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Aims Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. Methods and results We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites—D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. Conclusion Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT. [ABSTRACT FROM AUTHOR]

The primary inflammatory process in atherosclerosis, a major contributor to cardiovascular disease, begins with monocyte adhering to vascular endothelial cells. Actinidia arguta (kiwiberry) is an edible fruit that contains various bioactive components. While A. arguta extract (AAE) has been recognized for its anti-inflammatory characteristics, its specific inhibitory effect on early atherogenic events has not been clarified. We used tumor necrosis factor-α (TNF-α)–stimulated human umbilical vein endothelial cells (HUVECs) for an in vitro model. AAE effectively hindered the attachment of THP-1 monocytes and reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Transcriptome analysis revealed that AAE treatment upregulated phosphatase and tensin homolog (PTEN), subsequently inhibiting phosphorylation of AKT and glycogen synthase kinase 3β (GSK3β) in HUVECs. AAE further hindered phosphorylation of AKT downstream of the nuclear factor kappa B (NF-κB) signaling pathway, leading to suppression of target gene expression. Oral administration of AAE suppressed TNF-α–stimulated VCAM-1 expression, monocyte-derived macrophage infiltration, and proinflammatory cytokine expression in C57BL/6 mouse aortas. Myo-inositol, identified as the major compound in AAE, played a key role in suppressing THP-1 monocyte adhesion in HUVECs. These findings suggest that AAE could serve as a nutraceutical for preventing atherosclerosis by inhibiting its initial pathogenesis. [ABSTRACT FROM AUTHOR]

Excessive lipid accumulation in adipocytes is a primary contributor to the development of metabolic disorders, including obesity. The consumption of bioactive compounds derived from natural sources has been recognized as being safe and effective in preventing and alleviating obesity. Therefore, we aimed to explore the antilipidemic effects of pennogenin 3-O-β-chacotrioside (P3C), a steroid glycoside, on hypertrophied 3T3-L1 adipocytes. Oil Red O and Nile red staining demonstrated a P3C-induced reduction in lipid droplet accumulation. Additionally, the increased expression of adipogenic and lipogenic factors, including PPARγ and C/EBPα, during the differentiation process was significantly decreased by P3C treatment at both the protein and mRNA levels. Furthermore, P3C treatment upregulated the expression of fatty acid oxidation-related genes such as PGC1α and CPT1a. Moreover, mitochondrial respiration and ATP generation increased following P3C treatment, as determined using the Seahorse XF analyzer. P3C treatment also increased the protein expression of mitochondrial oxidative phosphorylation in hypertrophied adipocytes. Our findings suggest that P3C could serve as a natural lipid-lowering agent, reducing lipogenesis and enhancing mitochondrial oxidative capacity. Therefore, P3C may be a promising candidate as a therapeutic agent for obesity-related diseases. [ABSTRACT FROM AUTHOR]

Tamarixetin (TX) is an O-methylated flavonoid naturally derived from quercetin. TX has bioactive properties; however, whether it shows antilipogenic activity remains unknown. Therefore, in the present study, we aimed to determine the antilipogenic effects of TX using 3T3-L1 adipocytes. The 3T3-L1 adipocytes were cultured in a differentiation medium with or without TX. Lipid accumulation was diminished and the mRNA expression of lipogenesis-related genes was decreased following TX treatment. We found that TX exhibited antilipogenic effects by inhibiting the expression of p300/CBP-associated factor (pCAF), a histone acetyltransferase, as confirmed by pCAF knockdown. Furthermore, TX inhibited both pCAF expression and its activity, thereby reducing the total acetylation level of nonhistone and histone proteins. Finally, TX decreased the expression of CCAAT/enhancer-binding protein alpha and beta (CEBPα and CEBPβ), and peroxisome proliferator-activated receptor γ along with pCAF expression during adipogenesis of 3T3-L1 cells in a time-dependent manner. Collectively, our findings suggest that TX is a potent antilipogenic agent derived from natural products and may be used as a pCAF inhibitor. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease affecting the aorta and is a major cause of cardiovascular disease. Arctium lappa root is a plant widely used in traditional Chinese medicine (TCM), and Arctium lappa root extract (ALE) has been reported to exhibit anti-inflammatory capacity and to ameliorate endothelial dysfunction. Thus, we hypothesized that ALE would inhibit the early atherosclerotic stage. In this study, we evaluated the inhibitory effect of ALE on early arteriosclerosis and its mechanisms of action. ALE suppressed TNF-α-induced monocyte adhesion to the vascular endothelium by suppressing NF-κB signaling in HUVECs. In an acute mouse model of atherosclerosis, ALE suppressed TNF-α-induced monocyte infiltration of the vascular endothelium and the expression of genes encoding inflammatory cytokines including IL-1β, IL-6, TNF-α, and MCP-1 in the mouse aorta. Moreover, inulin-type fructan and amino acids, especially L-aspartate and L-arginine (60.27 and 42.17 mg/g, respectively) were detected by NMR, MALDI-TOF MS, and HPLC analysis as the main components of ALE. Notably, L-arginine suppressed TNF-α-induced monocyte adhesion to HUVECs. Therefore, these results suggest that ALE may be a functional food for the suppression or prevention of early stages of atherosclerosis. Unlabelled Image [ABSTRACT FROM AUTHOR]

Irisin is an exercise-induced myokine that has various physiological functions, such as roles in energy expenditure, glucose/lipid metabolism, and muscle development. In muscle development, myoblast proliferation is known to be a first step, and recent studies have reported that an increased irisin level is involved in the promotion of cell proliferation in various cell types, including myoblasts. However, the exact mechanism of action by which irisin promotes myoblast proliferation has not been reported. In this study, we aimed to determine the pro-proliferative effect of irisin on C2C12 myoblasts and its mechanism of action. Irisin induced C2C12 cell proliferation and upregulated the mRNA levels of markers of proliferation Pcna, Mki67, and Mcm2. Irisin increased extracellular signal-regulated kinase (ERK) phosphorylation, and U0126, an ERK pathway inhibitor, suppressed irisin-induced C2C12 cell proliferation. Transcriptomic and qRT-PCR analysis showed that Ccl2, Ccl7, Ccl8, and C3 are potential downstream regulators of ERK signaling that promote C2C12 cell proliferation. Knockdown of Ccl7 revealed that irisin upregulates chemokine (C-C motif) ligand 7 (CCL7) and subsequently promotes C2C12 cell proliferation. These results suggest that irisin promotes C2C12 myoblast proliferation via ERK-dependent CCL7 upregulation and may aid in understanding how irisin contributes to muscle development. [ABSTRACT FROM AUTHOR]