查看更多>>摘要：Diabetic nephropathy(DN)is a severe complication of diabetes,characterized by changes in kidney structure and function.The natural product rosmarinic acid(RA)has demonstrated therapeutic effects,including anti-inflammation and anti-oxidative-stress,in renal damage or dysfunction.In this study,we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels.Our results demonstrated that RA significantly alleviated renal tubular epithelial injury,particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes,while attenuating the inflammatory response of macrophages,oxidative stress,and cytotox-icity of natural killer cells.These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage,oxidative stress,and inflammation,offering valuable guidance for the clinical application of RA in the treatment of DN.
查看更多>>摘要：Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal conse-quences.Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis,the paucity of effective treatments for such damage is evident.In our study,we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells,thereby fortifying the integrity of the intestinal mucus barrier.This enhanced barrier function serves to resist microbial invasion and sub-sequently reduces the inflammatory response.Importantly,this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs.Mechanistically,E.copr up-regulates the expression of AUF1,leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells.An espe-cially significant finding is that E.copr activates the AhR pathway,thereby promoting the expression of AUF1.In summary,our results strongly indicate that E.copr enhances the intestinal mucus barrier,effec-tively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway,consequently enhancing Muc2 mRNA stability.
查看更多>>摘要：Protein tyrosine kinases(RTKs)modulate a wide range of pathophysiological events in several non-malignant disorders,including diabetic complications.To find new targets driving the devel-opment of diabetic cardiomyopathy(DCM),we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1(p-FGFR1)levels in cardiomyocytes,indicating that FGFR1 may contribute to the pathogenesis of DCM.Using pri-mary cardiomyocytes and H9C2 cell lines,we discovered that high-concentration glucose(HG)transac-tivates FGFR1 kinase domain through toll-like receptor 4(TLR4)and c-Src,independent of FGF ligands.Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes.RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs-NFκB signaling pathway in HG-challenged cardiomyocytes,which further results in fibrosis and hypertrophy.We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice.Pharmacological inhibition of FGFR1 by a selective inhibitor,AZD4547,also prevents cardiac inflammation,fibrosis,and dysfunction in both type 1 and type 2 diabetic mice.These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
查看更多>>摘要：Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHO1)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.
查看更多>>摘要：Pulmonary hypertension(PH)is a fatal disorder characterized by pulmonary vascular remo-deling and obstruction.The phosphodiesterase 4(PDE4)family hydrolyzes cyclic AMP(cAMP)and is comprised of four subtypes(PDE4A-D).Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however,this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes.Here,we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues.We also confirmed that PDE4B is mainly expressed in the lung endothelial cells(ECs).Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH.In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition(EndMT),and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRⅡ axis.Finally,treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH.Collectively,our findings indicate a critical role for PDE4B in EndMT and PH,prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
查看更多>>摘要：Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA(mtDNA),leading to the activation of cellular oxidative stress and immune responses.While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established,its effects on tumors have remained unclear.In this study,we designed a novel Pt(Ⅳ)complex,OAP2,which is composed of oxaliplatin(Oxa)and acetaminophen(APAP),to enhance its anti-tumor effects and amplify the immune response.Our findings demonstrate that OAP2 induces nuclear DNA damage,resulting in the production of nuclear DNA.Additionally,OAP2 downregulates the expression of mitochondrial Sam50,to promote mitochondrial membrane remodeling and trigger mtDNA secretion,leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway.The mitochondrial membrane remodeling induced by OAP2 overcomes the lim-itations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis.OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells,thereby inhibiting cancer cell proliferation and metastasis.Briefly,our study intro-duces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research,which may provide a creative idea for targeting organelle in anti-tumor therapy.
查看更多>>摘要：Bacterial biofilm-associated infection was one of the most serious threats to human health.However,effective drugs for drug-resistance bacteria or biofilms remain rarely reported.Here,we pro-pose an innovative strategy to develop a multifunctional antimicrobial agent with broad-spectrum anti-bacterial activity by coupling photosensitizers(PSs)with antimicrobial peptides(AMPs).This strategy capitalizes on the ability of PSs to generate reactive oxygen species(ROS)and the membrane-targeting property of AMPs(KRWWKWIRW,a peptide screened by an artificial neural network),syn-ergistically enhancing the antimicrobial activity.In addition,unlike conventional aggregation-caused quenching(ACQ)photosensitizers,aggregation-induced emission(AIE)PSs show stronger fluorescence emission in the aggregated state to help visualize the antibacterial mechanism.In vitro antibacterial ex-periments demonstrated the excellent killing effects of the developed agent against both Gram-positive(G+)and Gram-negative(G-)bacteria.The bacterial-aggregations induced ability enhanced the photo-activatable antibacterial activity against G-bacteria.Notably,it exhibited a significant effect on destroy-ing MRSA biofilms.Moreover,it also showed remarkable efficacy in treating wound infections in mice in vivo.This multifunctional antimicrobial agent holds significant potential in addressing the challenges posed by bacterial biofilm-associated infections and drug-resistant bacteria.
查看更多>>摘要：Human monoamine oxidase B(hMAO-B)has emerged as a pivotal therapeutic target for Par-kinson's disease.Due to adverse effects and shortage of commercial drugs,there is a need for novel,high ly selective,and reversible hMAO-B inhibitors with good blood-brain barrier permeability.In this study,a high-throughput at-line nanofractionation screening platform was established with extracts from Chuan-xiong Rhizoma,which resulted in the discovery of 75 active compounds,including phenolic acids,vol atile oils,and phthalides,two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent,selective,reversible and had good blood-brain permeability.Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism.Sedanolide(IC50=103 nmol/L;SI=645)and neocnidilide(IC50=131 nmol/L;SI=207)demonstrated their excellent potential as hMAO-B inhibitors.They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline.In SH-SY5Y cell assays,sedanolide(EC50=0.962 μmol/L)and neocnidilide(EC50=1.161 μmol/L)exhibited significant neuroprotective effects,comparable to the pos-itive drugs rasagiline(EC50=0.896 μmol/L)and safinamide(EC50=1.079 μmol/L).These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further devel-opment as a promising drug candidate.
查看更多>>摘要：Radiotherapy(RT)is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors.In particular,immune responses triggered by RT,known as radio-immunotherapy,can partially inhibit the growth of distantly spreading tumors and recurrent tumors.How-ever,the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immu-nogenicity of tumor.Herein,we report oxaliplatin(Ⅳ)-iron bimetallic nanoparticles(OXA/Fe NPs)as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy.The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(Ⅱ)and Fe2+in response to the reductive and acidic microenvironment within tumor cells.The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage,increasing ROS and O2 levels,and amplifying the immunogenic cell death(ICD)effect after RT to facilitate potent immune activation.As a result,OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect.Moreover,a long-term immunological memory effect to protect mice from tumor rechal-lenging is observed.Overall,the bimetallic NPs-based cascade sensitizing amplifier system offers an effi-cient radio-immunotherapy regimen that addresses the key challenges.
查看更多>>摘要：Antimicrobial resistance(AMR)has become a global health crisis in need of novel solutions.To this end,antibiotic combination therapies,which combine multiple antibiotics for treatment,have at-tracted significant attention as a potential approach for combating AMR.To facilitate advances in anti-biotic combination therapies,most notably in investigating antibiotic interactions and identifying synergistic antibiotic combinations however,there remains a need for automated high-throughput plat-forms that can create and examine antibiotic combinations on-demand,at scale,and with minimal reagent consumption.To address these challenges,we have developed a Robotic-Printed Combinatorial Droplet(RoboDrop)platform by integrating a programmable droplet microfluidic device that generates antibiotic combinations in nanoliter droplets in automation,a robotic arm that arranges the droplets in an array,and a camera that images the array of thousands of droplets in parallel.We further implement a resazurin-based bacterial viability assay to accelerate our antibiotic combination testing.As a demonstration,we use RoboDrop to corroborate two pairs of antibiotics with known interactions and subsequently identify a new synergistic combination of cefsulodin,penicillin,and oxacillin against a model E.coli strain.We therefore envision RoboDrop becoming a useful tool to efficiently identify new synergistic antibiotic combinations toward combating AMR.
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