Carnosol alleviates sepsis-induced pulmonary endothelial barrier dysfunction by targeting nuclear factor erythroid2-related factor 2/sirtuin-3 signaling pathway to attenuate oxidative damage.

Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti-inflammatory properties, but its role in treating sepsis-induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis-induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)-induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC-1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor-erythroid 2-related factor (Nrf2)/sirtuin-3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS-induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS-induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO-1, and vascular endothelial-Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway.

Epigallocatechin Gallate Protects Diabetes Mellitus Rats Complicated with Cardiomyopathy through TGF-ß1/JNK Signaling Pathway.

BACKGROUND: Epigallocatechin gallate (EGCG) is the main component of rhubarb tannin, with antioxidant, anti-angiogenic, anti-cancer and antiviral activities. Diabetes mellitus (DM) is a high blood sugar and protein metabolism disorder syndrome, which is caused by absolute or relative factors, such as deficiency of insulin and oxidative stress. Diabetes cardiomyopathy (DCM) is one of the most frequent complications of DM. OBJECTIVE: This study aims to explore whether EGCG can improve diabetic complication, myocardial fibrosis, in diabetic rats with an intraperitoneal injection of streptozotocin (STZ) through the transforming growth factor ß1 (TGF-ß1)/C-Jun N -terminal kinase (JNK) signaling pathway. METHODS: 50 male SD rats were randomly divided into five groups, including the control group, model group, and EGCG drug groups (10 mg/kg, 20 mg/kg, 40 mg/kg), with 10 rats in each group. Rats, except for the control group, were intraperitoneally injected with STZ (65 mg/kg) to induce the diabetic rats model. EGCG drug groups were given distilled water according to the dose, while the control group and model group were given the same volume of distilled water for 12 weeks. The levels of glucose (GLU), triglyceride (TG), cholesterol (CHO), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in serum were detected by ELISA of all rats. Myocardial function was observed by HE, Masson staining and Sirius red staining in DCM rats. Immunohistochemistry was used to detect the expression of Collagen I (COL-I) and Collagen III (COL-III), and detect the degree of myocardial fibrosis of DM rats. Western blot was used to detect the expression of matrix metalloproteinases (MMPs), tissue inhibitor of matrix metalloproteinase (TIMPs), TGF-ß1, JNK and p-JNK in the myocardium. RESULTS: Compared to the model group, the levels of GLU, TG, CHO, and LDL in serum were decreased while the level of HDL in serum was increased in EGCG groups rats; cardiac index and left ventricular mass index were decreased while heart function was improved in EGCG groups rats; the expressions of the COL-I and COL-III were decreased in EGCG groups, and the high dose group was the best; the expressions of TGF-ß1, JNK, p-JNK, and TIMP-1 were down-regulated, and the expression of MMP-9 was up-regulated in EGCG groups. CONCLUSION: The results demonstrated that EGCG could improve STZ-induced diabetic complication, i.e., myocardial fibrosis, in diabetic rats, and protect their heart through TGF-ß1/JNK signaling pathway.

Oxymatrine enhanced anti-tumor effects of Bevacizumab against triple-negative breast cancer via abating Wnt/ß-Catenin signaling pathway.

Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), was used in combination with traditional chemotherapy as the first line treatment for metastatic colorectal cancer (mCRC), non-small cell lung cancer (NSCLC) and advanced ovarian cancer. However, it shows limited efficacy for human triple-negative breast cancer (TNBC). Bevacizumab shows potent anti-angiogenesis activity, meanwhile, it also increases invasive and metastatic properties of TNBC cells by activiting Wnt/ß-Catenin pathway. To overcome this problem, and fully utilize its potency against cancer, further synergistic strategy is recommended to be developed, especially the concurrent use with those Wnt-targeting agents. Here, by screening a small library of traditional Chinese medicine, we identified a Chinese herb derived Oxymatrine, which could target Wnt/ß-Catenin signaling and compromise the oncogenic effects of Bevacizumab. Bevacizumab was validated to induce epithelial-mesenchymal cell transformation (EMT) and cancer stem-like properties of TNBC cells in hypoxia/nutritional stress environment. On the contrary, Oxymatrine reversed the EMT phenotype and depleted the subpopulation of TNBC stem cells induced by Bevacizumab. Oxymatrine enhanced the anti-tumor effects of Bevacizumab in vivo, and holded the potential of reducing the risk of relapse and metastasis by impairing the self-renewal ability of TNBC stem cells. The underlying mechanism was elucidated: Bevacizumab stimulated Wnt/ß-Catenin signaling pathway, and Oxymatrine could compromise this effect. On this foundation, factoring into the satisfactory anti-angiogenic activity and low toxicity, Oxymatrine is a good candidate for the synergistic therapy together with Bevacizumab for the treatment of TNBC.