Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis.

BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H+-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD+ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [3H]chloroquine (endosomal pH), and [14C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V1G1/V0d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.

Lingguizhugan decoction attenuates diet-induced obesity and hepatosteatosis via gut microbiota.

BACKGROUND: Obesity is a major risk factor for a variety of diseases such as diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Restricting energy intake, or caloric restriction (CR), can reduce body weight and improve metabolic parameters in overweight or obese patients. We previously found that Lingguizhugan decoction (LZD) in combination with CR can effectively lower plasma lipid levels in patients with metabolic syndrome. However, the mechanism underlying CR and LZD treatment is still unclear. AIM: To investigate whether CR and LZD improve metabolic parameters by modulating gut microbiota. METHODS: We extracted the water-soluble components out of raw materials and dried as LZD extracts. Eight-week old male C57BL/6 mice were treated with a 3-d treatment regime that included 24 h-fasting followed by gavage of LZD extracts for 2 consecutive days, followed by a normal diet (ND) ad libitum for 16 wk. To test the effects of gut microbiota on diet-induced obesity, 8-wk old male C57BL/6 mice received fecal microbiota transplantation (FMT) from CR and LZD-treated mice every 3 d and were fed with high-fat diet (HFD) ad libitum for 16 wk. Control mice received either saline gavage or FMT from ND-fed mice receiving saline gavage as mentioned above. Body weight was monitored bi-weekly. Food consumption of each cage hosting five mice was recorded weekly. To monitor blood glucose, total cholesterol, and total triglycerides, blood samples were collected via submandibular bleeding after 6 h fasting. Oxygen consumption rate was monitored with metabolic cages. Feces were collected, and fecal DNA was extracted. Profiles of gut microbiota were mapped by metagenomic sequencing. RESULTS: We found that CR and LZD treatment significantly reduced the body weight of mice fed with ND (28.71 ± 0.29 vs 28.05 ± 0.15, P < 0.05), but did not affect plasma total cholesterol or total triglyceride levels. We then transplanted the fecal microbiota collected from CR and LZD-treated mice under ND feeding to HFD-fed mice. Intriguingly, transplanting the mice with fecal microbiota from CR and LZD-treated mice potently reduced body weight (44.95 ± 1.02 vs 40.53 ± 0.97, P < 0.001). FMT also reduced HFD-induced hepatosteatosis, in addition to improved glycemic control. Mechanistic studies found that FMT increased OCR of the mice and suppressed the expression and protein abundance of lipogenic genes in the liver. Metagenomic analysis revealed that HFD drastically altered the profile of gut microbiota, and FMT modified the profile of the gut microbiota. CONCLUSION: Our study suggests that CR and LZD improve metabolic parameters by modulating gut microbiota.

Local generation of hydrogen for enhanced photothermal therapy.

By delivering the concept of clean hydrogen energy and green catalysis to the biomedical field, engineering of hydrogen-generating nanomaterials for treatment of major diseases holds great promise. Leveraging virtue of versatile abilities of Pd hydride nanomaterials in high/stable hydrogen storage, self-catalytic hydrogenation, near-infrared (NIR) light absorption and photothermal conversion, here we utilize the cubic PdH0.2 nanocrystals for tumour-targeted and photoacoustic imaging (PAI)-guided hydrogenothermal therapy of cancer. The synthesized PdH0.2 nanocrystals have exhibited high intratumoural accumulation capability, clear NIR-controlled hydrogen release behaviours, NIR-enhanced self-catalysis bio-reductivity, high NIR-photothermal effect and PAI performance. With these unique properties of PdH0.2 nanocrystals, synergetic hydrogenothermal therapy with limited systematic toxicity has been achieved by tumour-targeted delivery and PAI-guided NIR-controlled release of bio-reductive hydrogen as well as generation of heat. This hydrogenothermal approach has presented a cancer-selective strategy for synergistic cancer treatment.

Three New Polyynes from Codonopsis pilosula and Their Activities on Lipid Metabolism.

Three new polyynes, named choushenpilosulynes A-C (1-3), were isolated from an 85% aqueous EtOH extract of the roots of Codonopsis pilosula cultivated in Xundian County of Yunnan province, China. Their structures, including the absolute configuration of the glucose residue in 1 and 2, were determined by spectroscopic analysis and gas chromatography (GC). In addition, biological evaluation shows that all the compounds can inhibit the expression of the squalene monooxygenase (SQLE) gene in HepG2 cells, suggesting that these compounds may be involved in lipid metabolism.

Phenolic Compounds from Belamcanda chinensis Seeds.

Two new sucrose derivatives, namely, belamcanosides A (1) and B (2), together with five other known compounds (3-7), were isolated from the seeds of Belamcanda chinensis (L.) DC. Their structures were identified based on spectroscopic data. Especially, the absolute configurations of fructose and glucose residues in 1 and 2 were assigned by acid hydrolysis, followed by derivatization and gas chromatography (GC) analysis. Among the known compounds, (-)-hopeaphenol (3), (+)-syringaresinol (4), and quercetin (5), were isolated from B. chinensis for the first time. In addition, biological evaluation of 1 and 2 against cholesterol synthesis and metabolism at the gene level was carried out. The results showed that compounds 1 and 2 could regulate the expression of cholesterol synthesis and metabolism-associated genes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), squalene epoxidase (SQLE), low density lipoprotein receptor (LDLR), and sortilin (SORT1) genes in HepG2 cells.