查看更多>>摘要：Colorectal cancer(CRC)is a prevalent malignant tumor often leading to liver metastasis and mortality.Despite some success with PD-1/PD-L1 immunotherapy,the response rate for colon cancer pa-tients remains relatively low.This is closely related to the immunosuppressive tumor microenvironment mediated by tumor-associated macrophages(TAMs).Our previous work identified that a phosphoglyc-erate mutase 1(PGAM1)allosteric inhibitor,HKB99,exerts a range of anti-tumor activities in lung cancer.Here,we found that upregulation of PGAM1 correlates with increased levels of M2-like tumor-associated macrophages(TAMs)in human colon cancer samples,particularly in liver metastatic tissues.HKB99 suppressed tumor growth and metastasis in cell culture and syngeneic tumor models.M2-polarization,induced by colon cancer cell co-culture,was reversed by HKB99.Conversely,the increased migration of colon cancer cells by M2-TAMs was remarkably restrained by HKB99.Notably,a decrease in TAM infiltration was required for the HKB99-mediated anti-tumor effect,along with an increase in CD8+T cell infiltration.Moreover,HKB99 improved the efficacy of anti-PD-1 treatment in syngeneic tumors.Overall,this study highlights HKB99's inhibitory activity in TAM-mediated colon cancer progression.Targeting PGAM1 could lead to novel therapeutic strategies and enhance the effec-tiveness of existing immunotherapies for colon cancer.
查看更多>>摘要：Methamphetamine(METH)abuse is associated with significant neurotoxicity,high addiction potential,and behavioral abnormalities.Recent studies have identified a connection between the gut microbiota and METH-induced neurotoxicity and behavioral disorders.However,the underlying causal mechanisms linking the gut microbiota to METH pathophysiology remain largely unexplored.In this study,we employed fecal microbiota transplantation(FMT)and antibiotic(Abx)intervention to mani-pulate the gut microbiota in mice administered METH.Furthermore,we supplemented METH-treated mice with short-chain fatty acids(SCFAs)and pioglitazone(Pio)to determine the protective effects on gut microbiota metabolism.Finally,we assessed the underlying mechanisms of the gut-brain neural circuit in vagotomized mice.Our data provide compelling evidence that modulation of the gut micro-biome through FMT or microbiome knockdown by Abx plays a crucial role in METH-induced neurotox-icity,behavioral disorders,gut microbiota disturbances,and intestinal barrier impairment.Furthermore,our findings highlight a novel prevention strategy for mitigating the risks to both the nervous and intes-tinal systems caused by METH,which involves supplementation with SCFAs or Pio.
查看更多>>摘要：Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutri-ents and defend against environmental insults,whereas inappropriate death promotes the spread of inflam-mation.PPARα is highly expressed in the small intestine and regulates the absorption of dietary lipids.However,as a key mediator of inflammation,the impact of intestinal PPARα signaling on cell death path-ways is unknown.Here,we show that Pparα deficiency of intestinal epithelium up-regulates necroptosis signals,disrupts the gut vascular barrier,and promotes LPS translocation into the liver.Intestinal Pparαdeficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet(HFHS).PPARα levels correlate with TRIM38 and MLKL in the human ileum.Inhibition of PPARα up-regulates necroptosis signals in the intestinal organoids triggered by TNF-α and LPS stimuli via TRIM38/TRIF and CREB3L3/MLKL pathways.Butyric acid ameliorates hepatic steatosis induced by intestinal Pparα deficiency through the inhibition of necroptosis.Our data suggest that intestinal PPARα is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation via the gut-liver axis.
查看更多>>摘要：Hepatocyte hopping is the hepatocyte-to-sinusoid-to-hepatocyte shuttling that increases the ef-ficiency of hepatic elimination of xenobiotics.This phenomenon is mediated via efflux of hepatic metabolites by Mrp3 and reuptake by Oatp transporters in sequential hepatocytes until eventual biliary efflux by Mrp2.Sorafenib-glucuronide(SFB-G),the major metabolite of sorafenib(SFB),undergoes hepatocyte hopping,leading to efficient biliary elimination.Nonalcoholic steatohepatitis(NASH)alters the functioning of transporters involved in hepatocyte hopping.The purpose of this study was to quantify the effect of NASH on the three drug disposition processes of hepatocyte hopping.Male FVB and C57BL/6 wild-type(WT),Oatp1a/1b cluster knockout(O-/-),and Mrp2 knockout(Mrpp2-/-)mice were fed a methi-onine and choline deficient(MCD)diet to induce NASH.Mice were administered 10 mg/kg SFB via oral gavage and concentrations of SFB and SFB-G in plasma quantified using liquid-chromatography tandem mass spectrometry.Compared to WT,plasma area under the concentration-time curve(AUC)of SFB-G increased by 108-fold in the O-/--C group and by 345-fold in the Mrp2-/--C group.In the WT-NASH group,up-regulation of Mrp3 and decreased Mrp2 function,along with reduced Oatp uptake,elevated SFB-G AUC by 165-fold.SFB-G AUC in the O-/--NASH group increased by 108-fold compared to WT-C(3.2-fold compared to O-/--C).SFB-G AUC in the Mrp2-/--NASH group increased by 450-fold(1.2-fold compared to Mrp2-/--C).Taken together,the mislocalization of Mrp2 in NASH is a major contributor to the decrease in SFB-G biliary efflux,but decreased Oatp uptake and enhanced sinusoidal efflux also limit the contribution of downstream hepatocytes,resulting in plasma retention that recapitulates the altered pharmacokinetics observed in human NASH.
查看更多>>摘要：The adipose tissue of mammals represents an important energy-storing and endocrine organ,and its dysfunction is relevant to the onset of several health problems,including non-alcoholic fatty liver disease(NAFLD).However,whether treatments targeting adipose dysfunction could alleviate NAFLD has not been well-studied.Adrenomedullin 2(ADM2),belonging to the CGRP superfamily,is a protec-tive peptide that has been shown to inhibit adipose dysfunction.To investigate the adipose tissue-specific effects of ADM2 on NAFLD,adipose-specific ADM2-overexpressing transgenic(aADM2-tg)mice were developed.When fed a high-fat diet,aADM2-tg mice displayed decreased hepatic triglyceride accumu-lation compared to wild-type mice,which was attributable to the inhibition of hepatic de novo lipogen-esis.Results from lipidomics studies showed that ADM2 decreased ceramide levels in adipocytes through the upregulation of ACER2,which catalyzes ceramide catabolism.Mechanically,activation of adipocyte HIF2α was required for ADM2 to promote ACER2-dependent adipose ceramide catabolism as well as to decrease hepatic lipid accumulation.This study highlights the role of ADM2 and adipose-derived ceramide in NAFLD and suggests that its therapeutic targeting could alleviate disease symptoms.
查看更多>>摘要：Endosomal TLRs(TLR3/7/8/9)are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular pattems.Among them,TLR7,in particular,has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus er-ythematosus(SLE);but few small-molecule inhibitors with elaborated mechanism have been reported in literature.Here,we reported a well-characterized human TLR7-specific small-molecule inhibitor,TH-407b,with promising potency and negligible cytotoxicity through a novel binding mechanism.Notably,TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells(PBMCs)derived from SLE patients.Furthermore,TH-407b showed prominent efficacy in vivo,improved survival rate and ameliorated symptoms of SLE model mice.To obtain molec-ular insights into the TH-407b derivatives'inhibition mechanism,we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy(cryo-EM)method.As an atomistic reso-lution cryo-EM structure of the TLR family,it not only of value to facilitate structure-based drug design,but also shed light to methodology development of small proteins using EM.Significantly,TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state.Such a resting state could be generally applicable to all TLRs,rendering a useful method for targeting this group of important immunological receptors.
查看更多>>摘要：Due to the limitations of current anti-HBV therapies,the HBV core(HBc or HBcAg)protein assembly modulators(CpAMs)are believed to be potential anti-HBV agents.Therefore,discovering safe and efficient CpAMs is of great value.In this study,we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library.A novel lead compound 8a,a derivative of the marine natural product naamidine J,has been successfully screened for potential anti-HBV activity.Bioactivity-driven synthesis was then conducted,and the struc-ture-activity relationship was analyzed,resulting in the discovery of the most effective compound 11a(IC50=0.24 pmol/L).Furthermore,11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate(TDF)and IFNa2 in vitro for anti-HBV activity.Treatment with 11a in a hydrodynamic-injection mouse model demonstrated sig-nificant anti-HBV activity without apparent hepatotoxicity.These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.
查看更多>>摘要：The management of antibiotic-resistant,bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario.Pseudomonas aeruginosa infection is difficult to eradicate because of biofilm formation and antibiotic resistance.In this study,we identified a new benzothiazole derivative compound,SN12(IC50=43.3 nmol/L),demonstrating remarkable biofilm inhibition at nano-molar concentrations in vitro.In further activity assays and mechanistic studies,we formulated an uncon-ventional strategy for combating P.aeruginosa-derived infections by targeting the two-component(Gac/Rsm)system.Furthermore,SN12 slowed the development of ciprofloxacin and tobramycin resistance.By using murine skin wound infection models,we observed that SN12 significantly augmented the antibac-terial effects of three widely used antibiotics-tobramycin(100-fold),vancomycin(200-fold),and cipro-floxacin(1000-fold)—compared with single-dose antibiotic treatments for P.aeruginosa infection in vivo.The findings of this study suggest the potential of SN12 as a promising antibacterial synergist,highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.
查看更多>>摘要：The dynamic tracking of antibody-drug conjugates(ADCs)in serum is crucial.However,a versatile bioanalytical platform is lacking due to serious matrix interferences,the heterogeneity and complex biotransformation of ADCs,and the recognition deficiencies of traditional affinity technologies.To overcome this,a multiepitope recognition technology(MERT)was developed by simultaneously immobilizing CDR and non-CDR ligands onto MOF@AuNPs.MERT's excellent specificity,ultrahigh ligand density,and potential synergistic recognition ability enable it to target the different key regions of ADCs to overcome the deficiencies of traditional technologies.The binding capacity of MERT for antibodies is ten to hundred times higher than that of the mono-epitope or Fc-specific affinity technologies.Since MERT can efficiently capture target ADCs from serum,a novel bioanalytical platform based on MERT and RPLC-QTOF-MS has been developed to monitor the dynamic changes of ADCs in serum,including the fast changes of drug-to-antibody ratio from 3.67 to 0.22,the loss of payloads(maytansinol),and the unexpected hydrolysis of the succinimide ring of the linker,which will contribute to clarify the fate of ADCs and provide a theoretical basis for future design.In summary,the MERT-based versatile platform will open a new avenue for in-depth studies of ADCs in biological fluids.
查看更多>>摘要：A colon-specific drug delivery system has great potential for the oral administration of colo-rectal cancer.However,the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location,and intratumoral accumulation remains unsatisfactory.Here,an oral colon-specific drug delivery system(CBS-CS@Lipo/Oxp/MTZ)was constructed by covalently conjugating Clostridium butyricum spores(CBS)with drugs loaded chitosan(CS)-coated liposomes,where the model chemotherapy drug oxaliplatin(Oxp)and anti-anaerobic bacteria agent metronidazole(MTZ)were loaded.Following oral administration,CBS germinated into Clostridium butyricum(CB)and colonized in the colon.Combined with colonic specifically β-glucosidase responsive degrading of CS,dual colon-specific release of lipo-somes was achieved.And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold.Simultaneously,the released liposomes penetrated deep tumor tissue via the permeation enhance-ment effect of CS to kill localized intratumoral bacteria.Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB,the in-tratumoral pathogenic bacteria were eliminated fundamentally,blocking their recruitment to immunosup-pressive cells.Furtherly,synchronized with lipopolysaccharide(LPS)released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells,they jointly enhanced tumor infiltration of CD8+T cells and reactivated robust antitumor immunity.
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