Ginseng polysaccharide components attenuate obesity and liver lipid accumulation by regulating fecal microbiota and hepatic lysine degradation.

The increasing incidence of obesity has led to widespread attention in the exploration of natural ingredients. Ginseng polysaccharides (PGP), the main components from Panax ginseng, have been reported potential effect to attenuate obesity and regulate lipid metabolism. In this study, we found that PGP inhibited the high-fat diet (HFD)-induced weight gain, fat ratio and fat tissue weight after 8-week administration. Serum and liver lipid analysis showed that PGP decreased the levels of triglyceride and total cholesterol, which was mediated by the inhibition of key genes for fatty acid and cholesterol metabolisms. Metabolomics studies showed that the inhibitory effect of PGP on liver lipid accumulation was significantly correlated with its regulation of citric acid cycle and lysine degradation. PGP regulated the expression of genes related to lysine degradation in both liver tissue and hepatocytes. In addition, PGP reshaped the composition of fecal microbiota at the genus and species levels in obese mice. Spearman's correlation analysis demonstrated that Staphylococcus sciuri, Staphylococcus lentus, and Pseudoflavonifractor sp. An85 may be the potential targets that PGP maintains the abundance of l-lysine against obesity. It concluded that PGP can attenuate obesity and liver lipid accumulation by regulating fecal microbiota and hepatic lysine degradation.

The role of lncRNAKCNQ1OT1/miR-301b/Tcf7 axis in cardiac hypertrophy.

OBJECTIVE: Cardiac hypertrophy, acting as a pathologic process of chronic hypertension and coronary disease, and its underlying mechanisms still need to be explored. Long non-coding RNA (LncRNA) potassium voltage-gated channel subfamily Q member 1 Transcript 1 (KCNQ1OT1) has been implicated in myocardial infarction. However, its role in cardiac hypertrophy remains reported. METHOD: To explore the regulated effect of lncRNAKCNQ1OT1 and miR-301b in cardiac hypertrophy, gain-and-lose function assays were tested. The expression of lncRNAKCNQ1OT1 and miR-301b were tested by quantitative real time polymerase chain reaction (qRT-PCR). The levels of transcription factor 7 (Tcf7), Proto-oncogene c-myc (c-myc), Brainnatriureticpeptide (BNP) and ß-myosin heavy chain (ß-MHC) were detected by Western blot. Additionally, luciferase analysis revealed interaction between lncRNAKCNQ1OT1, BNPß-MHCmiR-301b, and Tcf7. RESULT: LncRNAKCNQ1OT1 overexpression significantly induced cardiac hypertrophy. Furthermore, lncRNAKCNQ1OT1 acts as a sponge for microRNA-301b, which exhibited lower expression in cardiac hypertrophy model, indicating an anti-hypertrophic role. Furthermore, the BNP and ß-MHC expression increased, as well as cardiomyocyte surface area, with Ang II treatment, while the effect was repealed by miR-301b. Moreover, the protein expression of Tcf7 was inversely regulated by miR-301b and Antisense miRNA oligonucleotides (AMO)-301b. CONCLUSION: Our study has shown that overexpression of lncRNAKCNQ1OT1 could promote the development of cardiac hypertrophy by regulating miR-301b and Tcf7. Therefore, inhibition of lncRNAKCNQ1OT1 might be a potential therapeutic strategy for cardiac hypertrophy.

Triptolide attenuates cardiac remodeling by inhibiting pyroptosis and EndMT via modulating USP14/Keap1/Nrf2 pathway.

Background: Cardiac remodeling is a common pathological feature in many cardiac diseases, characterized by cardiac hypertrophy and fibrosis. Triptolide (TP) is a natural compound derived from Tripterygium wilfordii Hook F. However, the related mechanism of it in cardiac remodeling has not been fully understood. Methods and results: Transverse aortic constriction (TAC)-induced cardiac hypertrophic mouse model and angiotensin II (Ang II)-induced cardiomyocytes hypertrophic model were performed. Firstly, the results indicate that TP can improve cardiac function, decreased cardiomyocyte surface area and fibrosis area, as well as lowered the protein expressions of brain natriuretic peptide (BNP), ß-major histocompatibility complex (ß-MHC), type I and III collagen (Col I and III). Secondly, TP suppressed cardiac pyroptosis, and decreased the levels of Interleukin-1ß (IL-1ß), Interleukin-18 (IL-18) by Enzyme-linked immunosorbent assay (ELISA), and pyroptosis-associated proteins. Furthermore, TP enhanced the expressions of Nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase 1 (HO-1). Interestingly, when Nrf2 was silenced by siRNA, TP lost its properties of reducing pyroptosis and cardiac hypertrophy. In addition, in the Transforming Growth Factor ß1 (TGF-ß1)-induced primary human coronary artery endothelial cells (HCAEC) model, TP was found to inhibit the process of endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial-specific markers and the gain of mesenchymal markers. This was accompanied by a suppression of Slug, Snail, and Twist expression. Meanwhile, the inhibitory effect of TP on EndMT was weakened when Nrf2 was silenced by siRNA. Lastly, potential targets of TP were identified through network pharmacology analysis, and found that Ubiquitin-Specific Protease 14 (USP14) was one of them. Simultaneously, the data indicated that decrease the upregulation of USP14 and Kelch-like ECH-Associated Protein 1 (Keap1) caused by cardiac remodeling. However, Keap1 was decreased and Nrf2 was increased when USP14 was silenced. Furthermore, CoIP analysis showed that USP14 directly interacts with Keap1. Conclusion: TP can observably reduce pyroptosis and EndMT by targeting the USP14/Keap1/Nrf2 pathway, thereby significantly attenuating cardiac remodeling.

Therapeutic application of natural products: NAD+ metabolism as potential target.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) metabolism is involved in the entire physiopathological process and is critical to human health. Long-term imbalance in NAD+ homeostasis is associated with various diseases, including non-alcoholic fatty liver disease, diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, aging, and cancer, making it a potential target for effective therapeutic strategies. Currently, several natural products that target NAD+ metabolism have been widely reported to have significant therapeutic effects, but systematic summaries are lacking. PURPOSE: To summarize the latest findings on the prevention and treatment of various diseases through the regulation of NAD+ metabolism by various natural products in vivo and in vitro models, and evaluate the toxicities of the natural products. METHODS: PubMed, Web of Science, and ScienceDirect were searched using the keywords "natural products sources," "toxicology," "NAD+ clinical trials," and "NAD+," and/or paired with "natural products" and "diseases" for studies published within the last decade until January 2023. RESULTS: We found that the natural products mainly include phenols (curcumin, cyclocurcumin, 4-hydroxybenzyl alcohol, salvianolic acid B, pterostilbene, EGCG), flavonoids (pinostrobin, apigenin, acacetin, tilianin, kaempferol, quercetin, isoliquiritigenin, luteolin, silybin, hydroxysafflor yellow A, scutellarin), glycosides (salidroside), quinones (emodin, embelin, ß-LAPachone, shikonin), terpenoids (notoginsenoside R1, ginsenoside F2, ginsenoside Rd, ginsenoside Rb1, ginsenoside Rg3, thymoquinone, genipin), pyrazines (tetramethylpyrazine), alkaloids (evodiamine, berberine), and phenylpropanoids (ferulic acid). These natural products have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic and anti-aging effects, which mainly influence the NAMPT/NAD+/SIRT, AMPK/SIRT1/PGC-1α, Nrf2/HO-1, PKCs/PARPs/NF-κB, and AMPK/Nrf2/mTOR signaling pathways, thereby regulating NAD+ metabolism to prevent and treat various diseases. These natural products have been shown to be safe, tolerable and have fewer adverse effects in various in vivo and in vitro studies and clinical trials. CONCLUSION: We evaluated the toxic effects of natural products and summarized the available clinical trials on NAD+ metabolism, as well as the recent advances in the therapeutic application of natural products targeting NAD+ metabolism, with the aim to provide new insights into the treatment of multiple disorders.

MiR-103 inhibiting cardiac hypertrophy through inactivation of myocardial cell autophagy via targeting TRPV3 channel in rat hearts.

Cardiac hypertrophy is a common pathological change frequently accompanied by chronic hypertension and myocardial infarction. Nevertheless, the pathophysiological mechanisms of cardiac hypertrophy have never been elucidated. Recent studies indicated that miR-103 expression was significantly decreased in heart failure patients. However, less is known about the role of miR-103 in cardiac hypertrophy. The present study was designed to investigate the relationship between miR-103 and the mechanism of pressure overload-induced cardiac hypertrophy. TRPV3 protein, cardiac hypertrophy marker proteins (BNP and ß-MHC) and autophagy associated proteins (Beclin-1 and LC3-II) were up-regulated, as well as, miR-103 expression and autophagy associated proteins (p62) were down-regulated in cardiac hypertrophy models in vivo and in vitro respectively. Further results indicated that silencing TRPV3 or forcing overexpression of miR-103 could dramatically inhibit cell surface area, relative fluorescence intensity of Ca2+ signal and the expressions of BNP, ß-MHC, Beclin-1 and LC3-II, but promote p62 expression. Moreover, TRPV3 protein was decreased in neonatal rat ventricular myocyte transfected with miR-103, but increased by AMO-103. Co-transfection of the miR-103 with the luciferase reporter vector into HEK293 cells caused a sharp decrease in luciferase activity compared with transfection of the luciferase vector alone. The miR-103-induced depression of luciferase activity was rescued by an AMO-103. These findings suggested that TRPV3 was a direct target of miR-103. In conclusion, miR-103 could attenuate cardiomyocyte hypertrophy partly by reducing cardiac autophagy activity through the targeted inhibition of TRPV3 signalling in the pressure-overloaded rat hearts.

The transient receptor potential vanilloid-3 regulates hypoxia-mediated pulmonary artery smooth muscle cells proliferation via PI3K/AKT signaling pathway.

OBJECTVES: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+ -permeant cation channels. In this study, we aim to investigate the role of TRPV3 in pulmonary vascular remodeling and PASMCs proliferation under hypoxia. MATERIALS AND METHODS: The expression of TRPV3 was evaluated in patients with pulmonary arterial hypertension (PAH) and hypoxic rats, using hematoxylin and eosin (H&E) and immunohistochemistry. In vitro, MTT assay, flow cytometry, Western blotting and immunofluorescence were performed to investigate the effects of TRPV3 on proliferation of PASMCs. RESULTS: We found that, in vivo, the expression of TRPV3 was increased in patients with PAH and hypoxic rats. Right ventricular hypertrophy measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery were increased in chronic hypoxic rats. Moreover, the expression of proliferating cell nuclear antigen (PCNA), Cyclin D, Cyclin E and Cyclin A, phospho-CaMKII (p-CaMKII) were induced by hypoxia. In vitro, we revealed that hypoxia promoted PASMCs viability, increased the expression of PCNA, Cyclin D, Cyclin E, Cyclin A p-CaMKII, made more cells from G0 /G1 phase to G2 /M + S phase, enhanced the microtubule formation, and increased [Ca2+ ]i , which could be suppressed by Ruthenium Red, an inhibitor of TRPV3, and TRPV3 silencing has similar effects. Furthermore, the up-regulated expression of PCNA, Cyclin D, Cyclin E and Cyclin A, the increased number of cells in G2 /M and S phase, and the enhanced activation and expression of PI3K and AKT proteins induced by hypoxia and in presence of carvacrol (an agonist of TRPV3), was significantly attenuated by incubation of LY 294002, a specific inhibitor for PI3K/AKT. CONCLUSIONS: These findings suggest that TRPV3 is involved in hypoxia-induced pulmonary vascular remodeling and promotes proliferation of PASMCs and the effect is, at least in part, mediated via the PI3K/AKT pathway.

Transient receptor potential vanilloid-3 (TRPV3) activation plays a central role in cardiac fibrosis induced by pressure overload in rats via TGF-ß1 pathway.

Cardiac fibrosis is a common pathologic change along with pressure overload. Recent studies indicated that transient receptor potential (TRP) channels played multiple roles in heart. However, the functional role of transient receptor potential vanilloid-3 (TRPV3) in cardiac fibrosis remained unclear. The present study was designed to investigate the relationship between TRPV3 activation and pressure overload-induced cardiac fibrosis. Pressure overload rats were successfully established by abdominal aortic constriction (AAC), and cardiac fibrosis was simulated by 100 nM angiotensin II (Ang II) in neonatal cardiac fibroblasts. Echocardiographic parameters, cardiac fibroblast proliferation, cell cycle, intracellular calcium concentration ([Ca2+] i ), and the protein expressions of collagen I, collagen III, transforming growth factor beta 1 (TGF-ß1), cyclin E, and cyclin-dependent kinase 2 (CDK2) were measured. Echocardiographic and histological measurements suggested that the activation of TRPV3 exacerbated the cardiac dysfunction and increased interstitial fibrosis in pressure overload rats. Further results showed that TRPV3 activation upregulated the expressions of collagen I, collagen III, TGF-ß1, cyclin E, and CDK2 in vivo and in vitro. At the same time, blocking TGF-ß1 pathway could partially reverse the effect of TRPV3 activation. These results suggested that TRPV3 activation exacerbated cardiac fibrosis by promoting cardiac fibroblast proliferation through TGF-ß1/CDK2/cyclin E pathway in the pressure-overloaded rat hearts.

Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats.

Cardiac fibrosis is pathological damage associated with nearly all forms of heart disease. AMP-activated protein kinase (AMPK) is an evolutionary conserved energy-sensing enzyme. Emerging evidences indicate that AMPK plays an important role in cardiac fibrosis and cell proliferation. However, less is known about the detailed mechanism of AMPK activation on cardiac fibrosis. In this study, we found the AMPK activation improved the impaired cardiac function of cardiac fibrosis rats and decreased interstitial fibrosis. Further results indicated AMPK activation promoted p21 and p27 and inhibited CDK2 and cyclin E protein expressions both in vivo and in vitro. Moreover, AMPK activation repressed downstream transcription factor hepatocyte nuclear factor 4 alpha (HNF-4α) expression and decreased the binding of HNF-4α to TGF-ß1 promoters, which eventually resulted in TGF-ß1 downregulation and miR-29 family upregulation. Furthermore, miR-29, in turn, inhibited the progression of cardiac fibrosis through suppressing its target CDK2. Taken together, activation of AMPK, on the one hand, upregulated p21 and p27 expression, further inhibited CDK2 and cyclin E complex, and finally suppressed the progression of cardiac fibrosis, and, on the other hand, repressed HNF-4α expression, further downregulated the activity of TGF-ß1 promoter, promoted miR-29 expression, and finally prevented the development of cardiac fibrosis.