Blood glucose-lowering activity of protocatechuic acid is mediated by inhibiting a-glucosidase

α-Glucosidase inhibitors are effective in controlling postprandial hyperglycemia,which play crucial roles in the management of type 2 diabetes.Protocatechuic acid(PCA)is one of phenolic acids existing not only in various plant foods but also as a major microbial metabolite of dietary anthocyanins in the large colon.The present study investigated the inhibitory mechanism of PCA on a-glucosidase in vitro and examined its effect on postprandial blood glucose levels in vivo.Results from in vitro experiments demonstrated that PCA was a mix-type inhibitor of a-glucosidase.Driven by hydrogen bonds and van der Waals interactions,PCA reversibly bound withα-glucosidase to form a stable a-glucosidase-PCA complex in a spontaneous manner.The computational simulation found that PCA could insert into the active cavity of a-glucosidase and establish hydrogen bonds with catalytic amino acid residues.PCA binding aroused the steric hindrance for substrates to enter active sites and caused the structural changes of interacted catalytic amino acid residues.PCA also exhibited postprandial hypoglycemic capacity in diabetic mice.This study may provide the theoretical basis for the application of PCA as an active ingredient of functional foods in dietary management of diabetes.

Patterns of alteration in boar semen quality from 9 to 37 months old and improvement by protocatechuic acid

Background Comprehending the patterns of alteration in boar semen quality and identifying effective nutritional interventions are crucial for enhancing the productivity of commercial pig systems.This study aimed to examine the alteration in semen quality in boars,and assess the impact of protocatechuic acid(PCA)on semen quality during the phase of declining semen quality.Methods In Exp.1,a total of 38 Pig Improvement Company(PIC)boars were selected and their semen quality data were recorded from the age of 9 to 37 months.In Exp.2,18 PIC boars(28 months old)were randomly assigned into three groups(n=6)and fed a basal diet,a basal diet containing 500 or 1,000 mg/kg PCA,respectively.The experiment lasted for 12 weeks.Results The semen volume,concentration,and total number of spermatozoa in boars exhibited an increase from 9 to 19 months old and showed a significant linear decreased trend in 28,24,and 22 months old.Sperm motility displayed an upward trajectory,reaching its peak at 20 months of age,and showed a significant linear decreased trend at 20 months old.Dietary supplementation of PCA demonstrated an effect to mitigate the decrease in semen volume,concentration of spermatozoa,total number of spermatozoa(P>0.05),and significantly increased the sperm motility(P<0.05).Moreover,supplementation of 1,000 mg/kg PCA significantly increased the sperm viability(P<0.05).Analysis on cellular signaling pathways revealed that PCA restored serum testosterone levels and alleviated oxidative damage by upregulating the expression of HO-1,SOD2,and NQO1 in testicular stromal cells.Notably,PCA can enhance phosphorylation by selectively binding to AMP-activated protein kinase(AMPK)protein,thereby improving sperm mitochondrial function and augmenting sperm motility via PGC-1/Nrf1.Conclusions These data elucidated the pattern of semen quality variation in boars within the age range of 9 to 37 months old,and PCA has the potential to be a natural antioxidant to enhance sperm quality through modulation of the AMPK/PGC-1/Nrf1 signaling pathway.

Mechanism of pachymic acid in the treatment of gastric cancer based on network pharmacology and experimental verification

BACKGROUND Pachymic acid(PA)is derived from Poria cocos.PA has a variety of pharmacological and inhibitory effects on various tumors.However,the mechanism of action of PA in gastric cancer(GC)remains unclear.AIM To investigate the mechanism of PA in treating GC via the combination of network pharmacology and experimental verification.METHODS The GeneCards and OMIM databases were used to derive the GC targets,while the Pharm Mapper database provided the PA targets.Utilizing the STRING database,a protein-protein interaction network was constructed and core targets were screened.The analyses of Gene Ontology,Kyoto Encyclopedia of Genes and Genomes(KEGG),and gene set enrichment analysis were conducted,and molecular docking and clinical correlation analyses were performed on the core targets.Ultimately,the network pharmacology findings were validated through in vitro cell assays,encompassing assessments of cell viability,apoptosis,cell cycle,cloning,and western blot analysis.RESULTS According to network pharmacology analysis,the core targets were screened,and the PI3K/AKT signaling pathway is likely to be the mechanism by which PA effectively treats GC,according to KEGG enrichment analysis.The experimental findings showed that PA could control PI3K/AKT signaling to prevent GC cell proliferation,induce apoptosis,and pause the cell cycle.CONCLUSION Network pharmacology demonstrated that PA could treat GC by controlling a variety of signaling pathways and acting on a variety of targets.This has also been supported by in vitro cell studies,which serve as benchmarks for further research.

Unraveling the therapeutic mechanisms of myristic acid and luteolin 7-rutinoside in oral cancer: insights from network pharmacology and molecular docking analysis

Background:The compound Luteolin-7-rutinoside(L7R)is a flavone derivative of luteolin,predominantly identified in plant species belonging to the families Asteraceae.Conversely,Myristic acid is characterized by its structure as a 14-carbon,unsaturated fatty acid.In this investigation,we endeavor to elucidate the putative mechanisms underlying the therapeutic effects of Myristic Acid and Luteolin 7-rutinoside in the context of oral cancer treatment,employing network pharmacology coupled with molecular docking methodologies.Methods:The protein targets of Myristic Acid and Luteolin 7-rutinoside were identified through a search on the Swiss Target Database.Subsequently,a compound-target network was constructed using Cytoscape 3.9.1.Targets associated with OC were retrieved from the OMIM and GeneCards databases.The overlap between compound targets and OC-related targets was determined,and the resulting shared targets were subjected to protein-protein interaction(PPI)network analysis using the STRING database.Additionally,gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were conducted on the identified targets.Molecular docking were performed to investigate the interactions between the core target and the active compound.Results:The component target network comprises 103 nodes and 102 edges.Among the proteins in the protein-protein interaction(PPI)network,those with higher degrees are TNF,PPARG,and TP53.Analysis through Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways indicates that the treatment of OC with Myristic Acid and Luteolin 7-rutinoside primarily involves the regulation of miRNA transcription and inflammatory response.The identified signaling pathways include Pathways in cancer,PPAR signaling pathway,EGFR signaling pathway,and TNF signaling pathway.Molecular docking studies reveal that Luteolin 7-rutinoside and Myristic acid exhibit higher affinity towards TNF,PPARG,TP53,and EGFR.Conclusion:This study reveals the potential molecular mechanism of Myristic Acid and Luteolin 7-rutinoside in the treatment of oral cancer,and provides a reference for subsequent basic research.

Protocatechuic acid and quercetin attenuate ETEC-caused IPEC-1 cell inflammation and injury associated with inhibition of necroptosis and pyroptosis signaling pathways

Background:Necroptosis and pyroptosis are newly identified forms of programmed cell death,which play a vital role in development of many gastrointestinal disorders.Although plant polyphenols have been reported to protect intestinal health,it is still unclear whether there is a beneficial role of plant polyphenols in modulating necroptosis and pyroptosis in intestinal porcine epithelial cell line(IPEC-1)infected with enterotoxigenic Escherichia coli(ETEC)K88.This research was conducted to explore whether plant polyphenols including protocatechuic acid(PCA)and quercetin(Que),attenuated inflammation and injury of IPEC-1 caused by ETEC K88 through regulating necroptosis and pyroptosis signaling pathways.Methods:IPEC-1 cells were treated with PCA(40μmol/L)or Que(10μmol/L)in the presence or absence of ETEC K88.Results:PCA and Que decreased ETEC K88 adhesion and endotoxin level(P<0.05)in cell supernatant.PCA and Que increased cell number(P<0.001)and decreased lactate dehydrogenases(LDH)activity(P<0.05)in cell supernatant after ETEC infection.PCA and Que improved transepithelial electrical resistance(TEER)(P<0.001)and reduced fluorescein isothiocyanate-labeled dextran(FD4)flux(P<0.001),and enhanced membrane protein abundance of occludin,claudin-1 and ZO-1(P<0.05),and rescued distribution of these tight junction proteins(P<0.05)after ETEC infection.PCA and Que also declined cell necrosis ratio(P<0.05).PCA and Que reduced mRNA abundance and concentration of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-8(P<0.001),and down-regulated gene expression of toll-like receptors 4(TLR4)and its downstream signals(P<0.001)after ETEC infection.PCA and Que down-regulated protein abundance of total receptor interacting protein kinase 1(t-RIP1),phosphorylated-RIP1(p-RIP1),p-RIP1/t-RIP1,t-RIP3,p-RIP3,mixed lineage kinase domain-like protein(MLKL),p-MLKL,dynamin-related protein 1(DRP1),phosphoglycerate mutase 5(PGAM5)and high mobility group box 1(HMGB1)(P<0.05)after ETEC infection.Moreover,PCA and Que reduced protein abundance of nod-like receptor protein 3(NLRP3),nod-like receptors family CARD domain-containing protein 4(NLRC4),apoptosis-associated speck-like protein containing a CARD(ASC),gasdermin D(GSDMD)and caspase-1(P<0.05)after ETEC infection.Conclusions:In general,our data suggest that PCA and Que are capable of attenuating ETEC-caused intestinal inflammation and damage via inhibiting necroptosis and pyroptosis signaling pathways.

Boswellic acids: a review on its pharmacological properties, molecular mechanism and bioavailability

Boswellic acids is a general term for a series of pentacyclic triterpenoid compounds that are isolated from the oleogin resin of the Boswellia genus and serve as the main active ingredient.It exhibits a wide range of biological activities,such as anti-inflammatory,anti-cancer,antibacterial,antiviral,hepatoprotective,neuroprotective,anti-diabetic,and anti-thrombotic properties.As a result,it has gained significant recognition among practitioners of traditional Chinese and Indian medicine.These biological effects may be associated with multiple molecular targets and signal transduction pathways.However,the poor pharmacokinetic properties of the substance lead to lower bioavailability,which affects its effectiveness.To address this issue,scientists have proposed a number of strategies,such as solid dispersions,phytosome®technologies,and novel drug delivery systems.This article aims to provide a comprehensive overview for boswellic acids on the phytochemistry,molecular mechanisms,potential therapeutic applications,and strategies to improve bioavailability.

Exploring the targets and molecular mechanism of glycyrrhetinic acid against diabetic nephropathy based on network pharmacology and molecular docking

BACKGROUND Diabetic nephropathy(DN)stands as the most prevalent chronic microvascular complication of diabetes mellitus.Approximately 50%of DN patients progress to end-stage renal disease,posing a substantial health burden.AIM To employ network pharmacology and molecular docking methods to predict the mechanism by which glycyrrhetinic acid(GA)treats DN,subsequently validating these predictions through experimental means.METHODS The study initially identified GA targets using Pharm Mapper and the TCMSP database.Targets relevant to DN were obtained from the Genecards,OMIM,and TTD databases.The Venny database facilitated the acquisition of intersecting targets between GA and DN.The String database was used to construct a protein interaction network,while DAVID database was used to conducted Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis and Gene Ontology(GO)analysis.Molecular docking experiments were performed using Autodock software with selected proteins.Experimental validation was conducted using renal proximal tubular cells(HK-2)as the study subjects.A hyperglycemic environment was simulated using glucose solution,and the effect of GA on cell viability was assessed through the cell counting kit-8 method.Flow cytometry was employed to detect cell cycle and apoptosis,and protein immunoblot(western blot)was used to measure the expression of proteins of the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and insulin resistance pathway,including insulin receptor(INSR),PI3K,p-PI3K,AKT,p-AKT,and glycogen synthase kinase-3(GSK3).RESULTS A total of 186 intersecting targets between GA and DN were identified,which were associated with 144 KEGGrelated enrichment pathways,375 GO biological process entries,45 GO cellular component entries,and 112 GO cellular function entries.Molecular docking demonstrated strong binding of GA to mitogen-activated protein kinase(MAPK)-1,SRC,PIK3R1,HSP90AA1,CASPASE9,HARS,KRAS,and MAPK14.In vitro experiments revealed that GA inhibited HK-2 cell viability,induced cell cycle arrest at the G2/M phase,and reduced apoptosis with increasing drug concentration.Western blot analysis showed that GA differentially up-regulated GSK3 protein expression,up-regulated AKT/p-AKT expression,down-regulated INSR,AKT,p-AKT,PI3K,and p-PI3K protein expression,and reduced p-PI3K/PI3K levels under high glucose conditions.CONCLUSION GA may protect renal intrinsic cells by modulating the PI3K/AKT signaling pathway,thereby inhibiting HK-2 cell viability,reducing HK-2 cell apoptosis,and inducing cell cycle arrest at the G0/G1 phase.

Beneficial effects of protocatechuic acid on diabetic retinopathy in streptozocin-induced diabetic rats

·AIM:To determine the effects of protocatechuic acid(PCA)on streptozocin-induced diabetic retinopathy(DR)in rats.·METHODS:Wistar rats were given a 50 mg/kg intraperitoneal injection of streptozocin to induce diabetes.Animals were assigned randomly one of four groups(8 rats per group):control,diabetic,diabetic plus PCA(25 mg/kg·d),and diabetic plus PCA(50 mg/kg·d).After inducing diabetes,treatments were started one week later and continued for eight weeks.After the experiment,the rats were sacrificed,and their retinas were taken for biochemical and molecular analysis.·RESULTS:PCA administration diminished the blood glucose and glycated haemoglobin levels relative to the diabetic group.In diabetic rats,PCA lowered elevated levels of advanced glycosylated end products(AGEs)and receptor for AGEs(RAGE).In the retina of diabetic rats,PCA effectively decreased inflammatory cytokine,nuclear factor-κB,tumour necrosis factor-α,interleukin-1β,and vascular endothelial growth factor,and increased antioxidant markers glutathione,superoxide dismutase,and catalase.·CONCLUSION:The protective benefits of PCA against DR may be attributable to its suppression of the AGEs and RAGE and its antioxidant and anti-inflammatory properties.

Dietary protocatechuic acid ameliorates inflammation and up-regulates intestinal tight junction proteins by modulating gut microbiota in LPS-challenged piglets

Background: Weaning is one of the major factors that cause stress and intestinal disease in piglets. Protocatechuic acid(PCA) is an active plant phenolic acid which exists in Chinese herb, Duzhong(Eucommia ulmoides Oliver), and is also considered as the main bioactive metabolite of polyphenol against oxidative stress and inflammation. This study aimed to investigate the effect of PCA on growth performance, intestinal barrier function, and gut microbiota in a weaned piglet model challenged with lipopolysaccharide(LPS).Methods: Thirty-six piglets(Pig Improvement Company line 337 × C48, 28 d of age, 8.87 kg ± 0.11 kg BW) were randomly allocated into 3 treatments and fed with a basal diet(CTL), a diet added 50 mg/kg of aureomycin(AUR), or a diet supplemented with 4000 mg/kg of PCA, respectively. The piglets were challenged with LPS(10 μg/kg BW) on d 14 and d 21 by intraperitoneal injection during the 21-d experiment. Animals(n = 6 from each group) were sacrificed after being anesthetized by sodium pentobarbital at 2 h after the last injection of LPS. The serum was collected for antioxidant indices and inflammatory cytokines analysis, the ileum was harvested for detecting mRNA and protein levels of tight junction proteins by PCR and immunohistochemical staining, and the cecum chyme was collected for intestinal flora analysis using 16 S rRNA gene sequencing.Results: Dietary supplementation of PCA or AUR significantly increased the expression of tight junction proteins including ZO-1 and claudin-1 in intestinal mucosa, and decreased the serum levels of thiobarbituric acid reactive substances(TBARS) and IL-6, as compared with CTL group. In addition, PCA also decreased the serum levels of IL-2 and TNF-α(P < 0.05). Analysis of gut microbiota indicated that PCA increased the Firmicutes/Bacteroidetes ratio(P < 0.05). Spearman's correlation analysis at the genus level revealed that PCA reduced the relative abundance of Prevotella 9, Prevotella 2, Holdemanella, and Ruminococcus torques group(P < 0.05), and increased the relative abundance of Roseburia and Desulfovibrio(P < 0.05), whereas AUR had no significant effect on these bacteria.Conclusions: These results demonstrated that both PCA and AUR had protective effect on oxidative stress, inflammation and intestinal barrier function in piglets challenged with LPS, and PCA potentially exerted the protective function by modulating intestinal flora in a way different from AUR.

Optimization of the Ultrasonic-assisted Extraction Process for Protocatechuic Acid from Emilia sonchifolia DC by Response Surface Methodology

[Objectives] This study was conducted to optimize the extraction process of protocatechuic acid from Emilia sonchifolia DC. [Methods] The optimal extraction conditions were determined by single factor,response surface analysis and variance analysis,and the content of protocatechuic acid was determined by HPLC. [Results] The protocatechuic acid standard curve equation was: y = 1 435 x + 8 403,R^2= 0. 999 8,indicating a good linear relationship. The optimal extraction conditions were as follows: a temperature at 80 ℃,an extraction time of 1 h,a material-to-liquid ratio at 1:10 and an ultrasonic power of 600 W,and the content of protocatechuic acid extracted was 1. 93 mg/g. The method showed a RSD of 0. 41%,less than 2%,and the detection limit was 0. 0000047261 g/ml.The experimental sample X1 was the low-level 0. 1 mg/ml standard solution,which showed recovery of protocatechuic acid between 100.8% and 105.2%,with a RSD of 0. 013%;and the sample X2 was the high-level 1. 0 mg/ml standard solution,which exhibited recovery between 100. 6% and 102. 2%,with a RSD of 0.076%. Thus,the recovery was high,and the requirements of the performance index were met. [Conclusions] The detection method is stable and reliable and can produce satisfactory results.

Caffeic acid and protocatechuic acid modulate Nrf2 and inhibit Ehrlich ascites carcinomas in mice

Objective:To assess the nuclear factor-erythroid 2-related factor-2(Nrf2)modulatory effect of caffeic acid and protocatechuic acid and determine the anti-tumor activity of these phenolic compounds against Ehrlich ascites carcinoma growth in mice.Methods:Antioxidant activity of protocatechuic acid and caffeic acid was assessed using ferric reducing antioxidant power(FRAP)and 2,2-diphenyl-1-picrylhydrazyl(DPPH).Nrf2 activation potential of phenolic compounds was tested by quantitative realtime polymerase chain reaction,and luciferase complementation reporter assays.In vivo efficacy was tested using the Ehrlich ascites carcinoma model.Results:FRAP and DPPH radical scavenging assays showed that caffeic acid and protocatechuic acid were more potent compared with cinnamic acid and benzoic acid.Luciferase complementation reporter assays identified caffeic acid and protocatechuic acid as the activators of Nrf2.Both caffeic acid and protocatechuic acid upregulated the expression of Nrf2 target genes heme oxygenase-1(HO-1),glutamate-cysteine ligase catalytic subunit(GCLC),and glutamate-cysteine ligase modifier subunit(GCLM)and the activity of NAD(P)H:quinone oxidoreductase 1(NQO1)when tested on HCT-116 cells using a cell-based assay system at 9 h.In addition,intraperitoneal administration of caffeic acid and protocatechuic acid to Ehrlich ascites carcinoma bearing mice suppressed tumor growth and angiogenesis.Conclusions:Caffeic acid and protocatechuic acid can modulate Nrf2 and inhibit Ehrlich ascites carcinoma cells.

Purification Process,Content Determination,Pharmacological Activity and Molecular Mechanism of Neogambogic Acid

Neogambogic acid is characterized by broad antitumor spectrum,good antitumor effect and low toxicity and side effects.This paper reviews the purification process,content determination and pharmacologic activity of neogambogic acid,in order to provide a theoretical reference for the research and application of neogambogic acid.

Research advances in phytochemistry,pharmacology and toxicology of oleanolic acid

Oleanolic acid(OA)is a pentacyclic triterpenoid chemical component that exists in natural plants with a molecular formula of C30H48O3 and a molecular weight at 456.71 g·mol-1.OA is widespread in traditional Chinese herbal medicine(Ligustri Lucidi Fructus,Achyranthis Bidentate Radix,Red Sage)and berries(blueberries,grapes).In recent years,because of the extensive pharmacological effects of OA,its advantages in disease treatment have become increasingly prominent and gradually attracted the attention of pharmaceutical researchers.OA has effective therapeutic effects on a series of chronic diseases such as inflammation,cancer,diabetes,and cardiovascular diseases through multiple signaling pathways and various targets.Especially in cancers,such as colorectal cancer,liver cancer,gastric cancer,lung cancer,breast cancer and other malignancies,OA presents substantial efficacy.However,its poor aqueous solubility,needy bioavailability,and unsatisfactory pharmacological activity excessively restrict its clinical application.More importantly,the improper utilization of OA can cause adverse reactions,toxic effects and even damage to organs in some specific situations.With the discovery of various pharmacological effects,the complex action mechanisms of OA,the continuous progress in structural modification of OA,as well as the synthesis of OA derivatives,its application is expanding gradually.Among numerous studies,there is a clear indication that OA and its derivatives,if fully developed,may provide an alternative and cheaper treatment for a variety of chronic diseases.However,the specific molecular mechanisms of OA and its derivatives as an alternative therapy and supplementary therapy for cancer,diabetes,cardiovascular disease and other chronic diseases remain to be clarified.Therefore,it is necessary to further study the pharmacokinetics,pharmacological activity,specific targets and related mechanisms of OA to lay a solid foundation for drug development and the application of OA in clinical settings.

Crystal Structure,Stability and Dissolution of a Drug-drug Molecular Salt Hydrate of Berberine with Protocatechuic Acid

A drug-drug molecular salt hydrate of berberine and protocatechuic acid has been prepared.Protocatechuic acid lost its carboxylic proton and turned to be protocatechuic anion to form a 1：1：1 organic salt hydrate with berberine,[C（20）H（18）NO4]＋[C7H5O4]^-·H2O（1）.Compound1 crystallizes in the triclinic system,space group P1 with a = 7.9849（5）,b =10.5437（5）,c = 14.3621（5）？,α = 77.983（4）,β = 82.900（4）,γ = 78.024（4）o,V = 1152.82（10） A^3,Mr= 507.48,Dc= 1.462 g/cm^3,μ = 0.929 mm^-1,F（000） = 532,Z = 2,the final R = 0.0488 and w R = 0.1322 for 3993 reflectionswith I 〉 2σ（I）.The hydrate exhibited good solid state stability against humidity,which may result from strong hydrogen-bonding interactions between water molecules and carboxylate groups.The hydrate also exhibited acceptable solubility and dissolution rate.

Protective and therapeutic effect of protocatechuic acid in assessment of letrozole- induced polycystic ovary syndrome in rats

Objective:To investigate the potential activity of protocatechuic acid in female Wistar rats with letrozole-induced polycystic ovary syndrome(PCOS).Methods:Thirty rats were divided into five groups of six each.Group 1 received 0.5%carboxy methyl cellulose orally and served as the normal control group;group 2 was treated orally with 1 mg/kg of letrozole daily for 21 days and served as the PCOS induced group;group 3 was orally administered with letrozole of 1 mg/kg for 21 days and further administered with standard drug of clomiphene citrate at a dose of 1 mg/kg body weight in 0.5%carboxy methyl cellulose per oral and served as the standard group;groups 4 and 5 were administered with letrozole of 1 mg/kg for 21 days and further treated with protocatechuic acid orally at low dose of 5 mg/kg body weight and high dose of 15 mg/kg body weight respectively for 15 days.At the end of the study period,rats were subjected for the estimation of invasive blood pressure and heart rate,biochemical estimations and antioxidant assay.In addition,ovarian histomorphology was examined.Results:The PCOS was confirmed in the letrozole induced rats with increased concentration of androgen,abnormal lipid levels,glucose,glycosylated haemoglobin and also depletion of antioxidants.After protocatechuic acid treatment,the increased levels of testosterone due to induction of PCOS were restored to normal levels.Additionally,there was a consistent decrease in luteinizing hormone and follicle stimulating hormone levels in the treatment groups,followed by decrease in the number of cysts after treatment with protocatechuic acid.Histopathological observations showed a remarkable recovery of the ovarian tissue and the presence of normalized structure of antral follicle.Protocatechuic acid treatment restored all the parameters to normalcy and abolished cysts formation in ovaries of female rats.Conclusions:Protocatechuic acid shows potential protective effects in letrozole-induced PCOS rats.The protective effect is comparable to that of clomiphene citrate and thus shows its potential in the treatment of PCOS.

Pharmacologic inducers of the uric acid exporter ABCG2 as potential drugs for treatment of gouty arthritis

Uric acid is the end product of purine catabolism and its plasma levels are maintained below its maximum solubility in water(6–7 mg/dl).The plasma levels are tightly regulated as the balance between the rate of production and the rate of excretion,the latter occurring in urine(kidney),bile(liver)and feces(intestinal tract).Reabsorption in kidney is also an important component of this process.Both excretion and reabsorption are mediated by specific transporters.Disruption of the balance between production and excretion leads to hyperuricemia,which increases the risk of uric acid crystallization as monosodium urate with subsequent deposition of the crystals in joints causing gouty arthritis.Loss-of-function mutations in the transporters that mediate uric acid excretion are associated with gout.The ATP-Binding Cassette exporter ABCG2 is important in uric acid excretion at all three sites:kidney(urine),liver(bile),and intestine(feces).Mutations in this transporter cause gout and these mutations occur at significant prevalence in general population.However,mutations that are most prevalent result only in partial loss of transport function.Therefore,if the expression of these partially defective transporters could be induced,the increased number of the transporter molecules would compensate for the mutation-associated decrease in transport function and hence increase uric acid excretion.As such,pharmacologic agents with ability to induce the expression of ABCG2 represent potentially a novel class of drugs for treatment of gouty arthritis.

Study on the effect of Danbei Yifei formula on pulmonary fibrosis based on network pharmacology and molecular docking technology

Objective:To determine the pharmacodynamic material basis and mechanism of Danbei Yifei formula on pulmonary fibrosis.Methods:Starting with the clear absorbed components of Danbei Yifei formula or the potential effective components in line with the five rules of Ribinsky,the network pharmacology method and technology of traditional Chinese medicine were used to predict and analyze the action targets of Danbei Yifei formula in vivo,such as Salvia miltiorrhiza,PINBEI,Taoren,etc.On the basis of enrichment analysis,the core pathway of Danbei Yifei formula in the treatment of pulmonary fibrosis was identified,and the binding energy of drug ligand and protein target was determined through molecular docking technology simulation and verification,and its affinity and stability were evaluated.To clarify the material basis and mechanism of Danbei Yifei formula in the treatment of pulmonary fibrosis.Result:The results of network pharmacology prediction of traditional Chinese medicine showed that Danbei Yifei formula contained 72 potential pharmacodynamic components and 26 corresponding targets,including CHRM1、MAPK14、CCL2、ADRB1、PTGS1、PPARG、ALOX5、Pde3a、CHRM2、Adrb2、TNF、JUN、Adora2a、LTA4H、CYP1A2、OPRD1、CHRM3、DRD2、OPRM1、ARG1、EDNRA、Il6st、TACR1、MMP1、MMP8、Ptgs2,which were related to pulmonary fibrosis and pulmonary fibrosis Lung related diseases are highly correlated.There were 26 Go items(P<0.05)in go functional enrichment analysis,including 22 biological process(BP),9 cellular component(CC)and 3 molecular function(MF)categories.The results of network pharmacology showed that many components,such as protocatechuic acid and aminosuccinic acid,had direct effects on known targets of pulmonary fibrosis.Conclusion:Danbei Yifei formula contains many effective components which have inhibitory effect on pulmonary fibrosis,and it may play its role through the mechanism of multi-component and multi-target synergistic effect.

Pharmacological research progress of ursolic acid for the treatment of liver diseases

Ursolic acid is a natural pentacyclic triterpenoid with various pharmacological activities such as anti-inflammatory,hepatoprotective,antitumor,and hypoglycemic activity.This natural product is widely present in many common Chinese herbal medicines such as Hedyotis diffusa and Prunella vulgaris.The present review highlights the pharmacological research progress of ursolic acid in liver disease,with a focus on providing directions for future research and clinical practice of ursolic acid.Modern studies have demonstrated that ursolic acid can adjust the activities of enzymes such as superoxide dismutase and NADPH oxidase to balance oxidative stress,reduce inflammation,as well as to repair damaged liver.Research also showed that ursolic acid targeted lipid metabolic genes,activating autophagy and reducing lipid deposition in hepatocytes,further preventing the progress of fatty liver.Besides,the combination of ursolic acid with caspase-3 was able to prevent apoptosis and relieve liver injury.Furthermore,ursolic acid was showed to target the intestine by alleviating mucosal injury and restoring the balance of the intestinal microecology and protect liver through the enterohepatic axis.In terms of antitumor activity,ursolic acid targeted several tumor suppressor genes including gene of phosphate and tension homology deleted on chromsome ten and p53,and affected the expression of cyclin and apoptosis-related proteins involving Bax,Bcl-2,and Bcl-x,which acted on signal transduction pathways including phosphatidylinositol-3-kinase/protein kinase B,extracellular regulated protein kinases and proteina fosforilata 21 wide-type actiated factorlp 1.The same compound interacted with caspases,resulting in inhibition of cell proliferation and induction of apoptosis.In addition,ursolic acid also exerted anticancer activity through inhibiting angiogenesis,tumor invasion and metastasis,and improving immunity.Other studies have noted the importance of nano-preparations of ursolic acid for its clinical applications.This review provides essential information on the role of ursolic acid in liver protection.Further research on the mechanisms of action of ursolic acid would be useful for its pharmaceutical development and clinical application.

Evaluation of Angelicae sinensis radix as a promising treatmentoption for hyperlipidemia based on network pharmacology

Background: Angelicae sinensis radix has been widely applied in traditional Chinese medicine while little isexplored in its potential mechanism. This study aims to elucidate the effective components and defattingmechanism based on network pharmacology. Methods: Traditional Chinese Medicine Systems PharmacologyDatabase and Analysis Platform was screened to collect the possible active ingredients and their CAS and SMILESwas searched in Pubchem, which further used for reverse molecular docking in Swiss Target Prediction database toobtain potential targets. Hyperlipidemia-related molecules were obtained from GeneCards database, and thepredicted targets of Angelicae sinensis radix for hyperlipidemia treatment were selected by Wayne diagram. Formechanism analysis, the protein-protein interactions were constructed with String, the Gene Oncology enrichmentanalysis and Kyoto Encyclopedia of Genes and Genomes analysis were conducted in DAVID. Results: Usingnetwork-based systems biology analysis, we predicted that 5 active ingredients in Angelicae sinensis radix hasantilipemic effects with 71 potential targets. Through Gene Oncology and Kyoto Encyclopedia of Genes andGenomes analysis, we found that the related signaling pathways mainly involved in arachidonic acid metabolism,and regulation of lipolysis in adipocytes. The related genes are ALOX5, CYP2C19, EPHX2, PTGS1, PTGS2,ADRB1, and ADRB3. Conclusion: Angelicae sinensis radix may alleviate hyperlipidemia through arachidonic acidmetabolism, and regulation of lipolysis in adipocytes. ALOX5, CYP2C19, EPHX2, PTGS1, PTGS2, ADRB1, andADRB3 may be new targets for treatment.

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.