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Oxymatrine ameliorates myocardial injury by inhibiting oxidative stress and apoptosis via the Nrf2/HO-1 and JAK/STAT pathways in type 2 diabetic rats.

ABSTRACT: The necessity of increasing the efficiency of organ preservation has encouraged researchers to explore the mechanisms underlying diabetes-related myocardial injuries. This study intended to evaluate the protective effects of oxymatrine (OMT) in myocardial injury caused by type 2 diabetes mellitus. A model of diabetic rats was established to simulate type 2 diabetes mellitus using an intraperitoneal injection of a single dose of 65 mg/kg streptozotocin with a high-fat and high-cholesterol diet, and diabetic rats were subsequently treated with OMT (60, 120 mg/kg) by gavage for 8 weeks. Thereafter, diabetic rats demonstrated notable decreases in left ventricular systolic pressure (LVSP), ±dp/dt_max, and in the activities of glutathione peroxidase, superoxide dismutase, and catalase. Moreover, we found notable increases in left ventricular end-diastolic pressure, fasting blood glucose, and malondialdehyde, as well as changes in cell apoptosis and decreased expression levels of Nrf2, HO-1, tyrosine protein kinase JAK (JAK), and signal transducer and transcription activator (STAT). Treatment with OMT alleviated all of the measured parameters. Collectively, these findings suggest that activation of the Nrf2/HO-1 and inhibition of the JAK/STAT signaling are involved in mediating the cardioprotective effects of OMT and also highlight the benefits of OMT in ameliorating myocardial injury in diabetic rats.

SUBMITTER: Huang Y

PROVIDER: S-EPMC9808977 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Oxymatrine ameliorates myocardial injury by inhibiting oxidative stress and apoptosis via the Nrf2/HO-1 and JAK/STAT pathways in type 2 diabetic rats.

Huang Yongpan Y He Bin B Song Chong C Long Xian X He Jianbin J Huang Yansong Y Liu Lijing L

BMC complementary medicine and therapies 20230103 1

The necessity of increasing the efficiency of organ preservation has encouraged researchers to explore the mechanisms underlying diabetes-related myocardial injuries. This study intended to evaluate the protective effects of oxymatrine (OMT) in myocardial injury caused by type 2 diabetes mellitus. A model of diabetic rats was established to simulate type 2 diabetes mellitus using an intraperitoneal injection of a single dose of 65 mg/kg streptozotocin with a high-fat and high-cholesterol diet, a ...[more]

PMID: 36597092

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Project description:Oxymatrine (OMT) is the major quinolizidine alkaloid extracted from the root of Sophora flavescens Ait and has been shown to exhibit a diverse range of pharmacological properties. The aim of the present study was to investigate the role of OMT in diabetic brain injury in vivo and in vitro. Diabetic rats were induced by intraperitoneal injection of a single dose of 65 mg/kg streptozotocin (STZ) and fed a high-fat and high-cholesterol diet. Memory function was assessed using a Morris water maze test. A SH-SY5Y cell injury model was induced by incubation with glucose (30 mM/l) to simulate damage in vitro. The serum fasting blood glucose, insulin, serum S100B, malondialdehyde (MDA), and superoxide dismutase (SOD) levels were analyzed using commercial kits. Morphological changes were observed using Nissl staining and electron microscopy. Cell apoptosis was assessed using Hoechst staining and TUNEL staining. NADPH oxidase (NOX) and caspase-3 activities were determined. The effects of NOX2 and NOX4 knockdown were assessed using small interfering RNA. The expression levels of NOX1, NOX2, and NOX4 were detected using reverse transcription-quantitative PCR and western blotting, and the levels of caspase-3 were detected using western blotting. The diabetic rats exhibited significantly increased plasma glucose, insulin, reactive oxygen species (ROS), S-100B, and MDA levels and decreased SOD levels. Memory function was determined by assessing the percentage of time spent in the target quadrant, the number of times the platform was crossed, escape latency, and mean path length and was found to be significantly reduced in the diabetic rats. Hyperglycemia resulted in notable brain injury, including histological changes and apoptosis in the cortex and hippocampus. The expression levels of NOX2 and NOX4 were significantly upregulated at the protein and mRNA levels, and NOX1 expression was not altered in the diabetic rats. NOX and caspase-3 activities were increased, and caspase-3 expression was upregulated in the brain tissue of diabetic rats. OMT treatment dose-dependently reversed behavioral, biochemical, and molecular changes in the diabetic rats. In vitro, high glucose resulted in increases in reactive oxygen species (ROS), MDA levels, apoptosis, and the expressions of NOX2, NOX4, and caspase-3. siRNA-mediated knockdown of NOX2 and NOX4 decreased NOX2 and NOX4 expression levels, respectively, and reduced ROS levels and apoptosis. The results of the present study suggest that OMT alleviates diabetes-associated cognitive decline, oxidative stress, and apoptosis via NOX2 and NOX4 inhibition.

Project description:BackgroundThe activation of CD8+ T cells and their trafficking to the skin through JAK-STAT signaling play a central role in the development of vitiligo. Thus, targeting this key disease pathway with innovative drugs is an effective strategy for treating vitiligo. Natural products isolated from medicinal herbs are a useful source of novel therapeutics. Demethylzeylasteral (T-96), extracted from Tripterygium wilfordii Hook F, possesses immunosuppressive and anti-inflammatory properties.MethodsThe efficacy of T-96 was tested in our mouse model of vitiligo, and the numbers of CD8+ T cells infiltration and melanocytes remaining in the epidermis were quantified using whole-mount tail staining. Immune regulation of T-96 in CD8+ T cells was evaluated using flow cytometry. Pull-down assay, mass spectrum analysis, molecular docking, knockdown and overexpression approaches were utilized to identify the target proteins of T-96 in CD8+ T cells and keratinocytes.ResultsHere, we found that T-96 reduced CD8+ T cell infiltration in the epidermis using whole-mount tail staining and alleviated the extent of depigmentation to a comparable degree of tofacitinib (Tofa) in our vitiligo mouse model. In vitro, T-96 decreased the proliferation, CD69 membrane expression, and IFN-γ, granzyme B, (GzmB), and perforin (PRF) levels in CD8+ T cells isolated from patients with vitiligo. Pull-down assays combined with mass spectrum analysis and molecular docking showed that T-96 interacted with JAK3 in CD8+ T cell lysates. Furthermore, T-96 reduced JAK3 and STAT5 phosphorylation following IL-2 treatment. T-96 could not further reduce IFN-γ, GzmB and PRF expression following JAK3 knockdown or inhibit increased immune effectors expression upon JAK3 overexpression. Additionally, T-96 interacted with JAK2 in IFN-γ-stimulated keratinocytes, inhibiting the activation of JAK2, decreasing the total and phosphorylated protein levels of STAT1, and reducing the production and secretion of CXCL9 and CXCL10. T-96 did not significantly inhibit STAT1 and CXCL9/10 expression following JAK2 knockdown, nor did it suppress upregulated STAT1-CXCL9/10 signaling upon JAK2 overexpression. Finally, T-96 reduced the membrane expression of CXCR3, and the culture supernatants pretreated with T-96 under IFN-γ stressed keratinocytes markedly blocked the migration of CXCR3+CD8+ T cells, similarly to Tofa in vitro.ConclusionOur findings demonstrated that T-96 might have positive therapeutic responses to vitiligo by pharmacologically inhibiting the effector functions and skin trafficking of CD8+ T cells through JAK-STAT signaling.

Dataset Information

Oxymatrine ameliorates myocardial injury by inhibiting oxidative stress and apoptosis via the Nrf2/HO-1 and JAK/STAT pathways in type 2 diabetic rats.

Publications

Oxymatrine ameliorates myocardial injury by inhibiting oxidative stress and apoptosis via the Nrf2/HO-1 and JAK/STAT pathways in type 2 diabetic rats.

Similar Datasets

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