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Aim: Post-transcriptional modifications and their specific mechanisms are the focus of research on the regulation of myocardial damage. Stress granules (SGs) can inhibit the inflammatory response by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. This study investigated whether alkylation repair homologue protein 5 (ALKBH5) could affect myocardial inflammation and apoptosis during diabetic myocardial ischaemia-reperfusion injury (IRI) through the cGAS-STING pathway via SGs., Methods: A diabetes ischaemia-reperfusion rat model and a high glucose hypoxia/reoxygenation cell model were established. Adeno-associated virus (AAV) and lentivirus (LV) were used to overexpress ALKBH5, while the SG agonist arsenite (Ars) and the SG inhibitor anisomycin were used as interventions. Then, the levels of apoptosis and related indicators in the cell and rat models were measured., Results: In the in vivo experiment, compared with the normal sham group, the degree of myocardial tissue damage, creatine kinase-MB and cardiac troponin I in serum, and myocardial apoptosis, the infarcted area of myocardium, and the level of B-cell lymphoma 2 associated X protein, cGAS-STING pathway and inflammatory factors in the diabetes ischaemia-reperfusion group were significantly increased. However, the expression of SGs and the levels of ALKBH5, rat sarcoma-GTPase-activating protein-binding protein 1, T-cell intracellular antigen-1 and Bcl2 were significantly decreased. After AAV-ALKBH5 intervention, the degree of myocardial tissue damage, degree of myocardial apoptosis, and extent of myocardial infarction in myocardial tissue were significantly decreased. In the in vitro experiment, compared with those in the normal control group, the levels of lactate dehydrogenase, inflammation and apoptosis were significantly greater, and cell viability and the levels of ALKBH5 and SGs were decreased in the high glucose and hypoxia/reoxygenation groups. In the high glucose hypoxia/reoxygenation cell model, the degree of cell damage, inflammation, and apoptosis was greater than those in the high glucose and hypoxia/reoxygenation models, and the levels of ALKBH5 and SGs were further decreased. LV-ALKBH5 and Ars alleviated the degree of cell damage and inhibited inflammation and cell apoptosis. The inhibition of SGs could partly reverse the protective effect of LV-ALKBH5. The cGAS agonist G140 antagonized the inhibitory effects of the SG agonist Ars on cardiomyocyte apoptosis, inflammation and the cGAS-STING pathway., Conclusion: Both ALKBH5 and SGs inhibited myocardial inflammation and apoptosis during diabetic myocardial ischaemia-reperfusion. Mechanistically, ALKBH5 might inhibit the apoptosis of cardiomyocytes by promoting the expression of SGs through the cGAS-STING pathway., (© 2024 John Wiley & Sons Ltd.)

Tiron functions as an effective antioxidant alleviating the intracellular reactive oxygen species (ROS) or the acute toxic metal overload. Previous studies have shown that cardiac myocyte apoptosis can be effectively inhibited by tiron administration in streptozotocin (STZ)-induced diabetic rats, primary neonatal rat cardiomyocytes (NRVMs), and H9c2 embryonic rat cardiomyocytes. However, the underlying signalling mechanism is ill-defined. In the present study, we found that tiron supplementation significantly inhibited apoptosis of high glucose (HG)-treated NRVMs and the left ventricular cardiomyocytes from STZ-diabetic rat, accompanied with a reduction of osteopontin (OPN) levels as well as an inhibition of PKCδ phosphorylation. OPN knockdown protected NRVMs against HG-induced cell apoptosis. In addition, genetic inhibition of PKCδ mitigated HG-stimulated enhancement of intracellular OPN levels in NRVMs. These findings indicate that ROS-mediated activation of PKCδ upregulated OPN expression, leading to cardiac myocyte apoptosis. Interfering with ROS/PKCδ pathway by antioxidants such as tiron provides an optional therapeutic strategy for treatment and prevention of apoptosis-related cardiovascular diseases including diabetic cardiomyopathy., (© 2017 John Wiley & Sons Australia, Ltd.)

Background . Histone deacetylases (HDACs) play a pivotal role in signaling modification and gene transcriptional regulation that are essential for cardiovascular pathophysiology. Diabetic hearts with higher HDACs activity were more vulnerable to myocardial ischemia/reperfusion (MI/R) injury compared with nondiabetic hearts. We are curious about whether suppression of excessive HDACs activity in diabetic heart protects against MI/R injury. Methods . Diabetic rats were subjected to 45 min of ischemia, followed by 3 h of reperfusion. H9C2 cardiomyocytes were exposed to high glucose for 24 h, followed by 4 h of hypoxia and 2 h of reoxygenation (H/R). Results . Both MI/R injury and diabetes mellitus elevated myocardium HDACs activity. MI/R induced apoptotic cell death was significantly decreased in diabetic rats treated with HDACs inhibitor trichostatin A (TSA). TSA administration markedly moderated dissipation of mitochondrial membrane potential, protected the integrity of mitochondrial permeability transition pore (mPTP), and decreased cell apoptosis. Notably, cotreatment with Akt inhibitor partly or absolutely inhibited the protective effect of TSA in vivo and in vitro. Furthermore, TSA administration activated Akt/Foxo3a pathway, leading to Foxo3a cytoplasm translocation and attenuation proapoptosis protein Bim expression. Conclusions . Both diabetes mellitus and MI/R injury increased cardiac HDACs activity. Suppression of HDACs activity triggered protective effects against MI/R and H/R injury under hyperglycemia conditions through Akt-modulated mitochondrial apoptotic pathways via Foxo3a/Bim., Competing Interests: The authors declare that they have no competing interest.

The non-small-cell lung cancer (NSCLC) is the most common type of lung cancer that affects the human health. But, the underlying mechanisms and effective therapy are still absent. MicroRNAs (miRNAs) are small RNAs that specifically bind to the 3' untranslated region (3'UTR) of its target and regulate the protein level of the target at post-transcriptional level. A lot of miRNAs had been found abnormally regulated in the NSCLC patients, and understanding their specific roles in the pathogenesis of NSCLC will help us to develop novel therapeutic approaches. Here, we reported that miR-25 is dramatically upregulated in NSCLC tissues and negatively correlated with RGS3 protein. A conserved binding sequence in the 3'UTR of RGS3 gene to miR-25 was identified, and overexpression of miR-25 induces the RGS3 inhibition. Importantly, suppression of miR-25 facilitates the cell apoptosis and retards the cell proliferation in A549 and H520 cell lines. Our data provide a novel miR-25/RGS3 signal in the development of lung cancer.

Apoptosis, necroptosis, and autophagy are the major programmed cell death in myocardial ischemia–reperfusion injury (MIRI). Maslinic acid (MA) has been found to regulate pathophysiological processes that mediate programmed cell death in MIRI, such as inflammation and oxidative stress. However, its effects on MIRI remain unclear. This study intends to explore the role of MA in MIRI. In vitro, MA had no obvious cytotoxic effects on H9C2 cells, and significantly improved the impaired cell viability caused by hypoxia reoxygenation (HR). In vivo, MA significantly alleviated ischemia reperfusion (IR)-induced left ventricular myocardial tissue injury, downregulated creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels in serum as well as reducing infarct size. Moreover, MA inhibited HR-induced mitochondrial apoptosis and necroptosis in vitro and in vivo. Of interest, MA interacts with lysosome-associated membrane protein 2 (LAMP2). MA protected LAMP2 from IR and promoting autophagic flux to inhibit apoptosis and necroptosis, whereas these effects were reversed by co-treatment with lysosomal inhibitor BarfA1. In conclusion, MA can inhibit MIRI-induced apoptosis and necroptosis by promoting autophagic flux. These results support that MA is a potential agent to ameliorate MIRI. [ABSTRACT FROM AUTHOR]

Emerging evidence has supported that TAZ (transcriptional co-activator with PDZ binding motif), one transcription co-activator in Hippo signaling pathway, plays an oncogenic role in liver carcinogenesis. Targeting TAZ could be a potential therapeutic approach for liver cancer patients. In the current study, we aim to determine whether diosgenin could be an inhibitor of TAZ in liver cancer cells. We found that diosgenin inhibited the expression of TAZ in liver cancer cells. Moreover, we found that diosgenin inhibited cell growth, induced apoptosis, suppressed cell migration and invasion in part via inhibition of TAZ in liver cancer cells. Our study provides the evidence to support that diosgenin could be a potential agent for treating human liver cancer. [ABSTRACT FROM AUTHOR]

Stroke patients are often complicated by cerebral ischemia-reperfusion injury (CIRI) after the restoration of cerebral perfusion, and how to prevent CIRI at an early stage has received close attention. The imbalance of iron metabolism is one of the essential factors in the aggravation of CIRI, and NCOA4-mediated ferritinophagy, as a critical pathway to regulate iron metabolism, is expected to be an effective intervention target. We established a mouse model of cerebral ischemia-reperfusion (CIR) with NCOA4 silencing. We found that activation of NCOA4-mediated ferritinophagy atthe early stage of CIR mediated the onset of oxidative stress and contributed to autophagy and apoptosis, and eventually resulted in increased brain injury. This suggests that NCOA4-mediated ferritinophagy plays a vital role in early CIR and can be an effective target to prevent and treat CIRI. We next explored the upstream regulatory targets of NCOA4-mediated ferritinophagy. The previous evidence for the cGAS-STING pathway's importance during CIR and its strong relationship with autophagy attracted our attention. To investigate whether the cGAS-STING pathway regulates NCOA4-mediated ferritinophagy, we further administered a cGAS inhibitor to mice with CIR and overexpressed NCOA4. Along with the inhibition of the cGAS-STING pathway, ferritinophagy, oxidative stress, autophagy, and apoptosis were inhibited, and CIRI was ameliorated, which was attenuated by NCOA4 overexpression. In conclusion, our results suggest that activation of the cGAS-STING pathway exacerbates CIRI at the early stage of CIR, which may be achieved by mediating NCOA4-mediated ferritinophagy. [Display omitted] • Activation of NCOA4-mediated ferritinophagy occurs at the early stage of CIR. • NCOA4 silencing mitigate cerebral infarction, oxidative stress, excessive autophagy, and apoptosis at the early stage of CIR. • The cGAS-STING inhibitor RU.521 exerts neuroprotection against CIRI, which can be abrogated by NCOA4 overexpression. [ABSTRACT FROM AUTHOR]