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The kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis plays an important role in regulating oxidative stress in ischemic cardiomyocytes. Targeting Keap1 in order to promote Nrf2 activation is considered a potential method for protecting cardiomyocytes against ischemic injury. In recent years, microRNAs (miRNAs or miRs) have emerged as powerful tools for controlling gene expression. The present study aimed to determine whether Keap1-Nrf2 was regulated by specific miRNAs in cardiomyocytes under hypoxic conditions. We demonstrated that miR-200a was significantly downregulated in ischemic myocardial tissues and hypoxic cardiomyocytes. The overexpression of miR-200a was found to protect cardiomyocytes from hypoxia-induced cell damage and the excessive production of reactive oxygen species. Through bioinformatics analysis and a dual-luciferase report assay, miR-200a was found to interact with the 3'-untranslated region of Keap1, the native regulator of Nrf2. Reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that miR-200a negatively regulated the expression of Keap1. The overexpression of miR-200a significantly increased the nuclear translocation of Nrf2 as well as downstream antioxidant enzyme gene expression. The inhibition of miR-200a displayed the opposite effects. Restoring the expression of Keap1 significantly abrogated the protective effect of miR‑200a. Taken together, these findings indicate that the suppression of Keap1 by miR-200a exerted a cardioprotective effect against hypoxia-induced oxidative stress and cell apoptosis, and suggest that the activation of Nrf2 signaling by miR‑200a represents a novel and promising therapeutic strategy for the treatment of ischemic heart disease.

Glioma is one of the most common primary brain tumors. Despite surgical resection, radiotherapy, and chemotherapy, the prognosis of patients with malignant glioma remains poor. Programmed cell death 5 (PDCD5) is a newly described pro-apoptotic protein. Our previous study showed that PDCD5 downregulation in gliomas was associated with higher pathological grade. Here, we investigated the effect of PDCD5 on chemosensitivity of glioma cells and its mechanism. We demonstrated that overexpression or knockdown of PDCD5 had no significant effect on the proliferation of glioma cell lines (U87, U251, and T98G) in the absence of chemotherapeutic agents. However, PDCD5 overexpression effectively sensitized U87 cells to chemotherapeutic drugs (cisplatin, carboplatin, and vincristine) in a concentration-dependent manner, while its knockdown resulted in decreased chemosensitivity in U251, T98G, and U87 cells. Importantly, expression of PDCD5 also markedly inhibited tumor cell proliferation and colony formation in the presence of low doses of cisplatin. Furthermore, we found that PDCD5 expression promoted cisplatin-induced apoptosis, increased markedly the activation of caspase-3 and caspase-9, and decreased significantly the ratio of Bcl-2/Bax proteins, but had no effect on the activation of caspase-8. Taken together, our findings indicate that PDCD5 promotes chemosensitivity by activating mitochondria-related apoptotic pathway, and that the combination of PDCD5 and chemotherapeutic drugs such as cisplatin, is expected to be an effective therapeutic strategy for the malignant glioma.

The objective of this study was to investigate the effect of atractyloside, a promoter of the mitochondrial membrane permeability transition pore (MPTP), on mitochondrial membrane permeability, cristae structure, cytochrome c release and tenderness of postmortem beef and to explore the effect of injury on meat tenderness by releasing cytochrome c and activating caspases. The postmortem longissimus dorsi muscle of adult crossbred cattle was treated or not treated (control) with atractyloside, stored at 4 ℃ and evaluated for mitochondrial ultrastructure, membrane potential, the amount of cytochrome c released to the cytoplasm, cell apoptotic rate, caspase-3 and myofibrillary fragmentation index (MFI) after 0, 12, 24, 72, and 120 h. With postmortem aging time, the number of mitochondrial cristae decreased significantly, and swelling and rupture were observed. The mitochondrial membrane potential decreased significantly, and cytochrome c was released gradually. Starting from 72 h postmortem, the activity of caspase-3 and the apoptosis rate of myocytes increased, and so did MFI. Compared with the control group, atractyloside treatment induced mitochondrial damage by destroying mitochondrial cristae structure, reducing the membrane potential and causing cytochrome c release. In addition, the apoptosis of muscle cells and the fragmentation of myofibrils were accelerated by atractyloside. The opening of the MPTP significantly affected mitochondrial injury in beef after slaughter. Apart from increasing cell membrane permeability, atractyloside also significantly altered the structure of mitochondrial cristae. The internal and external mitochondrial membranes could synergistically regulate the release of cytochrome c, which in turn could affect postmortem tenderization of beef.

BACKGROUND The objective of the study was to examine the expression profiles of mitochondrial proteins in at‐death and 24 h postmortem (PM) using tandem mass tag (TMT) approach to characterize the mitochondria possible mechanisms that are affiliated with tenderization. RESULTS: Results showed that the tender meat at 24 h PM emerged with more serious mitochondrial damage. Altogether 456 mitochondrial proteins were identified, including 442 down‐regulated and 14 up‐regulated proteins. These differentially‐expressed proteins were primarily involved in the progress of PM energy metabolism, apoptosis, and the morphological alterations of mitochondrial. Among them, 47 subunits (such as NDUFA2, COX4I1, and ATP5PB) were annotated into the oxidative phosphorylation pathway. VDAC1, VDAC2, and VDAC3 involving in the damage of MPTP, and IMMT, CHCHD3, APOL and APOO modulating the morphology of mitochondria, and DIABLO and AIFM1 released from mitochondria affect caspase's activation. HSPD1 and HSPE1 involved in apoptosis, mitochondrial physiological and morphological alterations. CONCLUSION: The earlier‐mentioned proteins were validated as potential indicators of tenderness regulated by mitochondrial damage. These results highlighted that mitochondrial damage possibly participate in PM tenderization of beef muscles by energy metabolism and cell apoptosis status. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Hypoxic ischemic encephalopathy (HIE) is the most common brain injury following hypoxia and/or ischemia caused by various factors during the perinatal period, resulting in detrimental neurological deficits in the nervous system. Tanshinone IIA (Tan‑IIA) is a potential agent for the treatment of cardiovascular and cerebrovascular diseases. In this study, the efficacy of Tan‑IIA was investigated in a newborn mouse model of HIE. The dynamic mechanism of Tan‑IIA was also investigated in the central nervous system of neonate mice. Intravenous injection of Tan‑IIA (5 mg/kg) was administered and changes in oxidative stress, inflammation and apoptosis‑associated proteins in neurons. Histology and immunohistochemistry was used to determine infarct volume and the number of damaged neurons by Fluoro‑Jade C staining. The effects of Tan‑IIA on mice with HIE were evaluated by body weight, brain water content, neurobehavioral tests and blood‑brain barrier permeability. The results demonstrated that the apoptosis rate was decreased following Tan‑IIA administration. Expression levels of pro‑apoptotic proteins, caspase‑3 and caspase‑9 and P53 were downregulated. Expression of Bcl‑2 anti‑apoptotic proteins was upregulated by Tan‑IIA treatment in neuro. Results also found that Tan‑IIA treatment decreased production of inflammatory cytokines such as interleukin‑1, tumor necrosis factor‑α, C‑X‑C motif chemokine 10, and chemokine (C‑C motif) ligand 12. Oxidative stress was also reduced by Tan‑IIA in neurons, as determined by the expression levels of superoxide dismutase, glutathione and catalase, and the production of reactive oxygen species. The results demonstrated that Tan‑IIA treatment reduced the infarct volume and the number of damaged neurons. Furthermore, body weight, brain water content and blood‑brain barrier permeability were markedly improved by Tan‑IIA treatment of newborn mice following HIE. Furthermore, the results indicated that Tan‑IIA decreased Toll‑like receptor‑4 (TLR‑4) and nuclear factor‑κB (NF‑κB) expression in neurons. TLR‑4 treatment of neuronal cell in vitro addition stimulated NF‑κB activity, and further enhanced the production of inflammatory cytokines and oxidative stress levels in neurons. In conclusion, these results suggest that Tan‑IIA treatment is beneficial for improvement of HIE through TLR‑4‑mediated NF‑κB signaling. [ABSTRACT FROM AUTHOR]

Neonatal necrotizing enterocolitis (NEC) is a severe acquired disease that predominantly affects the small intestine of neonates. NEC is caused by a combination of metabolic products, dysfunctions of the blood vessels, mucus and other unknown factors. Berberine may induce beneficial effects on necrotic and cardiovascular diseases due to its anti‑inflammatory and anti‑apoptotic effects on epithelial cells. In the present study, the therapeutic effects of berberine were investigated and the potential mechanisms by which it functions within a neonatal NEC mouse model were analyzed. Inflammation and levels of associated factors were measured in the serum of mice with NEC prior to and following treatment with berberine. Apoptotic rates in epithelial cells were analyzed following treatment with berberine. The expression of genes associated with apoptosis and apoptosis signaling were determined in epithelial cells in the small intestines of mice with NEC following treatment with berberine. The phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway was investigated in epithelial cells isolated from mice following treatment with either berberine or PBS. Histology and immunohistochemistry were used to determine the area of infarction and apoptosis. Body weight and food intake were measured to evaluate the physical effects of berberine on mice with NEC. The results indicated that berberine attenuated the inflammation caused by NEC in mice after 10 days of treatment. The apoptosis rate of epithelial cells isolated from experimental mice was decreased following berberine treatment. Western blot analysis indicated that the expression of the anti‑apoptotic genes c‑Myc and p53 were upregulated by berberine, whereas caspase‑3 and ‑9 levels were downregulated in epithelial cells following treatment with berberine. In addition, the expression and phosphorylation levels of PI3K and AKT were downregulated in epithelial cells following treatment with berberine. An in vitro assay indicated that treatment with PI3K alone increased the expression of AKT and promoted the apoptosis of epithelial cells. Treatment with berberine markedly increased epidermal growth factor (EGF) and Bcl‑2 expression levels, the activity of epithelial cells and decreased the infarction area of the small intestine. Accordingly, the body weight and food intake of mice with NEC were increased following berberine treatment. Therefore, the results of the present study demonstrate that berberine inhibits inflammation and apoptosis via the PI3K/AKT signaling pathway and may therefore attenuate the progression of NEC. These results suggest that berberine may be a potential therapeutic agent for the treatment of patients with NEC. [ABSTRACT FROM AUTHOR]