查看更多>>摘要：Bile acids(BAs)are natural metabolites in mammals and have the potential to function as drugs against viral infection.However,the limited understanding of chenodeoxycholic acid(CDCA)receptors and downstream signaling,along with its lower suppression efficiency in inhibiting virus infection limits its clinical application.In this study,we demonstrate that farnesoid X receptor(FXR),the receptor of CDCA,negatively regulates interferon signaling,thereby contributing to the reduced effectiveness of CDCA against virus replication.FXR deficiency or pharmacological inhibition enhances interferon signaling activation to suppress virus infection.Mechanistically,FXR impairs the DNA binding and transcriptional abilities of activated interferon regulatory factor 3(IRF3)through interaction.Reduced IRF3 transcriptional activity by FXR-IRF3 interaction significantly undermines the expression of Interferon Beta 1(IFNB1)and the antiviral response of cells,especially upon the CDCA treatment.In FXR-deficient cells,or when combined with Z-guggulsterone(GUGG)treatment,CDCA exhibits a more potent ability to restrict virus infection.Thus,these findings suggest that FXR serves as a limiting factor for CDCA in inhibiting virus replication,which can be attributed to the"signaling-brake"roles of FXR in interferon signaling.Targeting FXR inhibition represents a promising pharmaceutical strategy for the clinical application of BAs metabolites as antiviral drugs.
查看更多>>摘要：Osteoarthritis(OA)is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage.Traditional treatments for OA are limited to alleviating various OA symptoms.There is a lack of drugs available in clinical practice that can truly repair cartilage damage.Here,we developed the chondroitin sulfate analog CS-semi5,semi-synthesized from chondroitin sulfate A.In vivo,CS-semi5 alleviated inflammation,provided analgesic effects,and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model.A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats,revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment.Binding prediction revealed that miR-122-5p acted on the 3'-untranslated region of p38 mitogen-activated protein kinase,which was related to MMP13 regulation.Subsequent in vitro experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis,which was further validated in the articular cartilage of OA rats.This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5,revealing its cartilage-protecting,anti-inflammatory,and analgesic properties that show promising therapeutic effects in OA via the miR-122-5p/p38/MMP13 pathway.
查看更多>>摘要：Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available.In this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,especially in their fibroblasts and endothelial cells,and confirmed MEOX1 as a central orchestrator in the activation of profibrotic genes.By high-throughput screening,we identified Ailanthone(AIL)from a natural compound library as the first small molecule capable of directly targeting and suppressing MEOX1.AIL demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by trans-forming growth factor-β1(TGF-β1).In an animal model of bleomycin-induced pulmonary fibrosis,AIL effectively mitigated the fibrotic process and restored respiratory functions.Mechanistically,AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1,thereby inhibiting MEOX1 expression and activity.In summary,our find-ings pinpointed MEOX1 as a cell-specific and clinically translatable target in fibrosis.Moreover,we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis,specifically through the suppres-sion of JUN-dependent MEOX1 activation.
查看更多>>摘要：Rheumatoid arthritis(RA)is an inflammatory disease accompanied by abnormal synovial microenvironment(SM).Sesquiterpene lactones(SLs)are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment.α-Methylene-γ-butyrolactone(α-M-γ-B)is a core moiety that widely exists in natural SLs.This study was designed to investigate the anti-arthritic potential of α-M-γ-B as an independent small molecule in vitro and in vivo.α-M-γ-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs.α-M-γ-B inhibited the production of pro-inflammatory mediators via repolarizing Ml macrophages into M2 macrophages.The transcriptome sequencing suggested that α-M-γ-B regulated the immune system pathway.Consistently,α-M-γ-B attenuated collagen type Ⅱ-induced arthritic(CIA)phenotype,restored the balance of Tregs-macrophages and remodeled SM via repolarizing the synovial-associated macrophages in CIA mice.Mechanistically,although α-M-γ-B did not prevent the trans-nucleus of NF-κB it interfered with the DNA binding activity of NF-κB via direct interaction with the sulfhydryl in cysteine residue of NF-κB p65,which blocked the activation of NF-κB.Inhibition of NF-κB reduced the Ml polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis.α-M-γ-B failed to ameliorate CIA in the presence of N-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of Rela.In conclusion,α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding ability.These results suggest that α-M-γ-B has the potential to serve as an alternative candidate for treating RA.The greater electrophilicity of α-M-γ-B,the basis for triggering strong anti-inflammatory activity,accounts for the reason why α-M-γ-B is evolutionarily conserved in the SLs by medical plants.
查看更多>>摘要：Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid.Post-prandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients.The response of intestinal epithelial cells to mechanical stimulation is not fully understood.Piezo1,a mechan-osensitive ion channel,is widely expressed throughout the digestive tract.However,its function in intes-tinal nutrient absorption is not yet clear.In our study,excessive lipid deposition was observed in the duodenum of obese patients,while duodenal Piezo1-CaMKK2-AMPKα was decreased when compared to normal-weight individuals.Under high-fat diet condition,the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver.These phenotypes were mainly caused by the inhibition of duodenal CaMKK2-AMPKα and the upregulation of SGLT1 and DGAT2.In contrast,Yoda1,a Piezo1 agonist,was found to reduce intestinal lipid absorp-tion in diet induced obese mice.Overexpression of Piezo1,stretch and Yoda1 inhibited lipid accumula-tion and the expression of DGAT2 and SGLT1,whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells.Our study reveals a previously unexplored mechanical regu-lation of nutrient absorption in intestinal epithelial cells,which may shed new light on the therapy of obesity.
查看更多>>摘要：Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experi-mental models and clinical trials,whether XO is a target of AP and what its the main mechanism of ac-tion is remains unclear.Here,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models.We also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points.Moreover,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity.Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like re-ceptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of 13C6-glucose to 13C3-lactate.Lastly,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP patients.These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of se-vere AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.
查看更多>>摘要：Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer.Herein,a series of adenosine-containing derivatives were iden-tified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell.The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar concentrations.The cell permeability and cellular target engage-ment of 37 were verified by both CETSA and DARTS assays.In the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38％),without obvious toxicities.A pharmacokinetic study re-vealed that 37 possessed tolerable properties(t1/2=1.93±0.91 h,F=97.2％)after intraperitoneal administration in rats.Mechanism study confirmed that 37 suppressed malignant phenotypes of lung can-cer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway.Moreover,anal-ysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the"Induced-fit"allosteric model in favor to the discovery of potent DOT1L candidates.
查看更多>>摘要：Src homology-2-containing protein tyrosine phosphatase 2(SHP2)is a promising therapeutic target for cancer therapy.In this work,we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors,leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent,selective,orally bioavailable allosteric SHP2 inhibitor(SHP2WT IC50=2.7 nmol/L)with favor-able pharmacokinetic profiles(F=42.5％;t1/2=2.47 h).Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the"tunnel"allosteric site of SHP2.TK-642 could effectively suppress cell proliferation(KYSE-520 cells IC50=5.73 μmol/L)and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways.Addition-ally,oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xeno-graft mouse model,with a T/C value of 83.69％.Collectively,TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.
查看更多>>摘要：The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially validated celastrol(CEL)as an inducer of immunogenic cell death(ICD)by promoting ER stress and autophagy in colorectal cancer(CRC)cells.Subsequently,an ER-targeted strategy was posited,involving the codelivery of CEL with PD-L1 small interfering RNAs(siRNA)using KDEL peptide-modified exosomes derived from milk(KME),to enhance chemoimmunotherapy outcomes.Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway.Compared to their non-targeting counterparts,KME exhibited a significant augmentation of the CEL-induced ICD effect.Additionally,it facilitated the release of danger signaling molecules(DAMPs),thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor.Concurrently,the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression,consequently fostering the proliferation and activity of CD8+T cells.Ultimately,the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo.Collectively,a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.
查看更多>>摘要：Non-alcoholic steatohepatitis(NASH),an advanced form of non-alcoholic fatty liver disease(NAFLD),has emerged as the leading cause of liver failure and related death.Currently,no medication is specifically approved to treat NAFLD or NASH.Here we report that oral administration of honey vesicle-like nanoparticles(H-VLNs)to naturally aged mice protects the liver from NASH development.H-VLNs are dominantly taken up by Kupffer cells in the liver and suppress hepatic chronic inflammation and further development of fibrosis and nodule formation in aged mice.Besides their reported anti-inflammasome function,H-VLNs are found to inhibit the transcriptional activities of C-JUN and nuclear factor-kappa B(NF-κB).MicroRNAs miR5119 and miR5108 and phenolic compound luteolin in H-VLNs are identified in suppressing both the C-JUN and NF-κB pathways.Collectively,oral intake of H-VLNs represents a promising new user-friendly modality to prevent the development of NASH.
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