Si-Ni-San Reduces Hepatic Lipid Deposition in Rats with Metabolic Associated Fatty Liver Disease by AMPK/SIRT1 Pathway.

Background: Metabolic associated fatty liver disease (MAFLD) is a chronic disease characterized by excessive lipid deposition in the liver without alcohol or other clear liver-damaging factors. AMP-activated protein kinase (AMPK)/silencing information regulator (SIRT)1 signaling pathway plays an important role in MAFLD development. Si-Ni-San (SNS), a traditional Chinese medicine, has shown reducing hepatic lipid deposition in MAFLD rats, however, the underlying mechanisms of SNS are barely understood. Purpose: The aim of this research was to investigate the mechanisms of SNS in reducing hepatic lipid deposition in MAFLD rats by regulating AMPK/SIRT1 signaling pathways. Methods: The components of SNS were determined by high performance liquid chromatography with mass spectrometry (HPLC-MS) analysis. MAFLD rats were induced by high-fat and high-cholesterol diet (HFHCD), and treated by SNS. SNS-containing serum and Compound C (AMPK inhibitor) were used to treat palmitic acid (PA)-induced HepG2 cells. To elucidate the potential mechanism, lipid synthesis-related proteins (SREBP-1c and FAS), fatty acid oxidation (PPARα and CPT-1), and AMPK/SIRT1 signaling pathway (p-AMPK and SIRT1) were assessed by Western blot. Results: SNS improved serum lipid levels, liver function and reduced hepatic lipid deposition in MAFLD rats. SNS-containing serum reduced lipid deposition in PA-induced HepG2 cells. SNS could up-regulate protein expressions of PPARα, CPT-1, p-AMPK and SIRT1, and down-regulate protein expressions of SREBP-1c and FAS. Similar effects of SNS-containing serum were observed in PA-induced HepG2 cells. Meanwhile, Compound C weakened the therapeutic effects of SNS-containing serum on lipid deposition. Conclusion: SNS could reduce hepatic lipid deposition by inhibiting lipid synthesis and promoting fatty acid oxidation, which might be related with activating the AMPK/SIRT1 signaling pathway. This study could provide a theoretical basis for the clinical use of SNS to treat MAFLD.

Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

The active ingredients in many traditional Chinese medicines are isoprene oligomers with a diterpenoid or triterpenoid structure, which exert cardiovascular effects by signalling through nutrient surplus and nutrient deprivation pathways. Qiliqiangxin (QLQX) is a commercial formulation of 11 different plant ingredients, whose active compounds include astragaloside IV, tanshione IIA, ginsenosides (Rb1, Rg1 and Re) and periplocymarin. In the QUEST trial, QLQX reduced the combined risk of cardiovascular death or heart failure hospitalization (hazard ratio 0.78, 95% confidence interval 0.68-0.90), based on 859 events in 3119 patients over a median of 18.2 months; the benefits were seen in patients taking foundational drugs except for sodium-glucose cotransporter 2 (SGLT2) inhibitors. Numerous experimental studies of QLQX in diverse cardiac injuries have yielded highly consistent findings. In marked abrupt cardiac injury, QLQX mitigated cardiac injury by upregulating nutrient surplus signalling through the PI3K/Akt/mTOR/HIF-1α/NRF2 pathway; the benefits of QLQX were abrogated by suppression of PI3K, Akt, mTOR, HIF-1α or NRF2. In contrast, in prolonged measured cardiac stress (as in chronic heart failure), QLQX ameliorated oxidative stress, maladaptive hypertrophy, cardiomyocyte apoptosis, and proinflammatory and profibrotic pathways, while enhancing mitochondrial health and promoting glucose and fatty acid oxidation and ATP production. These effects are achieved by an action of QLQX to upregulate nutrient deprivation signalling through SIRT1/AMPK/PGC-1α and enhanced autophagic flux. In particular, QLQX appears to enhance the interaction of PGC-1α with PPARα, possibly by direct binding to RXRα; silencing of SIRT1, PGC-1α and RXRα abrogated the favourable effects of QLQX in the heart. Since PGC-1α/RXRα is also a downstream effector of Akt/mTOR signalling, the actions of QLQX on PGC-1α/RXRα may explain its favourable effects in both acute and chronic stress. Intriguingly, the individual ingredients in QLQX - astragaloside IV, ginsenosides, and tanshione IIA - share QLQX's effects on PGC-1α/RXRα/PPARα signalling. QXQL also contains periplocymarin, a cardiac glycoside that inhibits Na+ -K+ -ATPase. Taken collectively, these observations support a conceptual framework for understanding the mechanism of action for QLQX in heart failure. The high likelihood of overlap in the mechanism of action of QLQX and SGLT2 inhibitors requires additional experimental studies and clinical trials.

The effects of sodium butyrate supplementation on the expression levels of PGC-1α, PPARα, and UCP-1 genes, serum level of GLP-1, metabolic parameters, and anthropometric indices in obese individuals on weight loss diet: a study protocol for a triple-blind, randomized, placebo-controlled clinical trial.

BACKGROUND: Obesity is a multifaceted disease characterized by an abnormal accumulation of adipose tissue. Growing evidence has proposed microbiota-derived metabolites as a potential factor in the pathophysiology of obesity and related metabolic conditions over the last decade. As one of the essential metabolites, butyrate affects several host cellular mechanisms related to appetite sensations and weight control. However, the effects of butyrate on obesity in humans have yet to be studied. Thus, the present study was aimed to evaluate the effects of sodium butyrate (SB) supplementation on the expression levels of peroxisome proliferator activated-receptor (PPAR) gamma coactivator-1α (PGC-1α), PPARα and uncoupling protein 1 (UCP1) genes, serum level of glucagon-like peptide (GLP1), and metabolic parameters, as well as anthropometric indices in obese individuals on a weight loss diet. METHODS: This triple-blind randomized controlled trial (RCT) will include 50 eligible obese subjects aged between 18 and 60 years. Participants will be randomly assigned into two groups: 8 weeks of SB (600 mg/day) + hypo-caloric diet or placebo (600 mg/day) + hypo-caloric diet. At weeks 0 and 8, distinct objectives will be pursued: (1) PGC-1α, PPARα, and UCP1 genes expression will be evaluated by real-time polymerase chain reaction; (2) biochemical parameters will be assayed using enzymatic methods; and (3) insulin and GLP1 serum level will be assessed by enzyme-linked immunosorbent assay kit. DISCUSSION: New evidence from this trial may help fill the knowledge gap in this realm and facilitate multi-center clinical trials with a substantially larger sample size. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT20190303042905N2 . Registered on 31 January 2021.

Bombax ceiba Linn. leaf extract rich in phenolic compounds to mitigate non-alcoholic fatty liver-related complications in experimental model.

OBJECTIVES: Obesity, diabetes mellitus, insulin resistance (IR), and hypertriglyceridemia are common features observed in non-alcoholic fatty liver diseases (NAFLD). There is a critical medical necessity to find novel therapeutics that can halt the development of NAFLD. METHODS: Bombax ceiba Linn. leaf extract was prepared and its phytochemical profile was determined. Standard and high carbohydrate high-fat diets (HCHF) were prepared. Rats were fed HCHF for 18 weeks to induce a non-alcoholic fatty liver (NAFL) model. Forty male rats were divided into control, B. ceiba Linn. leaf extract, NAFL, prophylactic, and treated groups. Serum fasting blood sugar (FBS), insulin, insulin resistance (HOMA-IR), cholesterol, high-density lipoprotein (HDL), triglycerides (TG), low density lipoprotein (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), intelectin-1 (ITLN1), p38 MAP kinase (MAPK), peroxisome proliferator-activated receptor alpha (PPAR-α), and interleukin-6 (IL-6) were evaluated. RESULTS: Data obtained showed that HCHF-induced NAFL resulting in a significant increase in FBS, serum insulin, HOMA-IR, cholesterol, LDL, TG, ALT, AST, and IL-6 and a significant decrease in serum levels of HDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the control group. The analysis of B. ceiba Linn. leaf extract showed high content of phenol compounds which may cause a significant decrease in the levels of FBS, insulin, HOMA-IR values, lipid profile, and levels of IL-6 while a significant increase in serum levels of LDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the NAFL group. CONCLUSIONS: B. ceiba Linn. Leaf extract is a highly protective and promising therapeutic agent against inflammation and oxidative stress in the NAFLD model induced by HCHF.