Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice.

Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver.

Microbiome-gut-brain axis contributes to patients and Bama miniature pigs with acute large ischemic stroke.

Acute large hemispheric infarction (ALHI) is an overwhelming emergency with a great challenge of gastrointestinal dysfunction clinically. Here, we initially proposed delayed bowel movements as the clinical phenotype of strike to gut-brain axis (GBA) in ALHI patients by epidemiological analysis of 499 acute ischemic stroke (AIS) patients. H NMR-based metabolomics revealed that AIS markedly altered plasma global metabolic profiling of patients compared with healthy controls.

Microbial Tryptophan Metabolites Ameliorate Ovariectomy-Induced Bone Loss by Repairing Intestinal AhR-Mediated Gut-Bone Signaling Pathway.

Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut-bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole-3-propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)-induced postmenopausal osteoporosis mice in an AhR-dependent manner.

Long-Term Triclocarban Exposure Induced Enterotoxicity by Triggering Intestinal AhR-Mediated Inflammation and Disrupting Microbial Community in Mice.

Exposure to triclocarban (TCC), a commonly used antibacterial agent, has been shown to induce significant intestine injuries and colonic inflammation in mice. However, the detailed mechanisms by which TCC exposure triggered enterotoxicity remain largely unclear. Herein, intestinal toxicity effects of long-term and chronic TCC exposure were investigated using a combination of histopathological assessments, metagenomics, targeted metabolomics, and biological assays.

Dietary Isoquercetin Ameliorates Bone Loss via Restoration of the Gut Microbiota and Lipopolysaccharide-Triggered Inflammatory Status in Ovariectomy Mice.

Osteoporosis is one of the skeletal degenerative diseases accompanied by bone loss and microstructure disruption. Given that the gut-bone signaling axis highly contributes to bone health, here, dietary isoquercetin (IQ) was shown to effectively improve postmenopausal osteoporosis (PMO) in an ovariectomy (OVX) mouse model through the modulation of the gut-bone cross-talk. An study showed that OVX induced striking disruption of the microbial community, subsequently causing gut leakage and gut barrier dysfunction.

Discovery of a novel small molecule with efficacy in protecting against inflammation in vitro and in vivo by enhancing macrophages activation.

Immune response and inflammation highly contribute to many metabolic syndromes such as inflammatory bowel disease (IBD), ageing and cancer with disruption of host metabolic homeostasis and the gut microbiome. Icariin-1 (GH01), a small-molecule flavonoid derived from Epimedium, has been shown to protect against systemic inflammation. However, the molecular mechanisms by which GH01 ameliorates ulcerative colitis via regulation of microbiota-mediated macrophages polarization remain elusive.

Triclocarban exposure aggravates dextran sulfate sodium-induced colitis by deteriorating the gut barrier function and microbial community in mice.

Triclocarban (TCC) is an antibacterial component widely used in personal care products with potential toxicity possessing public health issues. Unfortunately, enterotoxicity mechanisms of TCC exposure remain largely unknown. Using a combination of 16S rRNA gene sequencing, metabolomics, histopathological and biological examinations, this study systematically explored the deteriorating effects of TCC exposure on a dextran sulfate sodium (DSS)-induced colitis mouse model.

A novel small molecule effectively ameliorates estrogen deficiency-induced osteoporosis by targeting the gut-bone signaling axis.

Postmenopausal osteoporosis stems mainly from estrogen deficiency leading to a gut microbiome-dependent disruption of host systemic immunity. However, the underlying mechanisms of estrogen deficiency-induced bone loss remain elusive and novel pharmaceutical intervention strategies for osteoporosis are needed. Here we reveal that ovariectomy (ovx)-induced estrogen deficiency in C57BL/6 mice causes significant disruption of gut microbiota composition, consequently leading to marked destruction of intestinal barrier function and gut leakage.

Dietary Isoquercetin Reduces Hepatic Cholesterol and Triglyceride in NAFLD Mice by Modulating Bile Acid Metabolism via Intestinal FXR-FGF15 Signaling.

Isoquercetin, a monosaccharide flavonoid, was recently reported to have significant amelioration effects on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) of mice. However, the underlying mechanism of hepatic cholesterol and triglyceride improvement in mice fed HFD by isoquercetin remains unclear. Here, a combination of 16S rRNA gene sequencing, targeted quantification of bile acids (BAs), and biological assays was employed to investigate the beneficial effects of isoquercetin on NAFLD in mice.

A Novel Prenylflavonoid Icariside I Ameliorates Estrogen Deficiency-Induced Osteoporosis via Simultaneous Regulation of Osteoblast and Osteoclast Differentiation.

Regulation of osteoblast-mediated bone formation and osteoclast-mediated bone resorption is crucial for bone health. Currently, most clinical drugs for osteoporosis treatment such as bisphosphonates are commonly used to inhibit bone resorption but unable to promote bone formation. In this study, we discovered for the first time that icariside I (GH01), a novel prenylflavonoid isolated from , can effectively ameliorate estrogen deficiency-induced osteoporosis with enhancement of trabecular and cortical bone in an ovariectomy (OVX) mouse model.

Multiomics Analyses Reveal That Long-Term Intake of Hesperetin-7--glucoside Modulates the Gut Microbiota and Bile Acid Metabolism in Mice.

Hesperetin-7--glucoside (Hes-7-G) is a typical flavonoid monoglucoside, which can be generated from hesperidin with the removal of rhamnose by hydrolysis. Untargeted and targeted metabolomics together with 16S rRNA gene sequencing were employed to explore the exact absorption site of Hes-7-G and its beneficial effect in mice. Intestinal H nuclear magnetic resonance (NMR)-based metabolomics screening showed that Hes-7-G is mainly metabolized in the small intestine of mice, especially the ileum segment.

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism.

The sugar moieties of natural flavonoids determine their absorption, bioavailability, and bioactivity in humans. To explore structure-dependent bioactivities of quercetin, isoquercetin, and rutin, which have the same basic skeleton linking different sugar moieties, we systemically investigated the ameliorative effects of dietary these flavonoids on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) of mice. Our results revealed that isoquercetin exhibits the strongest capability in improving NAFLD phenotypes of mice, including body and liver weight gain, glucose intolerance, and systemic inflammation in comparison with quercetin and rutin.

Acute and subchronic exposure of cyadox induced metabolic and transcriptomic disturbances in Wistar rats.

Cyadox, a potential antimicrobial growth promoter, has been widely studied and prospected to be used as an additive in livestock and poultry feed. Although high cyadox exposure has been reported to cause toxicity, the exact metabolic effects are not fully understood. Our study aim is to evaluate the metabolic effects of cyadox using comprehensive methods including serum clinical chemical test, histopathology analysis, metabolomics, and transcriptomics profile analysis.

Icariside I - A novel inhibitor of the kynurenine-AhR pathway with potential for cancer therapy by blocking tumor immune escape.

Background: Although therapeutic antibodies against immune checkpoints such as PD-1/PD-L1 have achieved unprecedented success in clinical tumor patients, there are still many patients who are ineffective or have limited responses to immune checkpoint blockade (ICB). Discovery of novel strategies for cancer immunotherapy including natural small molecules is needed.

Methods: Owing to its extremely low content in Epimedium genus, we firstly constructed a microbial cell factory to enzymatically biosynthesize icariside I, a natural flavonoid monosaccharide from Herbal Epimedium.

Characterization of triclosan-induced hepatotoxicity and triclocarban-triggered enterotoxicity in mice by multiple omics screening.

Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether, TCS) and triclocarban (3,4,4'-trichloro-carbanilide, TCC) are two antimicrobial agents commonly used for personal care products. Previous studies primarily focused on respective harmful effects of TCS and TCC. In terms of their structural similarities and differences, however, the structure-toxicity relationships on health effects of TCS and TCC exposure remain unclear.

Quantitative structure-retention relationship for reliable metabolite identification and quantification in metabolomics using ion-pair reversed-phase chromatography coupled with tandem mass spectrometry.

Hydrophilic metabolites are essential for all biological systems with multiple functions and their quantitative analysis forms an important part of metabolomics. However, poor retention of these metabolites on reversed-phase (RP) chromatographic column hinders their effective analysis with RPLC-MS methods. Herein, we developed a method for detecting hydrophilic metabolites using the ion-pair reversed-phase liquid-chromatography coupled with mass spectrometry (IPRP-LC-MS/MS) in scheduled multiple-reaction-monitoring (sMRM) mode.

and Studies Reveal that Hesperetin-7--glucoside, a Naturally Occurring Monoglucoside, Exhibits Strong Anti-inflammatory Capacity.

Hesperetin-7--glucoside (Hes-7-G) is a naturally occurring flavonoid monoglucoside in Citri Reticulatae Pericarpium and exhibits relatively high biological activities. To explore the anti-inflammatory capacity of dietary Hes-7-G, lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and dextran sodium sulfate (DSS)-induced colitis mice were used here as and inflammation models.

Long-term chronic exposure to di-(2-ethylhexyl)-phthalate induces obesity via disruption of host lipid metabolism and gut microbiota in mice.

Background: Numerous epidemiological findings have shown that di-(2-ethylhexyl)-phthalate (DEHP), one of industrial plasticizers with endocrine-disrupting properties, positively contributes to high incidence of obesity. However, potential pathogenesis of dietary DEHP exposure-induced obesity remains largely unknown.

Methods: Chronic DEHP exposure at different doses (0.

Microbiome analysis combined with targeted metabolomics reveal immunological anti-tumor activity of icariside I in a melanoma mouse model.

Recent studies report that the gut microbiome can enhance systemic and antitumor immunity by modulating responses to antibody immunotherapy in melanoma patients. In this study, we found that icariside I, a novel anti-cancer agent isolated from Epimedium, significantly inhibited B16F10 melanoma growth in vivo through regulation of gut microbiota and host immunity. Oral administration of icariside I improved the microbiota community structure with marked restoration of Lactobacillus spp.

Gut Microbiota and Its Metabolite Deoxycholic Acid Contribute to Sucralose Consumption-Induced Nonalcoholic Fatty Liver Disease.

As important signal metabolites within enterohepatic circulation, bile acids (BAs) play a pivotal role during the occurrence and development of diet-induced nonalcoholic fatty liver disease (NAFLD). Here, we evaluated the functional effects of BAs and gut microbiota contributing to sucralose consumption-induced NAFLD of mice. The results showed that sucralose consumption significantly upregulated the abundance of intestinal genera and , which produced deoxycholic acid (DCA) accumulating in multiple biological matrixes including feces, serum, and liver of mice.

Impaired Intestinal Akkermansia muciniphila and Aryl Hydrocarbon Receptor Ligands Contribute to Nonalcoholic Fatty Liver Disease in Mice.

Noncaloric artificial sweeteners (NAS) are extensively introduced into commonly consumed drinks and foods worldwide. However, data on the health effects of NAS consumption remain elusive. Saccharin and sucralose have been shown to pass through the human gastrointestinal tract without undergoing absorption and metabolism and directly encounter the gut microbiota community.

Metabolomics safety assessments of microcystin exposure via drinking water in rats.

Drinking water exposure to microcystin-leucine-arginine (MC-LR), the most widely occurring cyanotoxins, poses a highly potential risk for human health. However, the health risk of MC-LR exposure at current guideline value in drinking water has not yet entirely evaluated. In the current study, we used H NMR-based metabolomics combined with targeted metabolic profiling by GC/LC-MS to explore the toxic effects of MC-LR exposure at environmentally relevant concentrations via drinking water in rats.

Short-Term Intake of Hesperetin-7--Glucoside Affects Fecal Microbiota and Host Metabolic Homeostasis in Mice.

Hesperetin-7--glucoside (Hes-7-G) is a typical flavonoid monoglucoside isolated from Citri Reticulatae Pericarpium (CRP), which is commonly used as a food adjuvant and exhibits potential biological activities. To explore the interaction between Hes-7-G ingestion and microbiome and host metabolism, here, 16S rRNA gene sequencing was first used to analyze the alteration of fecal microbiome in mice after Hes-7-G intake. Metabolic homeostasis in mice was subsequently investigated using untargeted H NMR-based metabolomics and targeted metabolite profiling.

In vitro effects of Triclocarban on adipogenesis in murine preadipocyte and human hepatocyte.

Triclocarban (TCC), a widely used antibacterial agent, has aroused considerable public concern due to its potential toxicity. In the current study, we applied targeted metabolite profiling (LC/GC-MS) and untargeted H NMR-based metabolomics in combination with biological assays to unveil TCC exposure-induced cellular metabolic responses in murine preadipocyte and human normal hepatocytes. We found that TCC promoted adipocyte differentiation in 3T3L1 preadipocytes, manifested by marked triglyceride (TG) and fatty acids accumulation, which were consistent with significant up-regulation of mRNA levels in the key adipogenic markers Fasn, Srebp1 and Ap2.