Sugarcane leaves-derived polyphenols(SLP)have been demonstrated to have diverse health-promoting benefits,but the mechanism of action has not been fully elucidated.This study aimed to investigate the anti-metabolic di...Sugarcane leaves-derived polyphenols(SLP)have been demonstrated to have diverse health-promoting benefits,but the mechanism of action has not been fully elucidated.This study aimed to investigate the anti-metabolic disease effects of SLP and the underlying mechanisms in mice.In the current study,we prepared the SLP mainly consisting of three flavonoid glycosides,three phenol derivatives,and two lignans including one new compound,and further demonstrated that SLP reduced body weight gain and fat accumulation,improved glucose and lipid metabolism disorders,ameliorated hepatic steatosis,and regulated short-chain fatty acids(SCFAs)production and secondary bile acids metabolism in ob/ob mice.Notably,SLP largely altered the gut microbiota composition,especially enriching the commensal bacteria Akkermansia muciniphila and Bacteroides acidifaciens.Oral gavage with the above two strains ameliorated metabolic syndrome(MetS),regulated secondary bile acid metabolism,and increased the production of SCFAs in high-fat diet(HFD)-induced obese mice.These results demonstrated that SLP could be used as a prebiotic to attenuate MetS via regulating gut microbiota composition and further activating the secondary bile acids-mediated gut-adipose axis.展开更多
Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis.At the host-gut microbiome interface,cell wall-derived molecules from gut commen...Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis.At the host-gut microbiome interface,cell wall-derived molecules from gut commensal bacteria have been reported to play a pivotal role in training and remodeling host immune responses.In this article,we review gut bacterial cell wall-derived molecules with characterized chemical structures,including peptidoglycan and lipid-related molecules that impact host health and disease processes via regulating innate and adaptive immunity.Also,we aim to discuss the structures,immune responses,and underlying mechanisms of these immunogenic molecules.Based on current advances,we propose cell wall-derived components as important sources of medicinal agents for the treatment of infection and immune diseases.展开更多
The biosynthetic potential of actinobacteria to produce novel natural products is still regarded as immense.In this paper,we correlated a cryptic biosynthetic gene cluster to chemical molecules by genome mining and ch...The biosynthetic potential of actinobacteria to produce novel natural products is still regarded as immense.In this paper,we correlated a cryptic biosynthetic gene cluster to chemical molecules by genome mining and chemical analyses,leading to the discovery of a new group of catecholate-hydroxamate siderophores,nobachelins,from Nocardiopsis baichengensis DSM 44845.Nobachelin biosynthesis genes are conserved in several bacteria from the family Nocardiopsidaceae.Structurally,nobachelins feature fatty-acylated hydroxy-ornithine and a rare chlorinated catecholate group.Intriguingly,nobachelins rescued Caenorhabditis elegans from Pseudomonas aeruginosa-mediated killing.展开更多
Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversi...Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily(MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1 p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.展开更多
Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and ...Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.展开更多
Two potent anti-MRSA tanshinone glycosides(1 and 2)were discovered by targeted microbial biotransformation,along with rapid identification via MS/MS networking.Serial reactions including dehydrogenation,demethylations...Two potent anti-MRSA tanshinone glycosides(1 and 2)were discovered by targeted microbial biotransformation,along with rapid identification via MS/MS networking.Serial reactions including dehydrogenation,demethylations,reduction,glycosylation and methylation have been observed after incubation of tanshinone IIA and fungus Mucor rouxianus AS 3.3447.In addition,tanshinosides B(2)showed potent activities against serial clinical isolates of oxacillin-resistant Staphylococcus aureus with MIC values of 0.78 mg/mL.This is the first study that shows a significant increase in the level and activities of tanshinone glycosides relative to the substrate tanshinone IIA.展开更多
Tuberculosis drug resistance continues to threaten global health but the underline molecular mechanisms are not clear.Ethambutol(EMB),one of the well-known first-line drugs in tuberculosis treatment is,unfortunately,n...Tuberculosis drug resistance continues to threaten global health but the underline molecular mechanisms are not clear.Ethambutol(EMB),one of the well-known first-line drugs in tuberculosis treatment is,unfortunately,not free from drug resistance problems.Genomic studies have shown that some genetic mutations in Mycobacterium tuberculosis(Mtb)EmbR,and EmbC/A/B genes cause EMB resistance.EmbR-PknH pair controls embC/A/B operon,which encodes EmbC/A/B genes,and EMB interacts with EmbA/B proteins.However,the EmbR binding site on PknH was unknown.We conducted molecular simulation on the EmbR-peptides binding structures and discovered phosphorylated PknH 273-280(N′-HEALS^(P)DPD-C′)makesβstrand with the EmbR FHA domain,asβ-MoRF(MoRF;molecular recognition feature)does at its binding site.Hydrogen bond number analysis also supported the peptides’β-MoRF forming activity at the EmbR FHA domain.Also,we discovered that previously known phosphorylation residues might have their chronological order according to the phosphorylation status.The discovery validated that Mtb PknH 273-280(N′-HEALSDPD-C′)has reliable EmbR binding affinity.This approach is revolutionary in the computer-aided drug discovery field,because it is the first trial to discover the protein-protein interaction site,and find binding partner in nature from this site.展开更多
Phytopathogenic fungi have attracted great attention as a promising source for new drug discovery.In the progress of our ongoing study for bioactive natural products from an in-house phytopathogenic fungi library,a pa...Phytopathogenic fungi have attracted great attention as a promising source for new drug discovery.In the progress of our ongoing study for bioactive natural products from an in-house phytopathogenic fungi library,a pathogenic fungus,Fusarium proliferatum strain 13294(FP13294),was selected for chemical investigation.Two novel aliphatic unsaturated alcohols named fusariumnols A and B(1 and 2),together with one previously characterized sesquiterpenoid lignoren(3)were identified.Structures of 1-3 were assigned by mass spectrometry and NMR spectroscopy.Their bioactivities were assessed against Staphylococcus epidermidis,S.aureus,and Methicillin-resistant S.aureus(MRSA).Compounds 1 and 2 exhibited weak antibacterial activity against S.epidermidis(MIC=100μM).展开更多
基金supported by the National key research and development program of China(2019YFA0905600)the Science and Technology Service Network Program of the Chinese Academy of Sciences(KFJ-STS-QYZD-201-5-3)the Strategic Priority Research Program(Class B)of Chinese Academy of Sciences(XDB 38020300)。
文摘Sugarcane leaves-derived polyphenols(SLP)have been demonstrated to have diverse health-promoting benefits,but the mechanism of action has not been fully elucidated.This study aimed to investigate the anti-metabolic disease effects of SLP and the underlying mechanisms in mice.In the current study,we prepared the SLP mainly consisting of three flavonoid glycosides,three phenol derivatives,and two lignans including one new compound,and further demonstrated that SLP reduced body weight gain and fat accumulation,improved glucose and lipid metabolism disorders,ameliorated hepatic steatosis,and regulated short-chain fatty acids(SCFAs)production and secondary bile acids metabolism in ob/ob mice.Notably,SLP largely altered the gut microbiota composition,especially enriching the commensal bacteria Akkermansia muciniphila and Bacteroides acidifaciens.Oral gavage with the above two strains ameliorated metabolic syndrome(MetS),regulated secondary bile acid metabolism,and increased the production of SCFAs in high-fat diet(HFD)-induced obese mice.These results demonstrated that SLP could be used as a prebiotic to attenuate MetS via regulating gut microbiota composition and further activating the secondary bile acids-mediated gut-adipose axis.
基金The work was financially supported by a grant from National Key R&D Program of China(2022YFA1304200).
文摘Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis.At the host-gut microbiome interface,cell wall-derived molecules from gut commensal bacteria have been reported to play a pivotal role in training and remodeling host immune responses.In this article,we review gut bacterial cell wall-derived molecules with characterized chemical structures,including peptidoglycan and lipid-related molecules that impact host health and disease processes via regulating innate and adaptive immunity.Also,we aim to discuss the structures,immune responses,and underlying mechanisms of these immunogenic molecules.Based on current advances,we propose cell wall-derived components as important sources of medicinal agents for the treatment of infection and immune diseases.
基金support from the Helmholtz International Lab(InterLabs0007)Yuhao Ren acknowledges the support from the International Postdoctoral Exchange Fellowship Program(ZD202125)between Helmholtz AssociationGermany and the Office of China Postdoc Council(OCPC),China.
文摘The biosynthetic potential of actinobacteria to produce novel natural products is still regarded as immense.In this paper,we correlated a cryptic biosynthetic gene cluster to chemical molecules by genome mining and chemical analyses,leading to the discovery of a new group of catecholate-hydroxamate siderophores,nobachelins,from Nocardiopsis baichengensis DSM 44845.Nobachelin biosynthesis genes are conserved in several bacteria from the family Nocardiopsidaceae.Structurally,nobachelins feature fatty-acylated hydroxy-ornithine and a rare chlorinated catecholate group.Intriguingly,nobachelins rescued Caenorhabditis elegans from Pseudomonas aeruginosa-mediated killing.
基金supported by the National Key Research and Development Program of China (2020YFA0907800)the National Natural Science Foundation of China (31720103901)+2 种基金the “111” Project of China (B18022)the Fundamental Research Funds for the Central Universities (22221818014S)the Open Project Funding of the State Key Laboratory of Bioreactor Engineering,the Shandong Taishan Scholar Award,and the Novo Nordisk Foundation (NNF10CC1016517)。
文摘Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily(MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1 p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.
基金the National Program on Key Basic Research Project(973program,2013CB734000)in part by grants from the National Natural Science Foundation of China[31670052,31430002,31320103911,31400090,81302678 and 31125002]+2 种基金the Ministry of Science and Tech-nology of the People’s Republic of China[2011ZX09102-011-11,2013ZX10005004-005]China Ocean Mineral Resources R&D Association(Grant No.DY125-15-T-07)the European Union’s Seventh Framework Programme(FP7/2007-2013)under grant agreement no.312184.
文摘Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.
基金the National Program on Key Basic Research Project(973 program,2013CB734000)by grants from the China Ocean Mineral Resources R&D Association(DY125-15-T-07)+2 种基金the National Natural Science Foundation of China(81573341,81102369,81302678,31430002,31400090,31320103911,31125002)the Ministry of Science and Technology of China(2013ZX10005004-005 and 2011ZX09102-011-11)the European Union's Seventh Framework Programme(FP7/2007e2013)under grant agreement no.312184.
文摘Two potent anti-MRSA tanshinone glycosides(1 and 2)were discovered by targeted microbial biotransformation,along with rapid identification via MS/MS networking.Serial reactions including dehydrogenation,demethylations,reduction,glycosylation and methylation have been observed after incubation of tanshinone IIA and fungus Mucor rouxianus AS 3.3447.In addition,tanshinosides B(2)showed potent activities against serial clinical isolates of oxacillin-resistant Staphylococcus aureus with MIC values of 0.78 mg/mL.This is the first study that shows a significant increase in the level and activities of tanshinone glycosides relative to the substrate tanshinone IIA.
基金This work was supported by the National Institutes of Health Grant No.7R01GM118467-05the National Natural Science Foundation of China(31720103901).
文摘Tuberculosis drug resistance continues to threaten global health but the underline molecular mechanisms are not clear.Ethambutol(EMB),one of the well-known first-line drugs in tuberculosis treatment is,unfortunately,not free from drug resistance problems.Genomic studies have shown that some genetic mutations in Mycobacterium tuberculosis(Mtb)EmbR,and EmbC/A/B genes cause EMB resistance.EmbR-PknH pair controls embC/A/B operon,which encodes EmbC/A/B genes,and EMB interacts with EmbA/B proteins.However,the EmbR binding site on PknH was unknown.We conducted molecular simulation on the EmbR-peptides binding structures and discovered phosphorylated PknH 273-280(N′-HEALS^(P)DPD-C′)makesβstrand with the EmbR FHA domain,asβ-MoRF(MoRF;molecular recognition feature)does at its binding site.Hydrogen bond number analysis also supported the peptides’β-MoRF forming activity at the EmbR FHA domain.Also,we discovered that previously known phosphorylation residues might have their chronological order according to the phosphorylation status.The discovery validated that Mtb PknH 273-280(N′-HEALSDPD-C′)has reliable EmbR binding affinity.This approach is revolutionary in the computer-aided drug discovery field,because it is the first trial to discover the protein-protein interaction site,and find binding partner in nature from this site.
基金This work was supported by the National Key Research and Development Program of China(2020YFA0907200,2019YFA0906200,and 2020YFA0907800)the National Natural Science Foundation of China(21877038,21907031,21977029,31720103901,and 81903529)+1 种基金Shanghai Rising-Star Program(20QA1402800)the Open Project Funding of the State Key Laboratory of Bioreactor Engineering,and the 111 Project(B18022).
文摘Phytopathogenic fungi have attracted great attention as a promising source for new drug discovery.In the progress of our ongoing study for bioactive natural products from an in-house phytopathogenic fungi library,a pathogenic fungus,Fusarium proliferatum strain 13294(FP13294),was selected for chemical investigation.Two novel aliphatic unsaturated alcohols named fusariumnols A and B(1 and 2),together with one previously characterized sesquiterpenoid lignoren(3)were identified.Structures of 1-3 were assigned by mass spectrometry and NMR spectroscopy.Their bioactivities were assessed against Staphylococcus epidermidis,S.aureus,and Methicillin-resistant S.aureus(MRSA).Compounds 1 and 2 exhibited weak antibacterial activity against S.epidermidis(MIC=100μM).
