Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotect...Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A.membranaceus(TFA)and their protective mechanisms.TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)in the mouse model of Parkinsonism,by improving behavior performance in the gait analysis and pole test,and inhibiting the decline of tyrosine hydroxylase(TH)positive neurons and TH protein expression in substantia nigra of mice.TFA also prevented 1-methyl-4-phenylpyridinium(MPP+)induced neurotoxicity in SHSY5Y cells,by increasing GSH and GSH/GSSG ratio,and reducing reactive oxygen species.In addition,the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+induced downregulation of SLC7A11 and glutathione peroxidase 4(GPX-4).In conclusion,we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis,suggesting the use of TFA as a possible food supplement in the prevention of PD.展开更多
The rapid development of metagenomics,metabolomics,and metatranscriptomics provides novel insights into the intestinal microbiota factors linked to inflammatory bowel disease(IBD).Multiple microorganisms play a role i...The rapid development of metagenomics,metabolomics,and metatranscriptomics provides novel insights into the intestinal microbiota factors linked to inflammatory bowel disease(IBD).Multiple microorganisms play a role in intestinal health;these include bacteria,fungi,and viruses that exist in a dynamic balance to maintain mucosal homeostasis.Perturbations in the intestinal microbiota disrupt mucosal homeostasis and are closely related to IBD in humans and colitis in mice.Therefore,preventing or correcting the imbalance of microbiota may serve as a novel prevention or treatment strategy for IBD.We review the most recent evidence for direct or indirect interventions targeting intestinal microbiota for treatment of IBD in order to overcome the current limitations of IBD therapies and shed light on personalized treatment options.展开更多
AIM:To investigate the alleviation of scutellarein(SN)against inner blood-retinal-barrier(iBRB)dysfunction in microglia cells stimulated by hyperglycemia and to elucidate the engaged mechanism.METHODS:Microglia BV2 ce...AIM:To investigate the alleviation of scutellarein(SN)against inner blood-retinal-barrier(iBRB)dysfunction in microglia cells stimulated by hyperglycemia and to elucidate the engaged mechanism.METHODS:Microglia BV2 cells were stimulated by using 25 mmol/L D-glucose.The same concentration of mannitol(25 mmol/L)was applied as an isotonic contrast.Real-time PCR,Western-blot assay and immunofluorescence staining assay was performed.The dysfunction of iBRB in vitro was detected by using transendothelial electrical resistance(TEER)assay.Additionally,the leakage of fluorescein isothiocyanate(FITC)-conjugated dextran(70 kDa)was detected.RESULTS:SN abrogated microglia BV2 cells activation and reduced the phosphorylated activation of extracellular signal-regulated protein kinase(ERK)1/2.SN also decreased the transcriptional activation of nuclear factorκB(NFκB)and the elevated expression of tumor necrosis factorα(TNFα),interleukin(IL)-6 and IL-1βin BV2 cells treated with D-glucose(25 mmol/L).SN attenuated iBRB dysfunction in human retinal endothelial cells(HRECs)or choroid-retinal endothelial RF/6 A cells when those cells were treated with TNFα,IL-1βor IL-6,or co-cultured with microglia cells stimulated by D-glucose.Moreover,SN restored the decreased protein expression of tight junctions(TJs)in TNFα-treated HRECs and RF/6 A cells.CONCLUSION:SN not only alleviate iBRB dysfunction via directly inhibiting retinal endothelial injury caused by TNFα,IL-1βor IL-6,but also reduce the release of TNFα,IL-1βand IL-6 from microglia cells by abrogating hyperglycemia-mediated the activation of microglia cells.展开更多
Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective treatments.Nuciferine,an alkaloid found in lo...Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective treatments.Nuciferine,an alkaloid found in lotus leaf,has shown promising anti-inflammatory and anti-tumor effects,yet its efficacy in RA treatment remains unexplored.This study investigated the antiproliferative effects of nuciferine on the MH7A cell line,a human RA-derived fibroblast-like synoviocyte,revealing its ability to inhibit cell proliferation,promote apoptosis,induce apoptosis,and cause G1/S phase arrest.Additionally,nuciferine significantly reduced the migration and invasion capabilities of MH7A cells.The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis(CIA)rat model,where it markedly alleviated joint swelling,synovial hyperplasia,cartilage injury,and inflammatory infiltration.Nuciferine also improved collagen-induced bone erosion,decreased pro-inflammatory cytokines and serum immunoglobulins(IgG,IgG1,IgG2a),and restored the balance between T helper(Th)17 and regulatory T cells in the spleen of CIA rats.These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.展开更多
Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This...Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,cancer.Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular health.It also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient care.The advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular medicine.These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders.Furthermore,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment.This review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer immunity.In conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders.It emphasizes the clinical value and effect of PCSK9-iT,underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.展开更多
The management of colorectal cancer(CRC)poses a significant challenge,necessitating the development of innovative and effective therapeutics.Our research has shown that notoginsenoside Ft1(Ng-Ft1),a small molecule,mar...The management of colorectal cancer(CRC)poses a significant challenge,necessitating the development of innovative and effective therapeutics.Our research has shown that notoginsenoside Ft1(Ng-Ft1),a small molecule,markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8^(+)T cells in tumor-bearing mice,thus restraining tumor growth.Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X,undermining its role in shieldingβ-catenin.This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway.These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC,working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8^(+)T cell prevalence within the tumor environment.展开更多
Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration i...Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration is still poorly understood.This study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)mice.Egr-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE mice.Consistently,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y cells.Our results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.展开更多
Traditional Chinese medicine(TCM)has been paid much attentions due to the prevention and treatment of steroid hormone disorders.Ginseng,the root of Panax ginseng C.A.Meyer(Araliaceae),is one of the most valuable herbs...Traditional Chinese medicine(TCM)has been paid much attentions due to the prevention and treatment of steroid hormone disorders.Ginseng,the root of Panax ginseng C.A.Meyer(Araliaceae),is one of the most valuable herbs in complementary and alternative medicines around the world.A series of dammarane triterpenoid saponins,also known as phytosteroids,were reported as the primary ingredients of Ginseng,and indicated broad spectral pharmacological actions,including anti-cancer,anti-inflammation and anti-fatigue.The skeletons of the dammarane triterpenoid aglycone are structurally similar to the steroid hormones.Both in vitro and in vivo studies showed that Ginseng and its active ingredients have beneficial hormone-like role in hormonal disorders.This review thus summarizes the structural similarities between hormones and dammarane ginsenosides and integrates the analogous effect of Ginseng and ginsenosides on prevention and treatment of hormonal disorders published in recent twenty years(1998–2018).The review may provide convenience for anticipate structure-function relationship between saponins structure and hormone-like effect.展开更多
Ginsenosides are a series of glycosylated triterpenoids predominantly originated from Panax species with multiple pharmacological activities such as anti-aging, mediatory effect on the immune system and the nervous sy...Ginsenosides are a series of glycosylated triterpenoids predominantly originated from Panax species with multiple pharmacological activities such as anti-aging, mediatory effect on the immune system and the nervous system. During the biosynthesis of ginsenosides, glycosyltransferases play essential roles by transferring various sugar moieties to the sapogenins in contributing to form structure and bioactivity diversified ginsenosides, which makes them important bioparts for synthetic biology-based production of these valuable ginsenosides. In this review, we summarized the functional elucidated glycosyltransferases responsible for ginsenoside biosynthesis, the advance in the protein engineering of UDP-glycosyltransferases(UGTs) and their application with the aim to provide in-depth understanding on ginsenoside-related UGTs for the production of rare ginsenosides applying synthetic biology-based microbial cell factories in the future.展开更多
Acetaminophen(APAP)overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States.We investigated the role of p62/SQSTM1(referred to as p62)in APAP-induced liver injury(AIL...Acetaminophen(APAP)overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States.We investigated the role of p62/SQSTM1(referred to as p62)in APAP-induced liver injury(AILI)in mice.We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment,which was inversely correlated with the hepatic levels of APAPadducts.APAP also activated mTOR at 24 h,which is associated with increased cell proliferation.In contrast,p62 knockout(KO)mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment.Surprisingly,p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h.We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor(VWF)and platelet aggregation,which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment.Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.展开更多
L-tyrosine,an aromatic amino acid,is an important upstream precursor for the synthesis of a series of valuable natural products such as flavonoids and phenolic acids.In recent years,regulation of the L‑tyrosine metabo...L-tyrosine,an aromatic amino acid,is an important upstream precursor for the synthesis of a series of valuable natural products such as flavonoids and phenolic acids.In recent years,regulation of the L‑tyrosine metabolic pathway has been devoted to enhancing the production of L-tyrosine and the derived bioactive compounds in microorganisms,usually by increasing the supply of precursors,blocking competitive routes,and modulating the transport system.Here,we reviewed the strategies to promote L-tyrosine production in microbial hosts and the common strategies to produce bioactive compounds in engineered Escherichia coli and Saccharomyces cerevisiae to better understand and utilize the L-tyrosine metabolic pathway for microbial overproduction of diverse valuable aromatic compounds in the future.展开更多
Objective:To investigate the mechanisms of andrographolide against non-alcoholic steatohepatitis(NASH)based on network pharmacology,so as to provide a reference for further study of andrographolide in the treatment of...Objective:To investigate the mechanisms of andrographolide against non-alcoholic steatohepatitis(NASH)based on network pharmacology,so as to provide a reference for further study of andrographolide in the treatment of NASH and other metabolic diseases.Methods:The methionine-and choline-deficient(MCD)diet-induced NASH mice were treated by administration of andrographolide,and serum transaminase and pathological changes were analyzed.The network pharmacology-based bioinformatic strategy was then used to search the potential targets,construct protein–protein interaction(PPI)network,analyze gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment,and conduct molecular docking to explore the molecular mechanisms.Results:The predicted core targets TNF,MAPK8,IL6,IL1B and AKT1 were enriched in non-alcoholic fatty liver disease(NAFLD)signaling pathway and against NASH by regulation of de novo fatty acids synthesis,anti-inflammation and anti-oxidation.Conclusion:This work provides a scientific basis for further demonstration of the anti-NASH mechanisms of andrographolide.展开更多
Harmaline and harmine areβ-carboline alkaloids with effective pharmacological effects.Harmaline can be transformed into harmine after oral administration.However,enzymes involved in the metabolic pathway remain uncle...Harmaline and harmine areβ-carboline alkaloids with effective pharmacological effects.Harmaline can be transformed into harmine after oral administration.However,enzymes involved in the metabolic pathway remain unclear.In this study,harmaline was incubated with rat liver microsomes(RLM),rat brain microsomes(RBM),blood,plasma,broken blood cells,and heme peroxidases including horseradish peroxidase(HRP),lactoperoxidase(LPO),and myeloperoxidase(MPO).The production of harmine was determined by a validated UPLC-ESI-MS/MS method.Results showed that heme peroxidases catalyzed the oxidative dehydrogenation of harmaline.All the reactions were in accordance with the Hill equation.The reaction was inhibited by ascorbic acid and excess H_(2)0_(2).The transformation of harmaline to harmine was confirmed after incubation with blood,plasma,and broken blood cells,rather than RLM and RBM.Harmaline was incubated with blood,plasma,and broken cells liquid for 3 h,and the formation of harmine became stable.Results indicated an integrated metabolic pathway of harmaline,which will lay foundation for the oxidation reaction of dihydro-P-carboline.Moreover,the metabolic stability of harmaline in blood should not be ignored when the pharmacokinetics study of harmaline is carried out.展开更多
As the most aggressive breast cancer,triple-negative breast cancer(TNBC) is still incurable and very prone to metastasis.The transform growth factor β(TGF-β)-induced epithelial—mesenchymal transition(EMT) is crucia...As the most aggressive breast cancer,triple-negative breast cancer(TNBC) is still incurable and very prone to metastasis.The transform growth factor β(TGF-β)-induced epithelial—mesenchymal transition(EMT) is crucially involved in the growth and metastasis of TNBC.This study reported that a natural compound isotoosendanin(ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia.ITSN can directly interact with TGF-β receptor type-1(TGFβR1) and abrogated the kinase activity of TGFβR1,thereby blocking the TGF-β-initiated downstream signaling pathway.Moreover,the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1.Furthermore,Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1.Additionally,ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1(PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment.Our findings not only highlight the key role of TGFβR1 in TNBC metastasis,but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis.Moreover,this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.展开更多
Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In particular,increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of...Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In particular,increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD.As a precious traditional Chinese medicine,bear bile powder(BBP)has a long history of use in clinical practice.It has numerous activities,such as clearing heat,calming the liver wind and anti-inflammation,and also exhibits good therapeutic effect on convulsive epilepsy.However,whether BBP can prevent the development of PD has not been elucidated.Hence,this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD.PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)(30 mg·kg−1)for five days,followed by BBP(50,100,and 200 mg·kg−1)treatment daily for ten days.LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation.THe results indicated that BBP treatment significantly ameliorated dyskinesia,increased the levels of tyrosine hydroxylase(TH)and inhibited astrocyte hyperactivation in the substantia nigra(SN)of PD mice.Furthermore,BBP decreased the protein levels of glial fibrillary acidic protein(GFAP),cyclooxygenase 2(COX2)and inducible nitric oxide synthase(iNOS),and up-regulated the protein levels of takeda G protein-coupled receptor 5(TGR5)in the SN.Moreover,BBP significantly activated TGR5 in a dose-dependent manner,and decreased the protein levels of GFAP,iNOS and COX2,as well as the mRNA levels of GFAP,iNOS,COX2,interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)in LPS-stimulated C6 cells.Notably,BBP suppressed the phosphorylation of protein kinase B(AKT),inhibitor of NF-κB(IκBα)and nuclear factor-κB(NF-κB)proteins in vivo and in vitro.We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells.Taken together,BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.展开更多
Ginsenosides are a series of glycosylated triterpenoids which belong to protopanaxadiol(PPD)-,protopanaxatriol(PPT)-,ocotillol(OCT)-and oleanane(OA)-type saponins known as active compounds of Panax genus.They are accu...Ginsenosides are a series of glycosylated triterpenoids which belong to protopanaxadiol(PPD)-,protopanaxatriol(PPT)-,ocotillol(OCT)-and oleanane(OA)-type saponins known as active compounds of Panax genus.They are accumulated in plant roots,stems,leaves,and flowers.The content and composition of ginsenosides are varied in different ginseng species,and in different parts of a certain plant.In this review,we summarized the representative saponins structures,their distributions and the contents in nearly 20 Panax species,and updated the biosynthetic pathways of ginsenosides focusing on enzymes responsible for structural diversified ginsenoside biosynthesis.We also emphasized the transcription factors in ginsenoside biosynthesis and non-coding RNAs in the growth of Panax genus plants,and highlighted the current three major biotechnological applications for ginsenosides production.This review covered advances in the past four decades,providing more clues for chemical discrimination and assessment on certain ginseng plants,new perspectives for rational evaluation and utilization of ginseng resource,and potential strategies for production of specific ginsenosides.展开更多
The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such...The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such as Roux-en-Y gastric bypass(RYGB)and vertical sleeve gastrectomy(VSG),currently provide the most effective treatment for obesity and type 2 diabetes(T2D),as well as for non-alcoholic steatohepatitis(NASH).However,the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive.Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery.This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor(FXR)and G protein-coupled bile acid receptor 5(TGR5)in bariatric surgery.We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.展开更多
文摘Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A.membranaceus(TFA)and their protective mechanisms.TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)in the mouse model of Parkinsonism,by improving behavior performance in the gait analysis and pole test,and inhibiting the decline of tyrosine hydroxylase(TH)positive neurons and TH protein expression in substantia nigra of mice.TFA also prevented 1-methyl-4-phenylpyridinium(MPP+)induced neurotoxicity in SHSY5Y cells,by increasing GSH and GSH/GSSG ratio,and reducing reactive oxygen species.In addition,the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+induced downregulation of SLC7A11 and glutathione peroxidase 4(GPX-4).In conclusion,we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis,suggesting the use of TFA as a possible food supplement in the prevention of PD.
基金Supported by National Natural Science Foundation of China,No.81273572 and No.81530096the Natural Science Foundation of Shanghai,No.17ZR1427800.
文摘The rapid development of metagenomics,metabolomics,and metatranscriptomics provides novel insights into the intestinal microbiota factors linked to inflammatory bowel disease(IBD).Multiple microorganisms play a role in intestinal health;these include bacteria,fungi,and viruses that exist in a dynamic balance to maintain mucosal homeostasis.Perturbations in the intestinal microbiota disrupt mucosal homeostasis and are closely related to IBD in humans and colitis in mice.Therefore,preventing or correcting the imbalance of microbiota may serve as a novel prevention or treatment strategy for IBD.We review the most recent evidence for direct or indirect interventions targeting intestinal microbiota for treatment of IBD in order to overcome the current limitations of IBD therapies and shed light on personalized treatment options.
基金Supported by the National Key Research and Development Program of China(No.2018YFC1707302)National Natural Science Foundation of China(No.81960748)。
文摘AIM:To investigate the alleviation of scutellarein(SN)against inner blood-retinal-barrier(iBRB)dysfunction in microglia cells stimulated by hyperglycemia and to elucidate the engaged mechanism.METHODS:Microglia BV2 cells were stimulated by using 25 mmol/L D-glucose.The same concentration of mannitol(25 mmol/L)was applied as an isotonic contrast.Real-time PCR,Western-blot assay and immunofluorescence staining assay was performed.The dysfunction of iBRB in vitro was detected by using transendothelial electrical resistance(TEER)assay.Additionally,the leakage of fluorescein isothiocyanate(FITC)-conjugated dextran(70 kDa)was detected.RESULTS:SN abrogated microglia BV2 cells activation and reduced the phosphorylated activation of extracellular signal-regulated protein kinase(ERK)1/2.SN also decreased the transcriptional activation of nuclear factorκB(NFκB)and the elevated expression of tumor necrosis factorα(TNFα),interleukin(IL)-6 and IL-1βin BV2 cells treated with D-glucose(25 mmol/L).SN attenuated iBRB dysfunction in human retinal endothelial cells(HRECs)or choroid-retinal endothelial RF/6 A cells when those cells were treated with TNFα,IL-1βor IL-6,or co-cultured with microglia cells stimulated by D-glucose.Moreover,SN restored the decreased protein expression of tight junctions(TJs)in TNFα-treated HRECs and RF/6 A cells.CONCLUSION:SN not only alleviate iBRB dysfunction via directly inhibiting retinal endothelial injury caused by TNFα,IL-1βor IL-6,but also reduce the release of TNFα,IL-1βand IL-6 from microglia cells by abrogating hyperglycemia-mediated the activation of microglia cells.
基金supported by the National Natural Science Foundation of China(No.82274329,82304991)the China Postdoctoral Science Foundation(No,2023M732336)Shanghai Science and Technology Committee Sailing Program Foundation(No.23YF1442500)。
文摘Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective treatments.Nuciferine,an alkaloid found in lotus leaf,has shown promising anti-inflammatory and anti-tumor effects,yet its efficacy in RA treatment remains unexplored.This study investigated the antiproliferative effects of nuciferine on the MH7A cell line,a human RA-derived fibroblast-like synoviocyte,revealing its ability to inhibit cell proliferation,promote apoptosis,induce apoptosis,and cause G1/S phase arrest.Additionally,nuciferine significantly reduced the migration and invasion capabilities of MH7A cells.The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis(CIA)rat model,where it markedly alleviated joint swelling,synovial hyperplasia,cartilage injury,and inflammatory infiltration.Nuciferine also improved collagen-induced bone erosion,decreased pro-inflammatory cytokines and serum immunoglobulins(IgG,IgG1,IgG2a),and restored the balance between T helper(Th)17 and regulatory T cells in the spleen of CIA rats.These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.
基金supported by the National Natural Science Foundation of China(No.82272817,to X.B.)Shanghai Pujiang Program(No.22PJ1412400,to X.B.,and No.22PJ1402700,to Y.H.)Science and Technology Development Fund of Shanghai Pudong New Area(No.PKJ2022-Y50,to X.B.).
文摘Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,cancer.Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular health.It also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient care.The advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular medicine.These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders.Furthermore,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment.This review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer immunity.In conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders.It emphasizes the clinical value and effect of PCSK9-iT,underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
基金supported by Shanghai Pujiang Program(No.20PJ1413000)the National Natural Science Foundation of China(No.82173106,82130115,81290108033,82004004,and 82074011)。
文摘The management of colorectal cancer(CRC)poses a significant challenge,necessitating the development of innovative and effective therapeutics.Our research has shown that notoginsenoside Ft1(Ng-Ft1),a small molecule,markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8^(+)T cells in tumor-bearing mice,thus restraining tumor growth.Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X,undermining its role in shieldingβ-catenin.This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway.These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC,working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8^(+)T cell prevalence within the tumor environment.
基金supported by the National Natural Science Foundation of China(82074043,82104425,82374065,and 81673626)the China Postdoctoral Science Foundation(2021M702217).
文摘Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration is still poorly understood.This study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)mice.Egr-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE mice.Consistently,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y cells.Our results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.
基金supported by the National Natural Science Foundation of China(Nos.81530096,81920108033,81573581)the Shanghai Sailing Program(No.19YF 1448800)。
文摘Traditional Chinese medicine(TCM)has been paid much attentions due to the prevention and treatment of steroid hormone disorders.Ginseng,the root of Panax ginseng C.A.Meyer(Araliaceae),is one of the most valuable herbs in complementary and alternative medicines around the world.A series of dammarane triterpenoid saponins,also known as phytosteroids,were reported as the primary ingredients of Ginseng,and indicated broad spectral pharmacological actions,including anti-cancer,anti-inflammation and anti-fatigue.The skeletons of the dammarane triterpenoid aglycone are structurally similar to the steroid hormones.Both in vitro and in vivo studies showed that Ginseng and its active ingredients have beneficial hormone-like role in hormonal disorders.This review thus summarizes the structural similarities between hormones and dammarane ginsenosides and integrates the analogous effect of Ginseng and ginsenosides on prevention and treatment of hormonal disorders published in recent twenty years(1998–2018).The review may provide convenience for anticipate structure-function relationship between saponins structure and hormone-like effect.
基金supported by the National Natural Science Foundation of China (Nos. 81673540,81530096,81573581,and 81920108033)the Natural Science Foundation of Shanghai (No. 16ZR1434100)。
文摘Ginsenosides are a series of glycosylated triterpenoids predominantly originated from Panax species with multiple pharmacological activities such as anti-aging, mediatory effect on the immune system and the nervous system. During the biosynthesis of ginsenosides, glycosyltransferases play essential roles by transferring various sugar moieties to the sapogenins in contributing to form structure and bioactivity diversified ginsenosides, which makes them important bioparts for synthetic biology-based production of these valuable ginsenosides. In this review, we summarized the functional elucidated glycosyltransferases responsible for ginsenoside biosynthesis, the advance in the protein engineering of UDP-glycosyltransferases(UGTs) and their application with the aim to provide in-depth understanding on ginsenoside-related UGTs for the production of rare ginsenosides applying synthetic biology-based microbial cell factories in the future.
基金supported by fundings U01 AA024733,R37 AA020518,R21 AA027250,R01 DK102142,and R01 AG072895(USA)。
文摘Acetaminophen(APAP)overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States.We investigated the role of p62/SQSTM1(referred to as p62)in APAP-induced liver injury(AILI)in mice.We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment,which was inversely correlated with the hepatic levels of APAPadducts.APAP also activated mTOR at 24 h,which is associated with increased cell proliferation.In contrast,p62 knockout(KO)mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment.Surprisingly,p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h.We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor(VWF)and platelet aggregation,which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment.Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
基金This work was supported by the National Natural Science Foundation of China(No.81673540,82173924)“Synthetic Biology-based biosynthesis of salvianolic acids”.
文摘L-tyrosine,an aromatic amino acid,is an important upstream precursor for the synthesis of a series of valuable natural products such as flavonoids and phenolic acids.In recent years,regulation of the L‑tyrosine metabolic pathway has been devoted to enhancing the production of L-tyrosine and the derived bioactive compounds in microorganisms,usually by increasing the supply of precursors,blocking competitive routes,and modulating the transport system.Here,we reviewed the strategies to promote L-tyrosine production in microbial hosts and the common strategies to produce bioactive compounds in engineered Escherichia coli and Saccharomyces cerevisiae to better understand and utilize the L-tyrosine metabolic pathway for microbial overproduction of diverse valuable aromatic compounds in the future.
基金funded by the National Natural Science Foundation of China(31802242)Young Talents Visiting and Training Program for Foreign Country of Anhui Education Department(gxgwfx2019047)+3 种基金the National Natural Science Foundation of Anhui(2008085QC146)Natural Science Key Foundation of Anhui Education Department(KJ2017A503,KJ2017A504)Talent Project of Anhui Science and Technology University(ZRC2014447)Key ResearchandDevelopmentPlanofAnhuiProvince(202004a06020050)。
文摘Objective:To investigate the mechanisms of andrographolide against non-alcoholic steatohepatitis(NASH)based on network pharmacology,so as to provide a reference for further study of andrographolide in the treatment of NASH and other metabolic diseases.Methods:The methionine-and choline-deficient(MCD)diet-induced NASH mice were treated by administration of andrographolide,and serum transaminase and pathological changes were analyzed.The network pharmacology-based bioinformatic strategy was then used to search the potential targets,construct protein–protein interaction(PPI)network,analyze gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment,and conduct molecular docking to explore the molecular mechanisms.Results:The predicted core targets TNF,MAPK8,IL6,IL1B and AKT1 were enriched in non-alcoholic fatty liver disease(NAFLD)signaling pathway and against NASH by regulation of de novo fatty acids synthesis,anti-inflammation and anti-oxidation.Conclusion:This work provides a scientific basis for further demonstration of the anti-NASH mechanisms of andrographolide.
基金supported by the National Natural Science Foundation of China(Nos.82173885 and 81872933)the National Natural Science Foundation of Xinjiang Uyghur Autonomous Region of China(No.U1130303)+1 种基金the Technology Cooperation Projects of Science in Shanghai,China(No.20015800100)the Key Laboratory Open Project of Xinjiang Uyghur Autonomous Region(No.2019D04018).
文摘Harmaline and harmine areβ-carboline alkaloids with effective pharmacological effects.Harmaline can be transformed into harmine after oral administration.However,enzymes involved in the metabolic pathway remain unclear.In this study,harmaline was incubated with rat liver microsomes(RLM),rat brain microsomes(RBM),blood,plasma,broken blood cells,and heme peroxidases including horseradish peroxidase(HRP),lactoperoxidase(LPO),and myeloperoxidase(MPO).The production of harmine was determined by a validated UPLC-ESI-MS/MS method.Results showed that heme peroxidases catalyzed the oxidative dehydrogenation of harmaline.All the reactions were in accordance with the Hill equation.The reaction was inhibited by ascorbic acid and excess H_(2)0_(2).The transformation of harmaline to harmine was confirmed after incubation with blood,plasma,and broken blood cells,rather than RLM and RBM.Harmaline was incubated with blood,plasma,and broken cells liquid for 3 h,and the formation of harmine became stable.Results indicated an integrated metabolic pathway of harmaline,which will lay foundation for the oxidation reaction of dihydro-P-carboline.Moreover,the metabolic stability of harmaline in blood should not be ignored when the pharmacokinetics study of harmaline is carried out.
基金financially supported by the National Natural Science Foundation of China(82273994)the leadership in the Science and National Key Research and Development Program of China(2018YFC1707302)。
文摘As the most aggressive breast cancer,triple-negative breast cancer(TNBC) is still incurable and very prone to metastasis.The transform growth factor β(TGF-β)-induced epithelial—mesenchymal transition(EMT) is crucially involved in the growth and metastasis of TNBC.This study reported that a natural compound isotoosendanin(ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia.ITSN can directly interact with TGF-β receptor type-1(TGFβR1) and abrogated the kinase activity of TGFβR1,thereby blocking the TGF-β-initiated downstream signaling pathway.Moreover,the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1.Furthermore,Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1.Additionally,ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1(PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment.Our findings not only highlight the key role of TGFβR1 in TNBC metastasis,but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis.Moreover,this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.
基金the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(No.2023YZZ02).
文摘Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In particular,increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD.As a precious traditional Chinese medicine,bear bile powder(BBP)has a long history of use in clinical practice.It has numerous activities,such as clearing heat,calming the liver wind and anti-inflammation,and also exhibits good therapeutic effect on convulsive epilepsy.However,whether BBP can prevent the development of PD has not been elucidated.Hence,this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD.PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)(30 mg·kg−1)for five days,followed by BBP(50,100,and 200 mg·kg−1)treatment daily for ten days.LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation.THe results indicated that BBP treatment significantly ameliorated dyskinesia,increased the levels of tyrosine hydroxylase(TH)and inhibited astrocyte hyperactivation in the substantia nigra(SN)of PD mice.Furthermore,BBP decreased the protein levels of glial fibrillary acidic protein(GFAP),cyclooxygenase 2(COX2)and inducible nitric oxide synthase(iNOS),and up-regulated the protein levels of takeda G protein-coupled receptor 5(TGR5)in the SN.Moreover,BBP significantly activated TGR5 in a dose-dependent manner,and decreased the protein levels of GFAP,iNOS and COX2,as well as the mRNA levels of GFAP,iNOS,COX2,interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)in LPS-stimulated C6 cells.Notably,BBP suppressed the phosphorylation of protein kinase B(AKT),inhibitor of NF-κB(IκBα)and nuclear factor-κB(NF-κB)proteins in vivo and in vitro.We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells.Taken together,BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.
基金supported by National Natural Science Foundation of China(No.81673540,No.81530096)Natural Science Foundation of Shanghai(No.16ZR1434100,China)Shanghai local Science and Technology Development Fund Program guided by the Central Government(YDZX20203100002948,China)
文摘Ginsenosides are a series of glycosylated triterpenoids which belong to protopanaxadiol(PPD)-,protopanaxatriol(PPT)-,ocotillol(OCT)-and oleanane(OA)-type saponins known as active compounds of Panax genus.They are accumulated in plant roots,stems,leaves,and flowers.The content and composition of ginsenosides are varied in different ginseng species,and in different parts of a certain plant.In this review,we summarized the representative saponins structures,their distributions and the contents in nearly 20 Panax species,and updated the biosynthetic pathways of ginsenosides focusing on enzymes responsible for structural diversified ginsenoside biosynthesis.We also emphasized the transcription factors in ginsenoside biosynthesis and non-coding RNAs in the growth of Panax genus plants,and highlighted the current three major biotechnological applications for ginsenosides production.This review covered advances in the past four decades,providing more clues for chemical discrimination and assessment on certain ginseng plants,new perspectives for rational evaluation and utilization of ginseng resource,and potential strategies for production of specific ginsenosides.
基金This workwas supported by the National Cancer Institute 2R01CA139158,John Hench Foundation,George Schaeffer Foundation,Chinese National Natural Science Foundation(81270935)Transform Medicine Innovation Foundation of Shanghai Jiao Tong University School of Medicine(15ZH2001)+1 种基金Research Project Funded by the Shanghai Municipal Health Bureau(20114301)the Fund of the Key Laboratory of Stem Cell Biology of Chinese Academy of Sciences(201601).
文摘The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such as Roux-en-Y gastric bypass(RYGB)and vertical sleeve gastrectomy(VSG),currently provide the most effective treatment for obesity and type 2 diabetes(T2D),as well as for non-alcoholic steatohepatitis(NASH).However,the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive.Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery.This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor(FXR)and G protein-coupled bile acid receptor 5(TGR5)in bariatric surgery.We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.
