, thereby induced a total increase in C/EBPβ levels because of AML1-ETO negative regulation to C/EBPβ expression. Neither HDN-1 nor 17-AAG (an N-terminal inhibitor of Hsp90) led to the differentiation of NB4 cells because mutant PML-RARα was not affected as a client protein of Hsp90; thus, no additional expression of C/EBPβ was induced. 17-AAG did not affect the differentiation of HL-60 cells due to decreased AML1-ETO and C/EBPβ levels. These results indicate that HDN-1 drives cell differentiation toward apoptosis depending on its selective influence on client proteins of Hsp90, establishing the relationship between differentiation and apoptosis and uncovering the mechanism of HDN-1 in promyelocytic leukemia cell differentiation. Moreover, HDN-1 is very promising for the development of anticancer agents with the induction of differentiation., (Copyright © 2021. Published by Elsevier Inc.)

Gallbladder carcinoma (GC) is an extremely malignant gastrointestinal tumor, but relevant mechanisms are still under investigation. MicroRNA (miR) is differentially expressed in a variety of tumors. Here we explored miR-204 in patients with GC and related mechanisms. A GSE104165 chip was downloaded from the gene expression omnibus (GEO) for analysis. The qRT-PCR assay was used for quantifying miR-204 and Notch2 in the serum and tissues of the patients, and the patients were followed up for 3 years to analyze independent factors of prognosis. The CCK8, transwell, and flow cytometry assays were applied for analyzing proliferation, invasion, as well as apoptosis of cells, and the dual luciferase reporter (DLR) assay was adopted for determining the association of miR-204 with Notch2. MiR-204 was low in patients with GC, and it might serve as a diagnostic indicator for GC. In addition, patients with low e MiR-204 usually faced high rates of III+IV stage, distant metastasis, and low differentiation, and also showed a poor prognosis. DLR assay verified the targeted binding of miR-204 to Notch2 mRNA.

Non-small cell lung cancer (NSCLC) is the highest incidence and mortality of malignant tumors worldwide and has become a global public health problem. Long non-coding RNAs (LncRNAs) are expected to participate in the progression of NSCLC. This study aims to explore the effects and underlying mechanisms of LncRNA HOXC-AS2 on NSCLC cell proliferation, apoptosis, and migration. The Cell Counting Kit-8 (CCK-8) and clone formation assay were used to measure the A549 and HCC827 cell proliferation. The cell apoptosis and migration was respectively analyzed by flow cytometry and transwell assay. RNA immunoprecipitation (RIP) was used to detect the interaction between HOXC-AS2 and HOXC13. The expression of β-catenin, α-SMA, MMP-1, MMP-2 expression, E-cadherin, and Ki-67 expression were determined by Western blot or immunohistochemistry (IHC) assay. We found that HOXC-AS2 was significantly up-regulated in NSCLC tissues. Knockdown of HOXC-AS2 expression resulted in significant decreases in NSCLC cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process marker proteins, simultaneously activated A549 and HCC827 cell apoptosis. RIP assay suggested that HOXC13 was a functional target for HOXC-AS2. And HOXC-AS2 and HOXC13 could positively regulate each other. Compared with the normal tissues, the mRNA level of HOXC13 was increased in NSCLC tissues. HOXC13 silencing counteracted increases of A549 and HCC827 cell proliferation and migration, as well as a decrease of cell apoptosis induced by HOXC-AS2 overexpression. Moreover, HOXC-AS2 silencing reduced tumor growth rate and Ki-67 expression in vivo. Taken together, HOXC-AS2 knockdown inhibited NSCLC cell proliferation and migration, as well as stimulated NSCLC cell apoptosis through regulation of HOXC13 expression.

Unique plant-derived cyclic peptides family exhibiting various key biological activities has great possibility for anticancer therapy. In this study, we investigated the effects of orbitides isolated from flax ( Linum usitatissimum L.) on the growth of SGC-7901 cancer cells and the potential mechanism. Results showed that flaxseed orbitides killed off cancer cells by inducing apoptosis in a dose-dependent manner, which was confirmed by the appearance of nuclear shrinkage and DNA fragmentation, and the inhibitory effect was stronger than that of pure orbitide [1-9-NαC]-linusorb B2 or [1-9-NαC]-linusorb B3. Besides, the mitochondrial apoptosis pathway-related protein cytochrome C (Cyt C) was released from mitochondria to cytosol, associated with the activation of caspases 9 and 3, and the cleavage of PARP. Taken together, these results indicated that flaxseed orbitides induced apoptosis via the mitochondrial pathway, releasing Cyt C, increasing Bax/Bcl-2 ratio and elevating the expression of cleaved caspase 9 and 3 in SGC-7901 cells.

Endothelial microparticles (EMPs) are involved in various cardiovascular pathologies and play remarkable roles in communication between endothelial cells (ECs), which are constantly exposed to mechanical cyclic stretch (CS) following blood pressure. However, the roles of EMPs induced by CS in EC homeostasis are still unclear. Both fluorescence resonance energy transfer (FRET) and western blotting revealed the activation of Src in ECs was significantly increased by 5% CS-induced EMPs. Furthermore, proteomic analysis revealed that the contents were obvious different in the EMPs between 5%- and 15%-group. Based on the bioinformatic analysis, CD151 on EMPs was predicted to activate Src, which was further confirmed by both FRET and western blotting. Moreover, the expression of CD151 on EMPs was significantly increased by 5% CS and involved in the binding of EMPs to ECs. EC apoptosis, which was significantly decreased by 5% CS-derived EMPs, showed obvious increase after pretreatment with Src inhibitor in target ECs. Our present research suggests that mechanical stretch changes the components of EMPs, which in turn modulates EC apoptosis by Src activation. CD151 expressed on CS-induced EMPs may play important roles in EC communication and homeostasis., (© 2020 Federation of American Societies for Experimental Biology.)

We investigated the effects of velvet antler polypeptide on cognitive impairment and the underlying mechanisms. Hydrogen peroxide-induced cell injury was used to establish an in vitro model of SH-SY5Y cells. In addition, we established an in vivo mouse model of cognitive impairment using intraperitoneal injections of scopolamine hydrobromide in strain mice. We administered three different doses of velvet antler polypeptide in this mouse model and assessed the influence of velvet antler polypeptide on the morphology of hippocampal neurons, hippocampal neuronal apoptosis, adrenocorticotropic hormone, and corticosterone activities in brain tissue samples, and the molecular and biochemical regulation of B-cell lymphoma-2, B-cell lymphoma-2 Associated X-protein, Cysteine-aspartic acid protease-3, glucocorticoid receptor, mineralocorticoid receptor, and corticotropin-releasing hormone in murine hippocampal neurons. Our data suggest that velvet antler polypeptide decreases glucocorticoid receptor, mineralocorticoid receptor, and corticotropin-releasing hormone levels and regulates the hormones released by the hypothalamic-pituitary-adrenal axis, thus suppressing neuronal apoptosis., Competing Interests: All authors declare no conflicts of interest., (© 2020 Yang et al. Published by IMR press.)

Isochorismatase domain-containing 1 (ISOC1) is a coding gene that contains an isochorismatase domain. The precise functions of ISOC1 in humans have not been clarified; however, studies have speculated that it may be involved in unknown metabolic pathways. Currently, it is reported that ISOC1 is associated with breast cancer. In this research, the aim is to investigate the critical role of ISOC1 in colorectal cancer (CRC) and to explore its biological function and mechanism in colon cancer cells. In 106 paired clinical samples, we found that the levels of ISOC1 expression were widely increased in cancer tissues compared with matched adjacent non-tumor tissues and that increased expression of ISOC1 was significantly associated with tumor size, tumor invasion, local lymph node metastasis and Tumor, Node and Metastasis (TNM) stage. Moreover, higher expression levels of ISOC1 were correlated with shorter disease-free survival in patients 2 years after surgery. In vitro, ISOC1 knockdown inhibited the proliferation and migration and induced the apoptosis of colon cancer cells, and in vivo, the xenograft tumors were also inhibited by ISOC1 silencing. We also used MTS, Transwell and cell apoptosis assays to confirm that ISOC1 plays a critical role in regulating the biological functions of colon cancer cells through the AKT/GSK-3β pathway. Additionally, the results of confocal microscopy and western blot analysis indicated that ISOC1 knockdown could promote p-STAT1 translocation to the nucleus., (© The Author(s) 2019. Published by Oxford University Press.)

Aims: Dysfunction of the Hippo-Yes-Associated Protein (YAP) signaling pathway is known to be associated with hepatocellular carcinoma (HCC). Evodiamine (Evo), a plant-derived bioactive alkaloid, exerts inhibitory effects on cancer. However, the precise influence of Evo on HCC and its potential effects on Hippo-YAP signaling have yet to be ascertained. Here, the effects of Evo on cell proliferation and apoptosis were evaluated using HCC cell lines (HepG2 and Bel-7402) and nude mice with xenograft tumors. We further investigated whether Evo exerts anti-HCC activity through effects on Hippo-YAP signaling in vitro with the aid of XMU-MP-1, an inhibitor of the key component of this pathway, mammalian sterile 20-like kinase 1/2., Main Methods: Cell proliferation and apoptosis were assessed using 5-ethynyl-2'-deoxyuridine staining, colony formation, flow cytometry, hematoxylin-eosin and dUTP nick-end labeling experiments. Bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR) arrays were performed to determine the associations among Evo, HCC progression and the Hippo-YAP pathway. The expression patterns of components of Hippo-YAP signaling and apoptotic genes were further examined via RT-qPCR and immunoblotting., Key Findings: Evo inhibited proliferation and promoted apoptosis of HCC cell lines in vitro, and attenuated xenograft tumor formation in nude mice in vivo. Mechanistically, Evo treatment stimulated the Hippo-YAP signaling pathway. In vitro, the effects of Evo on HCC cell proliferation and apoptosis were alleviated by XMU-MP-1., Significance: Our collective results revealed that the anti-HCC effects of Evo were correlated with the Hippo-YAP signaling pathway., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study will examine the effects of artemisinin on proliferation and apoptosis of human liver cancer HepG2 cells (HLCHG-2C)., Methods: This study will systematically retrieve potential literatures in MEDLINE, Scopus, Web of Science, Cochrane Library, EMBASE, WANGFANG, and China National Knowledge Infrastructure from their initiation to the February 29, 2020. There are not limitations related to the language and publication time. All case-controlled studies (CCSs) or randomized controlled studies (RCSs) will be included in this study which investigated the effects of artemisinin on proliferation and apoptosis of HLCHG-2C. Two independent investigators will examine searched records, collect data from included studies, and will identify their methodological quality. Any divergences will be disentangled by discussion with another investigator. RevMan 5.3 software will be placed to pool the data and to carry out data analysis., Results: This study will summarize all eligible studies to test the effects of artemisinin on proliferation and apoptosis of HLCHG-2C., Conclusion: The results of this study will exert evidence to examine the effects of artemisinin on proliferation and apoptosis of HLCHG-2C, and it may benefit further research, patients, and healthcare providers., Systematic Review Registration: INPLASY202040075.

Background: Liver cancer remains the third leading cause of cancer-related mortality worldwide. The aim of this study was to explore the effect of saffron on liver cancer cell line QGY-7703 and the underlying molecular mechanism., Methods: Cell growth was detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and cell cycle was assessed by flow cytometry. Besides, cell apoptosis was analyzed by Annexin V/PI (Propidium Iodide) staining, and the senescent cells morphology staining of β-galactosidase was evaluated by microscopy. In addition, ELISA (enzyme-linked immunosorbent assay) Kit was used to assess the activity of telomerase. Moreover, reverse transcription-PCR (polymerase chain reaction) and Western blot analysis was applied to detect mRNA and protein expression levels, respectively., Results: Saffron treatment in QGY-7703 cells could significantly inhibit cell growth, arrest cell cycle in the G0/G1 phase, and induce cell apoptosis. Besides, the treatment of saffron could obviously decrease telomerase activity and hTERT level in QGY-7703 cells. In addition, enhanced Bax/Bcl-2 ratio and increased expression of P21 were found in saffron-treated cells. Moreover, we found that the number of senescent cells increased dramatically and the morphology of cells changed obviously after saffron treatment., Conclusions: Saffron administration may provide some experimental evidence for the inhibitory effect of saffron on the proliferation of QGY-7703 cells, suggesting that saffron may have potential utility for the treatment of liver cancer.

Demyelination resulting from Schwann cell injury is a main pathological feature of diabetic neuropathy, and a key contributor to this process may be inflammation due to advanced glycation end products (AGEs). Therefore, protection by anti-inflammation agents is anticipated. In this study, we showed that interleukin-10 (IL-10), an anti-inflammatory cytokine, inhibits apoptosis of Schwann cells induced by AGEs in vitro . We isolated and cultured Schwann cells from rat sciatic nerves. As detected by flow cytometry, apoptosis of Schwann cells markedly increased following incubation with AGEs for 48 h. However, pretreatment with IL-10 inhibited AGE-induced apoptosis. The effect of IL-10 on NF-κB, which is a very important regulator of inflammation, was also evaluated, and results showed high levels of phospho-NF-κB and nuclear localization of NF-κB in cells incubated with AGEs but low levels of phospho-NF-κB and cytoplasmic localization in the cells incubated with IL-10, indicating the activation of NF-κB by AGEs and inhibition of NF-κB by IL-10. Moreover, incubating Schwann cells with an NF-κB inhibitor (caffeic acid phenethyl ester) for 30 min before adding AGEs mimicked IL-10, lowering the amount of reactive oxygen species and activity of caspase-3 and also decreasing apoptosis in Schwann cells. These results indicate that IL-10 may protect Schwann cells against AGE-induced apoptosis by attenuating oxidative stress via the inhibition of activation of NF-κB., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

The neural cell adhesion molecule (NCAM) plays critical roles in multiple cellular processes in neural cells, mesenchymal stem cells, and various cancer cells. However, the effect and mechanism of NCAM in human melanoma cells are still unclear. In this study, we found that NCAM regulated the proliferation, apoptosis, autophagy, migration, and epithelial-to-mesenchymal transition of human melanoma cells by determining the biological behavior of NCAM knockdown A375 and M102 human melanoma cells. Further studies revealed that NCAM knockdown impaired the organization of actin cytoskeleton and reduced the phosphorylation of cofilin, an actin-cleaving protein. When cells were transfected with cofilin S3A (dephosphorylated cofilin), biological behavior similar to that of NCAM knockdown cells was observed. Research on the underlying molecular mechanism showed that NCAM knockdown suppressed activation of the Src/Akt/mTOR pathway. Specific inhibitors of Src and PI3K/Akt were employed to further verify the relationship between Src/Akt/mTOR signaling and cofilin, and the results showed that the phosphorylation level of cofilin decreased following inhibition of the Src/Akt/mTOR pathway. These results indicated that NCAM may regulate the proliferation, apoptosis, autophagy, migration, and epithelial-to-mesenchymal transition of human melanoma cells via the Src/Akt/mTOR/cofilin pathway-mediated dynamics of actin cytoskeleton., (© 2019 Wiley Periodicals, Inc.)

Histone demethylase KDM7A regulates neuronal differentiation and development in mammals. In this study, we found that KDM7A was also required for breast cancer stem cells (BCSCs) maintenance. Silencing KDM7A significantly reduced the BCSCs population and mamosphere formation in vitro, and inhibited breast tumor growth in vivo. Restoring KDM7A expression rescued the defect in stem cell maintenance. Our mechanism analysis suggested that KDM7A upregulated the stemness-associated factors KLF4 and c-MYC for BCSCs maintenance. In addition, KDM7A knockdown promoted apoptosis through decreasing BCL2 expression and BAD phosphorylation in breast cancer (BrCa). Furthermore, restoring KDM7A and BCL2 expression rescued apoptosis inhibition in breast cancer, suggesting that KDM7A inhibited apoptosis by upregulating the BCL2 level in breast cancer. In conclusion, KDM7A promotes cancer stem cell maintenance and apoptosis inhibition in breast cancer., (© 2019 Wiley Periodicals, Inc.)

Objective: This study aimed to investigate the effect of long non-coding RNA (lncRNA) DLGAP1 antisense RNA 1 (DLGAP1-AS1) on vascular endothelial cell (VEC) injury via the phosphoinositide 3-kinase (PI3K)/Akt pathway in rat models of acute lower limb ischaemia-reperfusion (I/R)., Methods: Differentially expressed lncRNAs related to I/R were screened using the gene expression omnibus database. Acute lower limb I/R models were induced in male Wistar rats, in which the regulatory mechanisms of DLGAP1-AS1 silencing were analysed after the treatment of small interfering RNA (siRNA) against DLGAP1-AS1 or an inhibitor of the PI3K/Akt pathway. The relationship between DLGAP1-AS1 and the PI3K/Akt pathway was analysed. The levels of tumour necrosis factor (TNF)-α and vascular cell adhesion molecule-1 (VCAM-1), as well as malondialdehyde (MDA) concentration and creatine kinase (CK) activity, were measured. The number of circulating endothelial cells (CECs) and apoptosis of VECs were identified., Results: Microarray based analysis indicated that DLGAP1-AS1 was highly expressed in I/R, which was further confirmed by detection of expression in rat models of acute lower limb I/R. Notably, the treatment of siRNA against DLGAP1-AS1 led to the activation of the PI3K/Akt pathway. In response to siRNA against DLGAP1-AS1, the levels of TNF-α and VCAM-1 were decreased, and MDA concentration and CK activity was downregulated. Reduced CEC numbers and suppressed VEC apoptosis were also observed., Conclusion: DLGAP1-AS1 silencing could further suppress the oxidative stress, exert an anti-apoptosis effect, and reduce inflammatory reaction, whereby VEC injury is alleviated by activation of the PI3K/Akt pathway in rats with acute lower limb I/R., (Copyright © 2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Pancreatic cancer is one of the most severe types of tumors, with a 5-year survival rate of less than 7%. The prognosis and treatment of pancreatic cancer are largely limited by the extent of tumor invasion and the presence of lymph node and distant metastases. Therefore, exploring the biological behavior of pancreatic cancer cells (PCCs) is extremely important for the understanding, diagnosis, and treatment of pancreatic cancer. Current studies have shown that pancreatic stellate cells (PSCs) regulate the biological behavior of PCCs, such as their proliferation, apoptosis, invasion, and migration, by remodeling the extracellular matrix. Though Hic-5 is an important gene in PSCs, no study has investigated the regulation of PCCs by Hic-5. Here, we demonstrate that Hic-5 expression is upregulated in pancreatic cancer and that siRNA transfection can effectively inhibit Hic-5 expression. Compared to the control group, Hic-5 inhibition significantly reduced proliferation, increased apoptosis, and reduced invasion and migration of PCCs. Moreover, the inhibition of Hic-5 expression simultaneously reduced matrix metalloproteinase-9 (MMP-9) expression. Statistical analysis revealed that Hic-5 expression was higher among the pancreatic cancer group than among the normal group and was negatively correlated with postoperative survival time among patients with pancreatic cancer. These results have important clinical significance for further exploring the molecular mechanism involved in Hic-5-mediated invasion and metastasis of pancreatic cancer and ameliorating the prognosis of patients with pancreatic cancer., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: In this study, we generated an Rbm14 knockout mouse model to explore its functions during early mouse embryogenesis., Materials and Methods: The Rbm14 knockout mouse model was generated by a combination of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and microinjection techniques. The developmental defects of the knockout embryos were characterized by histological analyses. The accumulation of DNA damage in mouse embryonic stem cells (ESCs) was detected by γH2AX staining and comet assay. The altered mRNA splicing of DNA damage response (DDR)-related genes was detected by RNA-Seq analysis and confirmed by semi-quantitative PCR. The interaction of RBM14 with alternative splicing-related genes was detected by immunoprecipitation-mass spectra (IP-MS) and confirmed by co-immunoprecipitation (Co-IP)., Results: Rbm14 knockout in mice results in apoptosis and cell proliferation defects in early post-implantation epiblast cells, leading to gastrulation disruption and embryonic lethality. FACS and immunostaining demonstrate accumulation of DNA damage in Rbm14 knockout ES cells. We also identified altered splicing of DDR-related genes in the knockout mouse ESCs by RNA-Seq, indicating that RBM14-mediated alternative splicing is required for the maintenance of genome integrity during early mouse embryogenesis., Conclusions: Our work reveals that Rbm14 plays an essential role in the maintenance of genome integrity during early mouse embryonic development by regulating alternative splicing of DDR-related genes., (© 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

Background: The aim of the present study was to investigate the protective effects of Tanshinone IIA (Tan IIA) on hypoxia-induced injury in the medial vestibular nucleus (MVN) cells., Methods: An in vitro hypoxia model was established using MVN cells exposed to hypoxia. The hypoxia-induced cell damage was confirmed by assessing cell viability, apoptosis and expression of apoptosis-associated proteins. Oxidative stress and related indicators were also measured following hypoxia modeling and Tan IIA treatment, and the genes potentially involved in the response were predicted using multiple GEO datasets., Results: The results of the present study showed that Tan IIA significantly increased cell viability, decreased cell apoptosis and decreased the ratio of Bax/Bcl-2 in hypoxia treated cells. In addition, hypoxia treatment increased oxidative stress in MVN cells, and treatment with Tan IIA reduced the oxidative stress. The expression of SPhase Kinase Associated Protein 2 (SKP2) was upregulated in hypoxia treated cells, and Tan IIA treatment reduced the expression of SKP2. Mechanistically, SKP2 interacted with large-conductance Ca2+-activated K+ channels (BKCa), regulating its expression, and BKCa knockdown alleviated the protective effects of Tan IIA on hypoxia induced cell apoptosis., Conclusion: The results of the present study suggested that Tan IIA had a protective effect on hypoxia-induced cell damage through its anti-apoptotic and anti-oxidative activity via an SKP2/BKCa axis. These findings suggest that Tan IIA may be a potential therapeutic for the treatment of hypoxia-induced vertigo., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)