7,8,3'-Trihydroxyflavone prevents doxorubicin-induced cardiotoxicity and mitochondrial dysfunction via activating Akt signaling pathway in H9c2 cells.

Clinical application of the widely used chemotherapeutic agent, doxorubicin (DOX), is limited by its cardiotoxicity. Mitochondrial dysfunction has been revealed as a crucial factor in DOX-induced cardiotoxicity. 7,8,3'-Trihydroxyflavone (THF) is a mimetic brain-derived neurotrophic factor with neuroprotective effects. However, the potential effects of THF on DOX-induced cardiomyocyte damage and mitochondrial disorders remain unclear. H9c2 cardiomyoblasts were exposed to DOX and/or THF at different concentrations. Cardiomyocyte injury was evaluated using lactate dehydrogenase (LDH) assay and Live/Dead cytotoxicity kit. Meanwhile, mitochondrial membrane potential (MMP), morphology, mitochondrial reactive oxygen species (mito-ROS) production, and the oxygen consumption rate of cardiomyocytes were measured. The protein levels of key mitochondria-related factors such as adenosine monophosphate-activated protein kinase (AMPK), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and optic atrophy protein 1 (OPA1) were examined. We found that THF reduced LDH content and death ratio of DOX-treated cardiomyocytes in a concentration-dependent manner, while increasing MMP without significantly affecting the routine and maximum capacity of mitochondrial respiration. Mechanistically, THF increased the activity of Akt and protein levels of Mfn2 and heme oxygenase 1 (HO-1). Moreover, inhibition of Akt reversed the protective role of THF, increased mito-ROS levels, and repressed Mfn2 and HO-1 expression. Therefore, we conclude, THF relieves DOX-induced cardiotoxicity and improves mitochondrial function by activating Akt-mediated Mfn2 and HO-1 pathways. This finding provides promising therapeutic insights for DOX-induced cardiac dysfunction.

BDNF mimetic 7,8-dihydroxyflavone rescues rotenone-induced cytotoxicity in cardiomyocytes by ameliorating mitochondrial dysfunction.

The relationship between mitochondrial dysfunction and cardiovascular disease pathogenesis is well recognized. 7,8-Dihydroxyflavone (7,8-DHF), a mimetic of brain-derived neurotrophic factor, inhibits mitochondrial impairments and improves cardiac function. However, the regulatory role of 7,8-DHF in the mitochondrial function of cardiomyocytes is not fully understood. To investigate the potential mito-protective effects of 7,8-DHF in cardiomyocytes, we treated H9c2 or HL-1 cells with the mitochondrial respiratory complex I inhibitor rotenone (Rot) as an in vitro model of mitochondrial dysfunction. We found that 7,8-DHF effectively eliminated various concentrations of Rot-induced cell death and reduced lactate dehydrogenase release. 7,8-DHF significantly improved mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species. Moreover, 7,8-DHF decreased routine and leak respiration, restored protein levels of mitochondrial complex I-IV, and increased ATP production in Rot-treated H9c2 cells. The protective role of 7,8-DHF in Rot-induced damage was validated in HL-1 cells. Nuclear phosphorylation protein expression of signal transducer and activator of transcription 3 (STAT3) was significantly increased by 7,8-DHF. The present study suggests that 7,8-DHF rescues Rot-induced cytotoxicity by inhibiting mitochondrial dysfunction and promoting nuclear translocation of p-STAT3 in cardiomyocytes, thus nominating 7,8-DHF as a new pharmacological candidate agent against mitochondrial dysfunction in cardiac diseases.

The regulatory role of the BDNF/TrkB pathway in organ and tissue fibrosis.

Fibrosis across diverse organ systems is one of the leading causes of morbidity and mortality by inducing progressive architectural remodeling and organ dysfunction. Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptor B (TrkB) play crucial roles in regulating neural survival, development, function and plasticity in the central and the peripheral nervous system. Previous studies demonstrated that the BDNF/TrkB pathway is widely distributed in different cell types such as neuron, epithelial cell, hepatocyte, and cardiomyocyte. Recently, there is increasing recognition that BDNF and TrkB are also expressed in fibroblasts in different organs. Moreover, growing evidence was obtained regarding the functional roles of BDNF/TrkB signaling in organ and tissue fibrosis. Thus, this review summarizes the basic molecular characteristics of the BDNF/TrkB cascade and the findings of the crucial roles and therapeutic value in organ and tissue fibrosis including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis, bladder fibrosis and skin fibrosis. Small molecule BDNF mimetic and BDNF-related non-coding RNAs are also discussed for developing new therapeutic approaches for fibrotic disorders.

The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases.

Brain-derived neurotrophic factor (BDNF) is one of the most abundantneurotrophins in the central nervous system. Numerous studies suggestthat BDNF has extensive roles by binding to its specific receptor, tropomyosin-related kinase receptor B (TrkB), and thereby triggering downstream signaling pathways. Recently, growing evidence highlightsthat the BDNF/TrkB pathway is expressed in the cardiovascular system andclosely associated with the development and outcome of cardiovascular diseases (CVD), including coronary artery disease, heart failure, cardiomyopathy, hypertension, and metabolic diseases. Furthermore, circulating BDNF has also been revealed as a new potential biomarker for both diagnosis and prognosis of CVD. In this review, we discuss the current evidence of the emerging role of BDNF/TrkBsignalingand address the challenges that remain in translating these discoveries to novel therapeutic strategies for CVD.