CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects.

Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet-induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination-proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis.

Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.

Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Whole-genome resequencing revealed the population structure and selection signal of 4 indigenous Chinese laying ducks.

The assessment of animal genetic structure had significant importance for the preservation and breeding of animal germplasm resources. Selection signals are genotype markers generated during the process of biological evolution, and the detection of selection signals could reveal the direction of species evolution. The aim of this study was to generate a whole-genome resequencing data from Jinding duck, Shanma duck, Youxian Partridge duck, and Taiwan Brown tsaiya duck to reveal their population structure and selection signals. The population structure analysis revealed significant genetic differences among the 4 indigenous laying ducks, indicating their independent lineage. Specifically, Shanma duck and Youxian partridge duck were closely and likely originated from a common ancestor. In addition, selection sweep analysis was performed using the population genetic differentiation coefficient (Fst) and nucleotide diversity ratio (π ratio). The top 5% was used as the threshold for the Fst and π ratio, and the 2 thresholds were combined to identify selected genomic regions. In the selected regions of the 3 comparison groups, 136, 143, and 268 candidate genes were detected. Further screening of all candidate genes revealed that 35 candidate genes appeared simultaneously in 3 comparative groups, with 16 genes annotated. The 16 genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The results revealed 5 functional genes (AQP3, PIK3C3, NOL6, RPP25, and DCTN3) that may be related to important economic traits in laying ducks and involved mainly invasopressin-regulated water reabsorption, ribosome biogenesis, and the PI3K signaling pathway. The results provide insights into the protection and exploitation of genetic resources of Chinese indigenous laying ducks.

Dietary cinnamaldehyde activation of TRPA1 antagonizes high-salt induced hypertension through restoring renal tubular mitochondrial dysfunction.

BACKGROUND: Renal proximal tubule plays a pivotal role in regulating sodium reabsorption and thus blood pressure. Transient receptor potential ankyrin 1 (TRPA1) has been reported to protect against renal injury by modulating mitochondrial function. We hypothesize that the activation of TRPA1 by its agonist cinnamaldehyde may mitigates high salt intake induced hypertension by inhibiting urinary sodium reabsorption through restoration of renal tubular epithelial mitochondrial function. METHODS: Trpa1-deficient (Trpa1-/-) mice and wild-type (WT) mice were fed standard laboratory chow [normal diet (ND) group, 0.4% salt], standard laboratory chow with 8% salt [high-salt diet (HS) group] or standard laboratory chow with 8% salt plus 0.015% cinnamaldehyde [high-salt plus cinnamaldehyde diet (HSC) group] for six months. Urinary sodium excretion, ROS production, mitochondrial function and the expression of NHE3 and Na+/K+-ATPase of renal proximal tubules were determined. RESULTS: Chronic dietary cinnamaldehyde supplementation reduced tail systolic blood pressure and 24-hour ambulatory arterial pressure in HS-fed WT mice. Compared with the mice fed HS, cinnamaldehyde supplementation significantly increased urinary sodium excretion, inhibited excess ROS production and alleviated mitochondrial dysfunction of renal proximal tubules in WT mice. However, these effects of cinnamaldehyde were absent in Trpa1-/- mice. Furthermore, chronic dietary cinnamaldehyde supplementation blunted HS-induced upregulation of NHE3 and Na+/K+-ATPase in WT mice but not Trpa1-/- mice. CONCLUSION: The present study demonstrated that chronic activation of Trpa1 attenuates HS-induced hypertension by inhibiting urinary sodium reabsorption through restoring renal tubular epithelial mitochondrial function. Renal TRPA1 may be a potential target for the management of excessive dietary salt intake-associated hypertension.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Leptin receptor deficiency impedes metabolic surgery related-weight loss through inhibition of energy expenditure in db/db mice.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective metabolic surgery against diabetes and obesity. Clinical evidence indicates that patients with severe obesity have a poor curative effect in losing weight if they suffer from leptin or its receptor deficiency, but the underlying mechanism remains elusive. Here, we investigated the effect of leptin receptor deficiency on metabolic dysfunction in db/db mice treated by RYGB surgery. METHODS: The db/db mice and their heterozygote control db/m mice were subjected to RYGB or sham surgery. Body weight, blood glucose, food intake and glucose tolerance were evaluated. Micro-PET/CT and histological analysis were performed to examine the glucose uptake of tissues and the fat changes in mice. The key factors in glucose and fatty acid metabolism were detected by western blot analysis. RESULTS: Compared with the sham group, the db/db mice in the RYGB group showed more significant weight regain after surgical recovery and improvement in hyperinsulinemia and glucose tolerance. However, the total body fat and multiple organ lipid deposition of RYGB-treated db/db mice was increased. The underlying mechanism studies suggested that the activation of AMPK regulated GLUT4 to increase glucose uptake, but AMPK could not promote fatty acid oxidation through the JAK2/STAT3 pathway under leptin receptor deficiency in db/db mice. CONCLUSION: We conclude that leptin receptor deficiency impedes the AMPK activation-mediated fat catabolism but does not affect AMPK-related glucose utilization after metabolic surgery in db/db mice. This result helps select surgical indications for patients with obesity and diabetes.

Thermodynamic Controlled Regioselective C1-Functionalization of Indolizines with 3-Hydroxyisoindolinones via Brønsted Acid Catalyzed aza-Friedel-Crafts Reaction.

A Brønsted acid catalyzed aza-Friedel-Crafts reaction of indolizines with 3-hydroxyisoindolinones has been established, which constructs isoindolinone derivatives bearing a tetrasubstituted stereocenter in good to high yields and enantioselectivities. Notably, this strategy provides a new access to C1-functionalization of indolizines with excellent regioselectivities. Moreover, this intriguing C1-regioselective transformation was induced under thermodynamic control.

CT energy spectral parameters of creeping fat in Crohn's disease and correlation with inflammatory activity.

OBJECTIVES: Creeping fat is a kind of unique abnormal mesenteric tissue at the sites of diseased bowel of Crohn's disease. By using dual-energy CT enterography, this study aimed to evaluate the feasibility of spectral parameters in the quantitative analysis of mesenteric adipose tissue or creeping fat. METHODS: In this study, patients with known or suspected Crohn's disease who underwent dual-energy CT enterography from March 1, 2019, to March 31, 2021, were enrolled. Among them, 40 patients with surgery and pathology-proven creeping fat were selected as the creeping fat Crohn's disease group, and 40 normal patients were selected as the control group. The quantitative spectral parameters including the slope of the Hounsfield unit curve, normalised fat-water concentration, normalised fat-iodine concentration, and normalised fat volume fraction at the enteric phases were obtained. Mann-Whitney U test, Kruskal-Wallis H test, and receiver operating characteristic curve analysis were applied to compare quantitative parameters among various groups. RESULTS: A significant difference was observed in the slope of the Hounsfield unit curve, normalised fat-water concentration, normalised fat-iodine concentration, and normalised fat volume fraction between mesenteric adipose tissue and creeping fat with Crohn's disease at the enteric phase (all p < 0.001). The slope of the Hounsfield unit curve of creeping fat at the enteric phase had a better capability to distinguish inactive and active Crohn's disease (AUC = 0.93, p < 0.001). CONCLUSION: Dual-energy CT enterography with quantitative spectral parameters is a potentially novel noninvasive tool for evaluating creeping fat in Crohn's disease. CRITICAL RELEVANCE STATEMENT: Energy spectral parameters of creeping fat in Crohn's disease are significantly different from normal mesenteric adipose tissues and are correlated with inflammatory activity. KEY POINTS: • Dual-energy CT enterography allows quantitatively assessing creeping fat with spectral parameters. • The creeping fat has distinct spectral parameters to normal mesenteric adipose. • The spectral parameters accurately differentiate active and inactive Crohn's disease.

The network regulation mechanism of the effects of heat stress on the production performance and egg quality of Jinding duck was analyzed by miRNA‒mRNA.

To explore the differential regulation mechanism of heat stress on the egg production performance and egg quality of Jinding ducks, 200 Jinding ducks (360-day-old) in good health and with similar body weights and a normal appetite were selected and randomly divided into a control (normal temperature [NT]) group (20°C-25°C) and a heat stress (HS) group (32°C-36°C), with 4 replicates in each group and 25 ducks in each replicate. The pretrial period was 1 wk, and the formal trial period was 4 wk. At the end of the 4th wk, 12 duck eggs were collected from each replicate to determine egg quality. Pituitary and ovarian tissues of Jinding ducks were collected, transcriptome sequencing was performed to screen differentially expressed miRNAs and mRNAs related to high temperature and heat stress, and a competitive endogenous RNA regulatory network was constructed. The sequencing data were verified by qRT‒PCR method. The following results were obtained: (1) Compared with the NT group, the HS group had a significantly lower laying rate, total egg weight, average egg weight, total feed intake, and feed intake per duck (P < 0.01), an extremely significantly higher feed-to-egg ratio (P < 0.01), and a higher mortality rate. (2) Compared with the NT group, the HS group had an extremely significantly lower egg weight, egg yolk weight, eggshell weight, and eggshell strength (P < 0.01) and an extremely significantly lower yolk ratio and eggshell thickness (P < 0.01, P < 0.05); however, there was no significant difference in the egg shape index, Haugh unit or protein height (P > 0.05). (3) A total of 1,974 and 1,202 genes were identified in the pituitary and ovary, respectively, and there were 5 significantly differentially expressed miRNAs. The differentially expressed genes were involved in the arginine and proline metabolism pathways, ether lipid metabolism pathway, and drug metabolism-cytochrome P450 pathway, which are speculated to be related to the egg production performance of Jingding ducks under high-temperature heat stress. (4) Novel_221 may target the PRPS1 gene to participate in egg production performance; novel_168 and novel_289 may target PIGW; novel_289 may target Q3MUY2; and novel_289 and novel_208 may target PIGN or genes that may be related to high-temperature heat stress. (5) In pituitary tissue, upregulated novel_141 (center of the network) formed a regulatory network with HSPB1 and HSP30A, and downregulated novel_366 (center of the network) formed a regulatory network with the JIP1 gene. In ovarian tissue, downregulated novel_289 (center of the network) formed a regulatory network with the ZSWM7, ABI3, and K1C23 genes, novel_221 formed a regulatory network with the IGF1, BCL7B, SMC6, APOA4, and FARP2 genes, and upregulated novel_40 formed a regulatory network with the HA1FF10 gene. In summary, heat stress affects the production performance and egg quality of Jinding ducks by regulating the secretion of endocrine-related hormones and the release of neurotransmitters as well as the expression of miRNAs and mRNAs in pituitary and ovarian tissues. The miRNA‒mRNA regulatory network provides a theoretical basis for the molecular mechanism that regulates the stress response in pituitary and ovarian tissues, egg quality, and production performance under heat stress.

Analysis of circRNA-miRNA-mRNA regulatory network of embryonic gonadal development in Mulard duck.

The aim of the study was to explore the regulatory mechanism of differences in embryonic gonadal development between intergeneric distance hybrid offspring Mulard ducks and parent ducks. The morphological differences gonadal tissues of Muscovy ducks, Pekin ducks and Mulard ducks at 12.5-day embryonic age were observed by sectioning and hematoxylin-eosin (HE) staining. Then followed by transcriptome sequencing to screen for gonadal development-related differentially expressed circRNAs and mRNAs to construct a competitive endogenous RNA (ceRNA) regulatory network. Finally, qRT-PCR and luciferase reporter system were used to verify the sequencing data and targeting relationship of ceRNA pairs. The results showed that the seminiferous tubule lumen of Mulard ducks was not obvious, while there were obvious seminiferous tubules and tubular structures in testis of Pekin ducks and Muscovy ducks, with number and shape indicating maturity. There were 18 upregulated circRNAs and 16 downregulated circRNAs in Mulard ducks and Pekin ducks, respectively, and 39 upregulated circRNAs and 1 downregulated circRNA in Mulard ducks and Muscovy ducks, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis found that genes involves in dorso-ventral axis formation, for example, neurogenic locus notch homolog protein 1 (NOTCH1), were significantly enriched (P < 0.05). The novel_circ_0002265-gga-miR-122-5p-PAFAH1B2 regulatory network was constructed. The qRT-PCR results showed that the sequencing results were reliable. The dual-luciferase reporter assay showed that gga-miR-122-5p exists binding site of circ_0002265 and PAFAH1B2, indicating circ_0002265-gga-miR-122-5p-PAFAH1B2 targeting relationship. In summary, the embryonic gonadal development of intergeneric hybrid Mulard ducks may be regulated by differentially expressed circRNAs and genes, such as novel_circ_0000519, novel_circ_0003537, NOTCH1, FGFR2, PAFAH1B1, and PAFAH1B2, among which circ_0002265-gga-miR-122-5p-PAFAH1B2 may participate in the targeted regulation of gonadal development in Mulard ducks. The findings of this study are helpful for analyzing the mechanism of embryonic gonadal development differences in avians.

Thermoinduced Radical Cyclization for the Synthesis of Sultines.

A thermoinduced radical homolytic substitution cyclization of alkenyl tethered sulfinate esters was displayed under mild metal-free conditions, enabling the functionalization of alkenes and leading to structurally diverse value-added sultine products. The process utilizes readily available substrates using inexpensive 5% benzoyl peroxide (BPO) as an initiator to generate functionalized sultines with broad functional group tolerance in medium to excellent yields in a highly atom-economical manner. In addition, the obtained sultines could be further readily functionalized toward valuable sultone frameworks in one pot. A thermo-catalytic radical chain process was proposed based on mechanistic studies.

Metabolic regulation of forkhead box P3 alternative splicing isoforms and their impact on health and disease.

Forkhead Box P3 (FOXP3) is crucial for the development and suppressive function of human regulatory T cells (Tregs). There are two predominant FOXP3 splicing isoforms in healthy humans, the full-length isoform and the isoform lacking exon 2, with different functions and regulation mechanisms. FOXP3 splicing isoforms show distinct abilities in the cofactor interaction and the nuclear translocation, resulting in different effects on the differentiation, cytokine secretion, suppressive function, linage stability, and environmental adaptation of Tregs. The balance of FOXP3 splicing isoforms is related to autoimmune diseases, inflammatory diseases, and cancers. In response to environmental challenges, FOXP3 transcription and splicing can be finely regulated by T cell antigen receptor stimulation, glycolysis, fatty acid oxidation, and reactive oxygen species, with various signaling pathways involved. Strategies targeting energy metabolism and FOXP3 splicing isoforms in Tregs may provide potential new approaches for the treatment of autoimmune diseases, inflammatory diseases, and cancers. In this review, we summarize recent discoveries about the FOXP3 splicing isoforms and address the metabolic regulation and specific functions of FOXP3 splicing isoforms in Tregs.

Kaempferol promotes non-small cell lung cancer cell autophagy via restricting Met pathway.

BACKGROUND: Kaempferol is extracted from Hedyotis diffusa, exerting an obvious anti-cancer effect. Here in the present study, we explored the anti-cancer effects and mechanism of kaempferol in non-small cell lung cancer cell (NSCLC). PURPOSE: Our objective is to figure out the molecular mechanism by which kaempferol promotes autophagy in NSCLC cells. STUDY DESIGN: A549 and H1299 NSCLC cell lines were used for in vitro experiments. And BALB/c nude mice of NSCLC were used to perform in vivo experiments. METHODS: For in vitro experiments, CCK-8 and EdU assay was used to observe the effect of kaempferol on NSCLC cell proliferation. Confocal microscopy of mCherry-EGFR-LC3 assay and electron microscopy assay were used to detect NSCLC cell autophagy. Protein expression was determined using Western blot, and mRNA expression was determined using qRT-PCR. Flow cytometry was performed to detect the cell apoptosis. For in vivo experiments, a subcutaneously implanted tumor model in BALB/C nude mice was performed using human NSCLC cell line A549-Luc. The kaempferol effect on NSCLC mice model was detected by measuring the tumor weight and bioluminescence intensity. Immunohistochemistry was done to measure the key protein expression from mice tumor tissues. RESULTS: Our results confirmed that kaempferol inhibited NSCLC cell proliferation significantly. And it promoted NSCLC cell autophagy, leading to NSCLC cell death. Interestingly, Met-was greatly inhibited at both protein and mRNA levels. Meanwhile, PI3K/AKT/mTOR signaling pathway was inhibited accordingly. Furthermore, overexpressing Met-reversed the effect of kaempferol on NSCLC cell viability and cell autophagy with significance. Finally, the above effect and pathway were validated using the xenograft model. CONCLUSION: Kaempferol may exert its anti-NSCLC effect by promoting NSCLC cell autophagy. Mechanistically, Met-and its downstream PI3K/AKT/mTOR signaling pathway were involved in the process, which provides a novel mechanism how kaempferol functions in inhibiting NSCLC.

Metabolomic characterization of Liancheng white and Cherry Valley duck breast meat and their relation to meat quality.

Liancheng white duck is a typical local duck breed in Fujian Province famous for its meat traits. To better understand how meat quality varies with breed, the chemical composition of breast meats of Liancheng white ducks (LD) and Cherry Valley ducks (CD) were examined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS).The correlation between meat quality and the differential metabolites was further analyzed. The results showed that the effects of breed on duck breast meat were significant for pH, color, cooking loss, and shear force. Liancheng white duck breast meat exhibited a higher shear force and pH, and lower cooking loss and lightness (L*24), redness (a*24), and yellowness (b*24) than CD. Metabolomic analysis revealed significant differences between the meat extracts from the 2 duck breeds. A total of 49 and 57 significantly different metabolites were identified in positive and negative ion modes, respectively. These differentially accumulated metabolites (DAMs) could be divided into 28 classes, of which the 4 main categories were carbohydrates, amino acids, fatty acids, and eicosanoids. Liancheng white duck might have better nutritional and medicinal value considering the higher content of (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), and prostaglandinF3α (PGF3α), having anti-inflammatory orantioxidant effects. Carbohydrate concentration negatively correlated with pH24. The 4 metabolites positively correlated with the shear force. These results provide an overall perspective for bridging the gap between variation of duck meat quality and metabolites with respect to breed.

A high-salt diet promotes hypertrophic scarring through TRPC3-mediated mitochondrial Ca2+ homeostasis dysfunction.

Diet High in salt content have been associated with cardiovascular disease and chronic inflammation. We recently demonstrated that transient receptor potential canonical 3 (TRPC3) channels regulate myofibroblast transdifferentiation in hypertrophic scars. Here, we examined how high salt activation of TRPC3 participates in hypertrophic scarring during wound healing. In vitro, we confirmed that high salt increased the TRPC3 protein expression and the marker of myofibroblast alpha smooth muscle actin (α-SMA) in wild-type mice (WT) primary cultured dermal fibroblasts but not Trpc3-/- mice. Activation of TRPC3 by high salt elevated cytosolic Ca2+ influx and mitochondrial Ca2+ uptake in dermal fibroblasts in a TRPC3-dependent manner. High salt activation of TRPC3 enhanced mitochondrial respiratory dysfunction and excessive ROS production by inhibiting pyruvate dehydrogenase action, that activated ROS-triggered Ca2+ influx and the Rho kinase/MLC pathway in WT mice but not Trpc3-/- mice. In vivo, a persistent high-salt diet promoted myofibroblast transdifferentiation and collagen deposition in a TRPC3-dependent manner. Therefore, this study demonstrates that high salt enhances myofibroblast transdifferentiation and promotes hypertrophic scar formation through enhanced mitochondrial Ca2+ homeostasis, which activates the ROS-mediated pMLC/pMYPT1 pathway. TRPC3 deficiency antagonizes high salt diet-induced hypertrophic scarring. TRPC3 may be a novel target for hypertrophic scarring during wound healing.

Effect of Bariatric Surgery on Metabolic Syndrome in Chinese Patients with Low Body Mass Index: a Propensity Score Matching Study.

BACKGROUND: Bariatric surgery (BS) is known to improve the components of metabolic syndrome (MS) in patients with obesity. However, few studies have evaluated the effect of BS on patients with MS at low BMI levels. The study aims to assess the effect of BS on MS in patients with low BMI by comparing BS with medical therapy (MT). METHODS: A total of 271 patients with MS who underwent BS and MT at a single institution were reviewed in this retrospective cohort study. A 1:1 propensity score matching was performed for the BS and MT groups with BMI<35 kg/m2. We analyzed the 5 years effect of BS versus MT on the remission of MS, its components, atherosclerotic cardiovascular disease (ASCVD) risk, and medication used. RESULTS: Patients in the MT group showed a decrease in the prevalence of MS to 62% at the 1st year and 10% at the 5th year. In the BS group, MS prevalence in patients with BMI<35 kg/m2 decreased to 30% and 9% at the 1st and 5th year, whereas in patients with BMI≥35 kg/m2 was 26% and 7%, respectively. The 10-year ASCVD risk and the lifetime ASCVD were significantly decreased 5 years after BS in patients with BMI<35 kg/m2. The number and daily drug dose of hypoglycemic drugs, antihypertensive medications, and lipid-lowering drugs were reduced from baseline in both BS and MT groups. CONCLUSION: Bariatric surgery significantly improves MS remission rates and long-term cardiovascular risk in Chinese patients with metabolic syndrome and a BMI <35 kg/m2.

Weight loss and metabolic benefits of bariatric surgery in China: A multicenter study.

BACKGROUND: This retrospective multicenter study evaluated the efficacy and safety of bariatric surgery in Chinese patients with obesity. METHODS: Patients with obesity who underwent laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass and completed a 12-month follow-up between February 2011 and November 2019 were enrolled. Weight loss, glycemic and metabolic control, insulin resistance, cardiovascular risk, and surgery-related complications at 12 months were analyzed. RESULTS: We enrolled 356 patients aged 34.3 ± 0.6 years with a mean body mass index of 39.4 ± 0.4 kg/m2 . Successful weight loss occurred in 54.6%, 86.8%, and 92.7% of patients at 3, 6, and 12 months, respectively, with no difference in percent excess weight loss between the laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass surgery groups. The average percentage of total weight loss was 29.5% ± 0.6% at 12 months; 99.4%, 86.8%, and 43.5% of patients achieved at least 10%, 20%, and 30% weight loss, respectively, at 12 months. Significant improvements in metabolic indices, insulin resistance, and inflammation biomarkers were observed at 12 months. CONCLUSIONS: Bariatric surgery resulted in successful weight loss and improved metabolic control, insulin resistance, and cardiovascular risk in Chinese patients with obesity. Both laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are suitable approaches for such patients.

Anti-oomycete ability of scopolamine against Phytophthora infestans, a terrible pathogen of potato late blight.

BACKGROUND: Phytophthora infestans causes late blight, threatening potato production. The tropane alkaloid scopolamine from some industrial plants (Datura, Atropa, etc.) has a broad-spectrum bacteriostatic effect, but its effect on P. infestans is unknown. RESULTS: In the present study, scopolamine inhibited the mycelial growth of phytopathogenic oomycete P. infestans, and the half-maximal inhibitory concentration (IC50 ) was 4.25 g L-1 . The sporangia germination rates were 61.43%, 16.16%, and 3.99% at concentrations of zero (control), 0.5 IC50 , and IC50 , respectively. The sporangia viability of P. infestans was significantly reduced after scopolamine treatment through propidium iodide and fluorescein diacetate staining, speculating that scopolamine destroyed cell membrane integrity. The detached potato tuber experiment demonstrated that scopolamine lessened the pathogenicity of P. infestans in potato tubers. Under stress conditions, scopolamine showed good inhibition of P. infestans, indicating that scopolamine could be used in multiple adverse conditions. The combination effect of scopolamine and the chemical pesticide Infinito on P. infestans was more effective than the use of scopolamine or Infinito alone. Moreover, transcriptome analysis suggested that scopolamine leaded to a downregulation of most P. infestans genes, functioning in cell growth, cell metabolism, and pathogenicity. CONCLUSION: To our knowledge, this is the first study to detect scopolamine inhibitory activity against P. infestans. Also, our findings highlight the potential of scopolamine as an eco-friendly option for controlling late blight in the future. © 2023 Society of Chemical Industry.