Nuclear receptors modulate inflammasomes in the pathophysiology and treatment of major depressive disorder

Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patients;therefore,there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms.Accumulated evidence has shown that immune inflammation,particularly inflammasome activity,plays an important role in the pathophysiology of MDD.In this review,we summarize the evidence on nuclear receptors(NRs),such as glucocorticoid receptor,mineralocorticoid receptor,estrogen receptor,aryl hydrocarbon receptor,and peroxisome proliferator-activated receptor,in modulating the inflammasome activity and depression-associated behaviors.This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD,and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.

Editor profile:Guest editor of special issue “Bile Acids and Nuclear Receptors in Digestive System and Therapy”

Associate Prof.Grace Liejun Guo is a tenured faculty in the Department of Pharmacology and Toxicology in the School of Pharmacy at the Rutgers University in New Jersey,USA.Dr.Guo graduated from the West China University of Medical Sciences in 1993.In 1997,Dr.Guo obtained a MS degree

Nuclear receptors and non-alcoholic fatty liver disease:An update

Non-alcoholic fatty liver disease(NAFLD)has become the leading cause of chronic liver disease in adults and children worldwide.The symptoms of NAFLD range from simple steatosis and non-alcoholic stea-tohepatitis(NASH)to hepatic fibrosis or cirrhosis,even ultimately develops to hepatocellular carcinoma.Nuclear receptors(NRs)are a superfamily of ligand-activated transcription factors,most of which are ligand-activated that control cellular homeostasis in the liver and other tissues.A growing number of studies demonstrated the important role of NRs in NAFLD.In this review,the current findings on the role of NRs in NAFLD are summarized and future perspectives to target NRs for NAFLD are discussed.

Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice

Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids(BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. h PXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

Endocrine pheromones couple fat rationing to dauer diapause through HNF4αnuclear receptors

Developmental diapause is a widespread strategy for animals to survive seasonal starvation and environmental harshness.Diapaused animals often ration body fat to generate a basal level of energy for enduring survival.How diapause and fat rationing are coupled,however,is poorly understood.The nematode Caenorhabditis elegans excretes pheromones to the environment to induce a diapause form called dauer larva.Through saturated forward genetic screens and CRISPR knockout,we found that dauer pheromones feed back to repress the transcription of ACOX-3,MAOC-1,DHS-28,DAF-22(peroxisomalβ-oxidation enzymes dually involved in pheromone synthesis and fat burning),ALH-4(aldehyde dehydrogenase for pheromone synthesis),PRX-10 and PRX-11(peroxisome assembly and proliferation factors).Dysfunction of these pheromone enzymes and factors relieves the repression.Surprisingly,transcription is repressed not by pheromones excreted but by pheromones endogenous to each animal.The endogenous pheromones regulate the nuclear translocation of HNF4αfamily nuclear receptor NHR-79 and its co-receptor NHR-49,and,repress transcription through the two receptors.The feedback repression maintains pheromone homeostasis,increases fat storage,decreases fat burning,and prolongs dauer lifespan.Thus,the exocrine dauer pheromones possess an unexpected endocrine function to mediate a peroxisome-nucleus crosstalk,coupling dauer diapause to fat rationing.

Aryl hydrocarbon receptor nuclear translocator 2 as a prognostic biomarker and immunotherapeutic indicator for clear cell renal cell carcinoma

Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.

Jianpi Gushen Huayu decoction ameliorated diabetic nephropathy through modulating metabolites in kidney,and inhibiting TLR4/NF-κB/NLRP3 and JNK/P38 pathways

BACKGROUND Jianpi Gushen Huayu Decoction(JPGS)has been used to clinically treat diabetic nephropathy(DN)for many years.However,the protective mechanism of JPGS in treating DN remains unclear.AIM To evaluate the therapeutic effects and the possible mechanism of JPGS on DN.METHODS We first evaluated the therapeutic potential of JPGS on a DN mouse model.We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics.Furthermore,we examined the effects of JPGS on c-Jun N-terminal kinase(JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB)/NOD-like receptor family pyrin domain containing 3(NLRP3).RESULTS The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress.Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice.A total of 51 differential metabolites were screened.Pathway analysis results indicated that nine pathways significantly changed between the control and model groups,while six pathways significantly altered between the model and JPGS groups.Pathways related to cysteine and methionine metabolism;alanine,tryptophan metabolism;aspartate and glutamate metabolism;and riboflavin metabolism were identified as the key pathways through which JPGS affects DN.Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors.CONCLUSION JPGS could markedly treat mice with streptozotocin(STZ)-induced DN,which is possibly related to the regulation of several metabolic pathways found in kidneys.Furthermore,JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathwaymediated apoptosis in DN mice.

Transcription factors specificity protein and nuclear receptor 4A1 in pancreatic cancer

Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.

Targeting nuclear receptors for NASH/MASH:From bench to bedside

The onset of metabolic dysfunction-associated steatohepatitis(MASH)or non-alcoholic steatohepatitis(NASH)represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD).With no pharmacological treat-ment currently available for MASH/NASH,the race is on to develop drugs targeting multiple facets of hepatic metabolism,inflammation,and pro-fibrotic events,which are major drivers of MASH.Nuclear receptors(NRs)regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation.Ligands of NRs may include hormones,lipids,bile acids,and synthetic ligands,which upon binding to NRs regulate the transcriptional activities of target genes.NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH.This review aims to cover the current understanding of NRs,including nuclear hormone receptors,non-steroid hormone receptors,circadian NRs,and orphan NRs,which are currently undergoing clinical trials for MASH treatment,along with NRs that have shown promising results in preclinical studies.

Influence of baicalin on the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin in human periodontal ligament cells

Objective To study the effect of baicalin on the expression of receptor activator of nuclear factor-κB ligand(RANKL)and osteoprotegerin(OPG)in cultured human periodontal ligament(HPDL)cells.Methods Small interfering RNA(siRNA)eukaryotic expression vector targeted transforming growth factor βⅡ receptor(TGF-β RⅡ)was constructed and transfected into T cells.HPDL cells with T cells transfected with siRNA or not were placed in the culture medium that had been added with lipopolysaccharide(LPS)and baicalin.The obtained solution was divided into six groups according to the components(group Ⅰ:HPDL cells+LPS+T cells transfected with siRNA1+baicalin;group Ⅱ:HPDL cells+LPS+T cells transfected with siRNA1;group Ⅲ:HPDL cells+LPS+T cells+baicalin;group Ⅳ:HPDL cells+LPS+T cells;group Ⅴ:HPDL cells+baicalin;group Ⅵ:HPDL cells)and was cultured for 48 hours.RT-PCR was used to observe the effect of baicalin on the expression of OPG-RANKL in HPDL cells.Results The ratio of RANKL/OPG in group Ⅰ was lower than that in group Ⅱ(P<0.01)and higher than that in group Ⅲ(P<0.01);The ratio of RANKL/OPG in group Ⅲ was lower than that in group Ⅳ(P<0.01);the ratio of RANKL/OPG in group Ⅳ was higher than that in group Ⅵ(P<0.01);the ratio of RANKL/OPG in group Ⅴ was lower than that in group Ⅵ(P<0.05).Conclusion ① Baicalin could decrease the ratio of RANKL/OPG in HPDL cells.② The TGF-β signaling transduction plays an important role in the effect of baicalin on the RANKL/OPG ratio in HPDL cells.③ Baicalin acts not only through TGF-β to regulate RANKL/OPG in HPDL cells,but also through other pathways.

Inhibition of autophagy rescues HT22 hippocampal neurons from erastin-induced ferroptosis

Ferroptosis is a regulated form of cell death which is considered an oxidative iron-dependent process.The lipid hydroperoxidase glutathione peroxidase 4 prevents the iron(Fe2+)-dependent formation of toxic lipid reactive oxygen species.While emerging evidence indicates that inhibition of glutathione peroxidase 4 as a hallmark of ferroptosis in many cancer cell lines,the involvement of this biochemical pathway in neuronal death remains largely unclear.Here,we investigate,first whether the ferroptosis key players are involved in the neuronal cell death induced by erastin.The second objective was to examine whether there is a cross talk between ferroptosis and autophagy.The third main was to address neuron response to erastin,with a special focus on ferritin and nuclear receptor coactivator 4-mediated ferritinophagy.To test this in neurons,erastin(0.5-8μM)was applied to hippocampal HT22 neurons for 16 hours.In addition,cells were cultured with the autophagy inhibitor,3-methyladenin(10 mM)and/or ferroptosis inhibitors,ferrostatin 1(10-20μM)or deferoxamine(10-200μM)before exposure to erastin.In this study,we demonstrated by immunofluorescence and western blot analysis,that erastin downregulates dramatically the expression of glutathione peroxidase 4,the sodium-independent cystine-glutamate antiporter and nuclear receptor coactivator 4.The protein levels of ferritin and mitochondrial ferritin in HT22 hippocampal neurons did not remarkably change following erastin treatment.In addition,we demonstrated that not only the ferroptosis inhibitor,ferrostatin1/deferoxamine abrogated the ferroptotic cell death induced by erastin in hippocampal HT22 neurons,but also the potent autophagy inhibitor,3-methyladenin.We conclude that(1)erastin-induced ferroptosis in hippocampal HT22 neurons,despite reduced nuclear receptor coactivator 4 levels,(2)that either nuclear receptor coactivator 4-mediated ferritinophagy does not occur or is of secondary importance in this model,(3)that ferroptosis seems to share some features of the autophagic cell death process.

Multiomics reveal human umbilical cord mesenchymal stem cells improving acute lung injury via the lung-gut axis

BACKGROUND Acute lung injury(ALI)and its final severe stage,acute respiratory distress syndrome,are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments.Gut microbiota homeostasis,including that in ALI,is important for human health.Evidence suggests that the gut microbiota improves lung injury through the lung-gut axis.Human umbilical cord mesenchymal cells(HUC-MSCs)have attractive prospects for ALI treatment.This study hypothesized that HUC-MSCs improve ALI via the lung-gut microflora.AIM To explore the effects of HUC-MSCs on lipopolysaccharide(LPS)-induced ALI in mice and the involvement of the lung-gut axis in this process.METHODS C57BL/6 mice were randomly divided into four groups(18 rats per group):Sham,sham+HUC-MSCs,LPS,and LPS+HUC-MSCs.ALI was induced in mice by intraperitoneal injections of LPS(10 mg/kg).After 6 h,mice were intervened with 0.5 mL phosphate buffered saline(PBS)containing 1×10^(6) HUC-MSCs by intraperitoneal injections.For the negative control,100 mL 0.9%NaCl and 0.5 mL PBS were used.Bronchoalveolar lavage fluid(BALF)was obtained from anesthetized mice,and their blood,lungs,ileum,and feces were obtained by an aseptic technique following CO_(2) euthanasia.Wright’s staining,enzyme-linked immunosorbent assay,hematoxylin-eosin staining,Evans blue dye leakage assay,immunohistochemistry,fluorescence in situ hybridization,western blot,16S rDNA sequencing,and non-targeted metabolomics were used to observe the effect of HUC-MSCs on ALI mice,and the involvement of the lung-gut axis in this process was explored.One-way analysis of variance with post-hoc Tukey’s test,independent-sample Student’s t-test,Wilcoxon rank-sum test,and Pearson correlation analysis were used for statistical analyses.RESULTS HUC-MSCs were observed to improve pulmonary edema and lung and ileal injury,and decrease mononuclear cell and neutrophil counts,protein concentrations in BALF and inflammatory cytokine levels in the serum,lung,and ileum of ALI mice.Especially,HUC-MSCs decreased Evans blue concentration and Toll-like receptor 4,myeloid differentiation factor 88,p-nuclear factor kappa-B(NF-κB)/NF-κB,and p-inhibitorαof NF-κB(p-IκBα)/IκBαexpression levels in the lung,and raised the pulmonary vascular endothelial-cadherin,zonula occludens-1(ZO-1),and occludin levels and ileal ZO-1,claudin-1,and occludin expression levels.HUC-MSCs improved gut and BALF microbial homeostases.The number of pathogenic bacteria decreased in the BALF of ALI mice treated with HUCMSCs.Concurrently,the abundances of Oscillospira and Coprococcus in the feces of HUS-MSC-treated ALI mice were significantly increased.In addition,Lactobacillus,Bacteroides,and unidentified_Rikenellaceae genera appeared in both feces and BALF.Moreover,this study performed metabolomic analysis on the lung tissue and identified five upregulated metabolites and 11 downregulated metabolites in the LPS+MSC group compared to the LPS group,which were related to the purine metabolism and the taste transduction signaling pathways.Therefore,an intrinsic link between lung metabolite levels and BALF flora homeostasis was established.CONCLUSION This study suggests that HUM-MSCs attenuate ALI by redefining the gut and lung microbiota.

Monoacylglycerol lipase reprograms lipid precursors signaling in liver disease

Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis,which eventually progress to cirrhosis and hepatocellular carcinoma.Monoacylglycerol lipase is the last enzymatic step in the hydrolysis of triglycerides,generating glycerol and fatty acids(FAs),which are signaling precursors in physiology and disease.Notably,monoacylglycerol lipase(MGL)also hydrolyzes 2-arachidonoylglycerol,which is a potent ligand within the endocannabinoid system,into arachidonic acid-a precursor for prostaglandin synthesis;thus representing a pivotal substrates provider in multiple organs for several intersecting biological pathways ranging from FA metabolism to inflammation,pain and appetite.MGL inhibition has been shown protective in limiting several liver diseases as FAs may drive hepatocyte injury,fibrogenesis and de-activate immune cells,however the complexity of MGL network system still needs further and deeper understanding.The present review will focus on MGL function and FA partitioning in the horizons of liver disease.

Ganoderma lucidum polysaccharide peptide alleviates hepatoteatosis via modulating bile acid metabolism dependent on FXR-SHP/FGF

OBJECTIVE Ganoderma lucidum polysaccharide peptide(GLPP)is a group of extract from Ganoderma lucidum with a molecular mass of approximately 5×10^5,which ratio of polysaccharide to peptide is approximately 95%/5%.The purpose of this study was to determine whether GLPP has therapeutic effect on Non-alcoholic fatty liver disease(NAFLD).METHODS Ob/ob mouse model and ApoC3 transgenic mouse model were used for exploring the effect of GLPP on NAFLD.Key metabolic pathways and enzymes were identified by metabolomics combining with KEGG and PIUmet analyses and key enzymes were detected by Western blotting.Hepatosteatosis models of HepG2 cells and primary hepatocytes were used to further confirm the therapeutic effect of GLPP on NAFLD.RESULTS GLPP administrated for a month alleviated hepatosteatosis,dyslipidemia,liver dysfunction and liver insulin resistance.Pathways of glycerophos⁃pholipid metabolism,fatty acid metabolism and primary bile acid biosynthesis were involved in the therapeutic effect of GLPP on NAFLD.Detection of key enzymes revealed that GLPP reversed low expression of CYP7A1,CYP8B1,FXR,SHP and high expression of FGFR4 in ob/ob mice and ApoC3 mice.Besides,GLPP inhibited fatty acid synthesis by reducing the expression of SREBP1c,FAS and ACC via a FXR-SHP dependent mechanism.Additionally,GLPP reduced the accumulation of lipid droplets and the content of TG in HepG2 cells and primary hepatocytes induced by oleic acid and palmitic acid.CONCLUSION GLPP significantly improves NAFLD via regulating bile acid synthesis dependent on FXR-SHP/FGF pathway,which finally inhibits fatty acid synthesis,indicating that GLPP might be developed as a ther⁃apeutic drug for NAFLD.

Co-regulator NCOA5 and cancer

NCOA5 encodes a co-regulator for estrogen receptors(ERαand ERβ),orphan nuclear receptors(REV-ERBαand REV-ERBβ)and liver X receptor.It can influence many cellular processes by either promoting or inhibiting gene expression through its two important functional motifs:LxxLL(co-activator)andΦxxΦΦ(co-repressor).Many reports have revealed the important roles of NCOA5 in diseases,such as diabetes,reproductive defects and autoimmune disease.In this review,we focus on its function in cancers and summary the current research progresses regarding its different roles in various cancers.

Interleukin-1βinduces human cementoblasts to support osteoclastogenesis

Injury of the periodontium followed by inflammatory response often leads to root resorption. Resorption is accomplished by osteoclasts and their generation may depend on an interaction with the cells in direct contact with the root, the cementoblasts.Our study aimed to investigate the role of human cementoblasts in the formation of osteoclasts and the effect of interleukin(IL)-1β hereupon. Extracted teeth from healthy volunteers were subjected to sequential digestion by type I collagenase and trypsin.The effect of enzymatic digestion on the presence of cells on the root surface was analyzed by histology. Gene expression of primary human cementoblasts(p HCB) was compared with a human cementoblast cell line(HCEM). The p HCBs were analyzed for their expression of IL-1 receptors as well as of receptor activator of nuclear factor kappa-B ligand(RANKL) and osteoprotegerin(OPG). In a co-culture system consisting of osteoclast precursors(blood monocytes) and p HCBs, the formation of osteoclasts and their resorptive activity was assessed by osteo-assay and ivory slices. The cells obtained after a 120 min enzyme digestion expressed the highest level of bone sialoprotein, similar to that of HCEM. This fraction of isolated cells also shared a similar expression pattern of IL-1 receptors(IL1-R1 and IL1-R2). Treatment with IL-1β potently upregulated RANKL expression but not of OPG. p HCBs were shown to induce the formation of functional osteoclasts. This capacity was significantly stimulated by pretreating the p HCBs with IL-1β prior to their co-culture with human blood monocytes. Our study demonstrated that cementoblasts have the capacity to induce osteoclastogenesis, a capacity strongly promoted by IL-1β. These results may explain why osteoclasts can be formed next to the root of teeth.

A Novel NR0B1 Gene Mutation Causes Different Phenotypes in Two Male Patients with Congenital Adrenal Hypoplasia

X-linked congenital adrenal hypoplasia is characterised by the acute onset of primary adrenal insufficiency in infancy or early childhood and hypogonadotropic hypogonadism(HH)at puberty,arising from mutations of the nuclear receptor subfamily 0 group B member 1(NR0B1)gene.This study investigated an extended family with two affected males(patient A:23 years and patient B:2 months old)and three carrier females.Sequencing analysis of the NR0B1 gene coding region from the family revealed a novel hemizygous deletion[c.604delT;p.(C202Afs*62)]in the two male patients.Furthermore,the patients'respective mothers and their common grandmother had this heterozygous mutation,but it was not present in the Human Gene Mutation Database.The two male patients showed inconsistent clinical features at onset,particularly in early childhood;however,it is possible that the younger patient will eventually show a delay of puberty,feminisation,and nonspermatogenesis in adulthood,similar to that in the older patient.Identification of a novel NR0BI mutation in this family is important for the diagnosis and genetic counselling of children with primary adrenal insufficiency and HH,and will be helpful for predicting long-term clinical symptoms.

Investigating mechanism of Jiang-zhi-dai-pao-cha for treatment of hyperlipidemia by network pharmacology

Objective:To collect the main components and targets of Jiang-zhi-dai-pao-cha(JZDPC)and investigate the mechanism of JZDPC for the treatment of hyperlipidemia by network pharmacology.Methods:The components and targets of JZDPC were searched from ETCM databases,the targets related to hyperlipidemia were searched from DisGeNET and GeneCards databases,and then the intersection targets and corresponding key components were obtained.Cytoscape 3.8.2 software was used to construct and analyze networks,and then Metascape online database was applied for gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of core putative targets.Results:There were 99 overlapping targets between JZDPC and hyperlipidemia,among which NR3C1,ESR1,NR1I2,NFKB1,ESR2,ALOX5,PTGS1,PPARA,RXRA,LPL,PLA2G1B,PYGM,CYP2C9 were the core putative targets,and many members of nuclear receptor 1(NR1)subfamily were included.The core components of JZDPC,such as Ursolic Acid,β-Sitosterol,Resveratrol,Arirubic Acid,Alisol A,Oleanolic Acid,Rhein,Chrysophanol and Emodin,can regulate blood lipid by regulating a series of signaling pathways including the above core potential targets,such as non-alcoholic fatty liver disease(NAFLD)signaling pathway,pathways in cancer,arachidonic acid(AA)metabolism signaling pathway and peroxisome proliferator activated receptor(PPAR)signaling pathway,Starch and sucrose metabolism signaling pathway,etc.They play many roles in the treatment of hyperlipidemia by participating in lipid synthesis and metabolism,anti inflammation,anti oxidative stress,regulating hormone levels and carbohydrate metabolism.Conclusion:Network pharmacology provides a theoretical basis for investigating the mechanism of action of JZDPC,and the NAFLD signaling pathway is one of the most valuable pathways.

Bile acid receptors and gastrointestinal functions

Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.

Bile acid receptors link nutrient sensing to metabolic regulation

Non-alcoholic fatty liver disease(NAFLD)is a common liver disease in Western populations.Nonalcoholic steatohepatitis(NASH)is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation,which significantly increase the risk of end-stage liver and cardiovascular diseases.Unfortunately,there are no available drug therapies for NASH.Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes.Bile acids circulate between the liver and intestine,where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut.Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes.Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor(FXR)and the G protein-coupled receptor TGR5.Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations,which in turn control metabolic homeostasis.The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials.Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases.Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids,which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment.