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Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), characterized by neuronal cell death and neurocognitive impairment. We focus on the accumulated mitochondrial DNA (mtDNA) in the cytosol, which acts as a damage-associated molecular pattern (DAMP) and activates the cyclic GMP-AMP synthase (cGAS)—stimulator of interferon genes (STING) pathway, a known trigger for immune responses and neuronal death in degenerative diseases. However, the specific role and mechanism of the mtDNA-cGAS-STING axis in IH-induced neural damage remain largely unexplored. Here, we investigated the involvement of PANoptosis, a novel type of programmed cell death linked to cytosolic mtDNA accumulation and the cGAS-STING pathway activation, in neuronal cell death induced by IH. Our study found that PANoptosis occurred in primary cultures of hippocampal neurons and HT22 cell lines exposed to IH. In addition, we discovered that during IH, mtDNA released into the cytoplasm via the mitochondrial permeability transition pore (mPTP) activates the cGAS-STING pathway, exacerbating PANoptosis-associated neuronal death. Pharmacologically inhibiting mPTP opening or depleting mtDNA significantly reduced cGAS-STING pathway activation and PANoptosis in HT22 cells under IH. Moreover, our findings indicated that the cGAS-STING pathway primarily promotes PANoptosis by modulating endoplasmic reticulum (ER) stress. Inhibiting or silencing the cGAS-STING pathway substantially reduced ER stress-mediated neuronal death and PANoptosis, while lentivirus-mediated STING overexpression exacerbated these effects. In summary, our study elucidates that cytosolic escape of mtDNA triggers cGAS-STING pathway-dependent neuronal PANoptosis in response to IH, mainly through regulating ER stress. The discovery of the novel mechanism provides theoretical support for the prevention and treatment of neuronal damage and cognitive impairment in patients with OSA. [ABSTRACT FROM AUTHOR]

Background: Submucosal fibrosis (OSF) of the oral cavity is a chronic scarring disease. Arecoline (Are) is the driving factor for the occurrence and deterioration of OSF. Curcumin plays a vital anti‐inflammatory role in Are‐induced OSF development. However, its potential pharmacological mechanism needs to be elucidated. Methods: The relative molecular level was measured via qRT‐PCR or Western blot. MTT assay, transwell assay and flow cytometry detected cell proliferation, migration, and apoptosis. The correlation between hypoxia‐inducible factor‐1α (HIF‐1α) and LTBP2 promoter was confirmed through dual‐luciferase reporter assay. ELISA was performed to detect inflammatory cytokines levels. Results: Curcumin alleviated Are‐induced oral mucosal fibroblast cells fibrosis by reducing oral mucosa fibroblasts viability, promoting cell apoptosis, suppressing cell migration, and down‐regulating the levels of fibrosis markers and inflammatory factors. Curcumin relieved Are‐induced OSF via inhibiting HIF‐1α. Mechanically, HIF‐1α bound to the promoter of LTBP2 to transcriptionally activated LTBP2. LTBP2 knockdown relieved Are‐induced OSF, and curcumin down‐regulated LTBP2 via inhibiting HIF‐1α to relieve Are‐induced OSF. Moreover, curcumin decreased NF‐κB signal associated proteins via inhibiting LTBP2 to relieve Are‐induced OSF. Conclusion: Curcumin reduced the transcription level of LTBP2 by inhibiting HIF‐1α, thereby inactivating NF‐κB pathway to alleviate Are‐induced OSF. [ABSTRACT FROM AUTHOR]

Background/Aims: Intermittent hypoxia (IH) causes apoptosis in pancreatic β-cells, but the potential mechanisms remain unclear. Endoplasmic reticulum (ER) stress, autophagy, and apoptosis are interlocked in an extensive crosstalk. Thus, this study aimed to investigate the contributions of ER stress and autophagy to IH-induced pancreatic β-cell apoptosis. Methods: We established animal and cell models of IH, and then inhibited autophagy and ER stress by pharmacology and small interfering RNA (siRNA) in INS-1 cells and rats. The levels of biomarkers for autophagy, ER stress, and apoptosis were evaluated by immunoblotting and immunofluorescence. The number of autophagic vacuoles was observed by transmission electron microscopy. Results: IH induced autophagy activation both in vivo and in vitro, as evidenced by increased autophagic vacuole formation and LC3 turnover, and decreased SQSTM1 level. The levels of ER-stress-related proteins, including GRP78, CHOP, caspase 12, phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and activating transcription factor 4 (ATF4) were increased under IH conditions. Inhibition of ER stress with tauroursodeoxycholic acid or 4-phenylbutyrate partially blocked IH-induced autophagy in INS-1 cells. Furthermore, inhibition of PERK with GSK2606414 or siRNA blocked the ERstress-related PERK/eIF2α/ATF4 signaling pathway and inhibited autophagy induced by IH, which indicates that IH-induced autophagy activation is dependent on this signaling pathway. Promoting autophagy with rapamycin alleviated IH-induced apoptosis, whereas inhibition of autophagy with chloroquine or autophagy-related gene (Atg5 and Atg7) siRNA aggravated pancreatic β-cell apoptosis caused by IH. Conclusion: IH induces autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 signaling pathway, which is a protective response to pancreatic β-cell apoptosis caused by IH. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a common cellular stress response that is triggered by a variety of conditions that disturb cellular homeostasis, and induces cell apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis induced by ER stress. There are common upstream signaling pathways between autophagy and apoptosis induced by ER stress, including PERK/ATF4, IRE1α, ATF6, and Ca2+. Autophagy can not only block the induction of apoptosis by inhibiting the activation of apoptosis-associated caspase which could reduce cellular injury, but also help to induce apoptosis. In addition, the activation of apoptosis-related proteins can also inhibit autophagy by degrading autophagy-related proteins, such as Beclin-1, Atg4D, Atg3, and Atg5. Although the interactions of different autophagy- and apoptosis-related proteins, and also common upstream signaling pathways have been found, the potential regulatory mechanisms have not been clearly understood. In this review, we summarize the dual role of autophagy, and the interplay and potential regulatory mechanisms between autophagy and apoptosis under ER stress condition. [ABSTRACT FROM AUTHOR]

Silent information regulator factor 2-related enzyme 1 (sirtuin 1, Sirt1) is a nicotinamide adenine dinucleotide-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, and is involved in the regulation of many physiological functions, including cell senescence, gene transcription, energy balance, and oxidative stress. Ischemia/hypoxia injury remains an unresolved and complicated situation in the diseases of ischemia stroke, heart failure, and coronary heart disease, especially among the old folks. Studies have demonstrated that aging could enhance the vulnerability of brain, heart, lung, liver, and kidney to ischemia/hypoxia injury and the susceptibility in old folks to ischemia/hypoxia injury might be associated with Sirt1. In this review, we mainly summarize the role of Sirt1 in modulating pathways against energy depletion and its involvement in oxidative stress, apoptosis, and inflammation under the condition of ischemia/hypoxia. [ABSTRACT FROM AUTHOR]

Bladder cancer is a common tumour of the urinary system, and more than 90% is urothelial carcinoma. Therefore, it is important for discovering the key target genes and molecules of bladder tumour cell metastasis and invasion. Our research initially explored the regulation of deltaN p63 on the progression and metastasis of bladder cancer and found that deltaN p63 can influence the occurrence of EMT through PTEN and ultimately regulate the growth and metastasis of bladder cancer. In summary, this study identified a new EMT regulator, deltaN p63, further revealed the mechanism of the invasion and metastasis of bladder cancer cells, and provided a theoretical basis for finding new target molecules and drugs to treat bladder cancer. In conclusion, this study will further reveal the mechanism of tumour cell invasion and metastasis and provide a theoretical basis for cancer treatment to find new target molecules and drugs. [ABSTRACT FROM AUTHOR]

Miracle fruit (Synsepalum dulcificum) is an edible berry, and is known for its ability to turn sour to sweet. The leaf of S. dulcificum has been used as additives in food, medicine and cosmetic industries. In this study, two new pairs of enantiomeric coumarinolignans, synsepalumins A and B (1 and 2), three new pentacyclic triterpenoids, 3- O - cis - p -coumaroyl-2 α ,3 β ,29-trihydroxy-olean-12-en-28-oic acid (3), 3- O - trans - p -coumaroyl-2 α ,3 β ,29-trihydroxy-olean-12-en-28-oic acid (4), and 3- O - cis - p -coumaroyl-3 β ,19 α -hydroxy-urs-12-en-28-oic acid (6), along with twenty-five known compounds (5 , 7 − 30) were isolated from the leaves of S. dulcificum. Compounds 1 and 2 are two rare tricyclic 7-hydroxycoumarins featuring a classic bicyclic 7-hydroxycoumarin fused with a (1,4)-dioxane ring. Their structures were elucidated by the spectroscopic data analyses and quantum chemical electronic circular dichroism calculations. Meanwhile, compound 4 (SMG-1) significantly inhibited proliferation of HepG2 (IC 50 = 13.9 ± 0.3 μM) and HCCLM3 (IC 50 = 11.8 ± 0.2 μM) cells. We further explored the underlying mechanism of SMG-1 for hepatocellular carcinoma (HCC) cells death, and found that SMG-1 induced reactive oxygen to increase the level of BNIP3 through JNK/p53 pathway and decreased mitochondrial membrane potential, resulting in activating mitophagy. Moreover, SMG-1 up-regulated the Bax and cytoplasm level of Cyt-c to promote Caspase-9/Caspase-3-mediated apoptosis in HCC cells. Therefore, the leaves of S. dulcificum possess the ability to treat HCC. [Display omitted] • Synsepalum dulcificum has high medicinal and economic values. • Two pairs of undescribed enantiomeric coumarinolignans, three undescribed triterpenoids, along with twenty-five known compounds were isolated from Synsepalum dulcificum leaves. • Some compounds showed significantly antitumor activity against hepatocellular carcinoma cells. • Compound 4 induced reactive oxygen to activate mitophagy and promote Caspase-9/Caspase-3-mediated apoptosis in hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

• Silencing VCAM-1 and BMSCs synergistically improve cardiac function of MI rats. • Injection with BMSCs and sh-VCAM-1 increases CPR and survival rate of MI rats. • Injection with BMSCs and sh-VCAM-1 reduce the IS and myocardial apoptosis. • sh-VCAM-1 could inhibit the NF-κB signaling pathway. • sh-VCAM-1 enhances the therapeutic effects of BMSCs by NF-κB pathway. Bone mesenchymal stem cells (BMSCs) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). VCAM-1 can promote the migration of lymphocytes to the inflammatory zone. In the present study, we tried to explore whether VCAM-1 silenced-BMSCs have better therapeutic effects on MI. BMSCs were isolated and cultured followed by treatment of a lentivirus silencing VCAM-1 and NF-κB activator (PMA). Besides, MI rat models were also established and injected with treated BMSCs to detect the effect of VCAM-1 silenced-BMSCs in MI, as evidenced by detection of cardiac function, survival of rats within 72 h, infarct size and myocardial cell apoptosis. Moreover, the expression of NF-κB-regulated gene products was also determined. The implantation of sh-VCAM-1 BMSCs into MI rats resulted in more reductions in myocardial infarct size as well as myocardial cell apoptosis, improved cardiac function, the number of survived rats within 72 h, and survival time within 72 h compared with the individual treatments of either BMSCs or control. In addition, transplanted BMSCs down-regulated the expression of NF-κB-p65, MMP-9, TNF-α, and Bax, and up-regulated VEGF and Bcl-2 in myocardial tissue, which could be further enhanced by sh-VCAM-1 and rescued by PMA. Our study demonstrated that silencing VCAM-1 in BMSCs could inhibit inflammation and apoptosis, thus improving cardiac function in MI. [ABSTRACT FROM AUTHOR]