Piericidin A1, 3’-rhamnopiericidin A1, and a novel compound piericidin E, a new quorum-sensing (QS) inhibitor against Chromobacterium violaceum CV026, were isolated from the culture broth of Streptomyces sp. QS is we...Piericidin A1, 3’-rhamnopiericidin A1, and a novel compound piericidin E, a new quorum-sensing (QS) inhibitor against Chromobacterium violaceum CV026, were isolated from the culture broth of Streptomyces sp. QS is well known as a microbial signaling system and controls certain types of gene expression resulting in bioluminescence, biofilm formation, swarming motility, antibiotic biosynthesis, and virulence factor production. C. violaceum CV026 is commonly used to determine qualitative and quantitative QS activity. The structures of piericidin derivatives were characterized, and their QS activities were determined.展开更多
The rising prevalence of multidrug-resistant pathogens poses a substantial threat to global healthcare systems,demanding urgent therapeutic interventions.Microorganisms exhibit diverse resistance mechanisms against va...The rising prevalence of multidrug-resistant pathogens poses a substantial threat to global healthcare systems,demanding urgent therapeutic interventions.Microorganisms exhibit diverse resistance mechanisms against various classes of antibiotics,highlighting the urgent need to discover novel antimicrobial agents for combating bacterial infections.Anti-virulence therapy has emerged as a promising therapeutic strategy that neutralizes pathogens by targeting their virulence determinants.The strategies for screening virulence arresting drugs(VADs)in bacteria represent a multifaceted approach that involves elucidating molecular pathogenesis mechanisms of bacterial pathogenicity,identifying evolutionarily conserved virulence factors across different pathogens,and employing integrated approaches combining in silico prediction with experimental validation.Recent technological advancements have established standardized protocols for effective identification and validation of anti-virulence compounds.This review systematically examines contemporary screening methodologies,primarily focusing on quorum-sensing disruption and biofilm suppression strategies,including in silico screening,activity-based screening with bioassays,in vitro and in vivo models.Additionally,we emphasize the imperative for standardized preclinical validation through physiologically relevant animal models,while proposing framework recommendations for developing next-generation VAD screening platforms.This synthesis not only outlines current best practices but also proposes innovative avenues for future antimicrobial discovery research.展开更多
Chitosan(CS),a natural polymer derived from chitin found in the exoskeletons of crustaceans,has garnered significant interest in the pharmaceutical field due to its unique properties,including biocompatibility and bio...Chitosan(CS),a natural polymer derived from chitin found in the exoskeletons of crustaceans,has garnered significant interest in the pharmaceutical field due to its unique properties,including biocompatibility and biodegradability.In recent years,various studies have reported that CS can affect drug bioavailability,and interestingly,it works as an oral absorption enhancer and inhibitor.This review offers an in-depth analysis of the mechanisms underlying such a phenomenon and supports its application as a pharmaceutical excipient.CS enhances oral drug absorption through various mechanisms,such as interaction with the intestinal mucosa,tight junction modulation,inhibition of efflux transporters,enzyme inhibition,solubility and stability enhancement,and complexation.On the other side,CS exhibits the ability to inhibit the absorption of certain drugs by adsorbing to lipids and sterols,modulating bile acids and gut microbiota,altering drug-cell interaction at the polar interface,and mucus-mediated entrapment and interference.Future potential pharmaceutical research in this field includes elucidating the underneath absorption relevant mechanisms,rational use in formulations as excipient,exploring functional CS derivatives,and developing CS-based drug delivery systems.This comprehensive review highlights CS's versatile and significant role in enhancing and inhibiting oral drug absorption,providing insights into the complexities of drug delivery and the potential of CS to improve therapeutic outcomes.展开更多
The effect of low concentrated green inhibitors based on Ce-adipate and Ce-chloride on the corrosion of 7075 aluminum alloy in neutral NaCl electrolyte was studied.Corrosion studies were carried out using electrochemi...The effect of low concentrated green inhibitors based on Ce-adipate and Ce-chloride on the corrosion of 7075 aluminum alloy in neutral NaCl electrolyte was studied.Corrosion studies were carried out using electrochemical impedance spectroscopy(EIS)and linear sweep voltammetry(LSV)while scanning electron microscopy(SEM)and X-ray photoelectron spectroscopy(XPS)were used to conduct surface studies of the alloy upon immersion in the corrosion media.The electrochemical experiments reveal a better inhibitory effect of Ce-adipate than Ce-chloride owing to a higher polarization resistance value(about two times),and a lower corrosion current density.However,both inhibitors act as cathodic inhibitors,show high resistance to pitting corrosion,and enable sufficient protection during prolonged immersion(240 h)in corrosion media.The XPS analysis confirms the presence of cerium in the oxidation states of Ce(III)and Ce(IV)together with the carboxylate-COO−groups and C-C and C-H bonds on the tested specimen with Ce-adipate inhibitor,which are connected to the increased anti-corrosion efficiency.展开更多
Alzheimer's disease(AD)is a common neurodegenerative disorder among the elderly population.There are currently no effective therapeutic drugs available,the multi-target-directed ligands(MTDLs)strategy has been con...Alzheimer's disease(AD)is a common neurodegenerative disorder among the elderly population.There are currently no effective therapeutic drugs available,the multi-target-directed ligands(MTDLs)strategy has been considered as the promising approach.Given the structural diversity of natural products,Rivastigmine's pharmacophore was integrated with diverse natural product scaffolds to construct a combinatorial compound library.This library was subsequently screened and optimized to identify a novel butyrylcholinesterase(Bu Ch E)inhibitor,compound 3c.The results showed that compound 3c exhibited favorable Bu Ch E inhibitory activity(half-maximal inhibitory concentration(IC_(50))=0.43μmol/L),potential anti-inflammatory potency,good Aβ_(1-42) aggregation inhibitory capacity and remarkable neuroprotective effects.The in vivo study exhibited that 3c significantly ameliorated AlCl_(3)-induced zebrafish AD model and scopolamine-induced memory impairment.Collectively,compound 3c was the artificial intelligence(AI)-driven promising multifunctional agent with Bu Ch E inhibition for the treatment of AD.展开更多
BACKGROUND Post-stroke depression(PSD)is associated with hypothalamic-pituitary-adrenal(HPA)axis dysfunction and neurotransmitter deficits.Selective serotonin reuptake inhibitors(SSRIs)are commonly used,but their effi...BACKGROUND Post-stroke depression(PSD)is associated with hypothalamic-pituitary-adrenal(HPA)axis dysfunction and neurotransmitter deficits.Selective serotonin reuptake inhibitors(SSRIs)are commonly used,but their efficacy is limited.This study investigated whether combining SSRIs with traditional Chinese medicine(TCM)Free San could enhance their therapeutic effects.AIM To evaluate the clinical efficacy and safety of combining SSRIs with Free San in treating PSD,and to assess its impact on HPA axis function.METHODS Ninety-two patients with PSD were enrolled and randomly divided into control groups(n=46)and study groups(n=46).The control group received the SSRI paroxetine alone,whereas the study group received paroxetine combined with Free San for 4 weeks.Hamilton Depression Scale and TCM syndrome scores were assessed before and after treatment.Serum serotonin,norepinephrine,cortisol,cor-ticotropin-releasing hormone,and adrenocorticotropic hormone were measured.The treatment responses and adverse reactions were recorded.RESULTS After treatment,the Hamilton Depression Scale and TCM syndrome scores were significantly lower in the study group than in the control group(P<0.05).Serum serotonin and norepinephrine levels were significantly higher in the study group than in the control group,whereas cortisol,corticotropin-releasing hormone,and adrenocorticotropic hormone levels were significantly lower(P<0.05).The total efficacy rates were 84.78%and 65.22%in the study and control groups,respectively(P<0.05).No significant differences in adverse reactions were observed between the two groups(P>0.05).CONCLUSION Combining SSRIs with Free San can enhance therapeutic efficacy,improve depressive symptoms,and regulate HPA axis function in patients with PSD with good safety and clinical application value.展开更多
Acute myeloid leukemia(AML)remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes.The development of menin inhibitors represents a promising shift,particularly for ...Acute myeloid leukemia(AML)remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes.The development of menin inhibitors represents a promising shift,particularly for patients harboring KMT2A rearrangements(KMT2Ar)and NPM1 mutations(NPM1m).This manuscript reviews the molecular rationale of menin inhibition for aberrant homeobox/myeloid ectopic insertion site 1(HOX/MEIS1)-driven gene expression and leukemogenesis,clinical trial outcomes,and safety data for menin inhibitors,with a focus on recently FDA-approved revumenib and several other agents in development,ziftomenib(KO-539),bleximenib(JNJ-75276617),and icovamenib(BMF-219).We also focused our discussion on future directions to include resistance mechanisms,biomarker identification and monitoring strategies,and combination therapies.Menin inhibition is now being clinically integrated into relapsed/refractory and frontline treatment settings.展开更多
Tumor survival,genomic stability,and therapy resistance are dictated by the DNA damage response(DDR).Although poly(ADP-ribose)polymerase(PARP)inhibitors have established the DDR as a therapeutic target,many tumors eva...Tumor survival,genomic stability,and therapy resistance are dictated by the DNA damage response(DDR).Although poly(ADP-ribose)polymerase(PARP)inhibitors have established the DDR as a therapeutic target,many tumors evade first-generation drugs by rewiring their adaptive repair pathways and imposing microenvironmental constraints.This review synthesizes recent discoveries in key DDR pathways,such as PARP,ataxia telangiectasia and Rad3-related kinase(ATR),ataxia telangiectasia mutated kinase(ATM),checkpoint kinase 1(CHK1),WEE1 G2 checkpoint kinase(WEE1),and DNA-dependent protein kinase(DNA-PK),and describes the next-generation inhibitors designed to increase selectivity and circumvent resistance.We also analyze the role of hypoxia,stromal remodeling,inflammatory cytokines,and immune-cell plasticity in the tumor microenvironment in determining DDR dependency and response.Special attention is paid to cGAS-STING,immunogenic signaling via damage-associated molecular patterns(DAMPs),and mechanisms that convert a cold tumor into a hot one.Lastly,we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics,target resistant tumor niches,and expand the possibilities for combinatorics with immunotherapy and radiotherapy.Collectively,these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate,durable,and context-specific cancer therapy.展开更多
As a representative insensitive high explosive,3-nitro-1,2,4-triazol-5-one(NTO)has garnered significant attention due to its ability to substantially reduce the risk of accidental detonation in munitions.However,its i...As a representative insensitive high explosive,3-nitro-1,2,4-triazol-5-one(NTO)has garnered significant attention due to its ability to substantially reduce the risk of accidental detonation in munitions.However,its inherent acidity induces severe interfacial corrosion of metal casings,thereby limiting its engineering applications.Based on the micro-corrosion mechanism of NTO on carbon steel(CS),this study designs an arginine-derived corrosion inhibitor,N2-[(phenylamino)thioxomethyl]-arginine(PTA).Electrochemical tests reveal that PTA exhibits an outstanding corrosion inhibition efficiency of 98.0%in NTO solution.Density functional theory(DFT)and molecular dynamics(MD)simulations elucidate the inhibition mechanism of PTA,demonstrating that it not only co-adsorbs with NTO^(−) onto the CS surface to form a dense and stable protective film but also disrupts the strong interactions between NTO^(−) and Fe,thereby suppressing nitro group-induced reduction,decomposition,and excessive surface oxidation.Furthermore,a PTA-loaded mesoporous silica(mSiO_(2))nanoparticles(NPs)-reinforced epoxy resin(EP)composite coating was constructed.Benefiting from the enhanced barrier properties of PTA@mSiO_(2) NPs and the synergistic effect between PTA and NTO^(−),the low-frequency impedance of the composite coating remained as high as 1.29×10^(9)Ω·cm^(2) after 30 days of immersion in NTO solution,exhibiting a two-order-of-magnitude improvement compared to the pure EP coating.This study proposes an effective corrosion control strategy to mitigate NTO-induced corrosion,providing insights into the development of advanced corrosion protection strategies for broader applications.展开更多
Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenv...Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.展开更多
The detection of acyl homoserine lactones（AHLs） in activated sludge is essential for clarifying their function in wastewater treatment processes. An LC–MS/MS method was developed for the detection of AHLs in both t...The detection of acyl homoserine lactones（AHLs） in activated sludge is essential for clarifying their function in wastewater treatment processes. An LC–MS/MS method was developed for the detection of AHLs in both the aqueous and solid phases of activated sludge. In addition, the effects of proteases and extracellular polymeric substances（EPS） on the detection of AHLs were evaluated by adding protease inhibitors and extracting EPS,respectively. Recoveries of each AHL were improved by adding 50 μL of protease inhibitor,and recoveries were also improved from 0 to 56.9% to 24.2%–105.8% by EPS extraction.Applying the developed method to determine the type and concentration of AHLs showed that C4-HSL, C6-HSL, C8-HSL and 3-oxo-C8-HSL were widely detected in a suspended activated sludge system. The dominant AHL was C8-HSL, with a highest concentration of304.3 ng/L. C4-HSL was mainly distributed in the aqueous phase, whereas C6-HSL, C8-HSL and 3-oxo-C8-HSL were preferentially distributed in the sludge phase.展开更多
Background:Urinary tract infections(UTIs)caused by uropathogenic E.coli(UPEC)pose a global health challenge,largely due to UPEC bioflms that drive persistent infections and antibiotic resistance.Materials and methods:...Background:Urinary tract infections(UTIs)caused by uropathogenic E.coli(UPEC)pose a global health challenge,largely due to UPEC bioflms that drive persistent infections and antibiotic resistance.Materials and methods:To explore the role of UPEC bioflms in antibiotic-resistant UTIs and summarize emerging therapeutic strategies,this study conducted a systematic review adhering to PRISMA guidelines and registered in PROSPERO(CRD420251040212).A structured search of Pub Med,Google Scholar,Scopus,and Web of Science identifed English-language studies published up to 2024,with 57 eligible studies selected after three-stage screening and analyzed via thematic synthesis.Results:This study explored UPEC bioflms enhance resistance through extracellular matrix barriers,persister cell formation,efflux pump upregulation,and horizontal gene transfer;emerging therapies including bacteriophage therapy,quorum-sensing inhibitors,and nanoparticle-based drug delivery effectively target bioflms by penetration,signaling disruption,and improved drug effcacy.Additional approaches such as antibioflm peptides,probiotics,and immunotherapy also demonstrate potential.Conclusions:The UPEC bioflms are key to chronic UTIs,and novel targeted therapies offer promising solutions,but clinical validation,regulatory hurdles,and combination therapy optimization are critical for translation to clinical practice.展开更多
Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. In Gram-positive bacteria, oligopeptides (called autoinducers) are the signaling molecules to elicit quorum sensin...Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. In Gram-positive bacteria, oligopeptides (called autoinducers) are the signaling molecules to elicit quorum sensing. In Bacillus thuringiensis, NprR is a transcriptional regulator whose activity depends on the NprX signalling peptide. Bacillus thuringiensis is closely related to Bacillus cereus and Bacillus anthracis. The principal difference between them is that Bacillus thuringiensis is the only one that produced Cry protein. The aim of this study is to explore the relation of nprR and 16S rRNA genes in Bacillus thurin-giensis. Phylogenetic trees of nucleotide sequences of nprR and 16S rRNA genes were built. Sequences of fourteen new isolates from Papaloapan region were included in those phylo-genetic trees. In order to identify the isolates, a simple and fast methodology considering the Cry protein formation was used. The 16S rRNA phylogenetic tree allows identify eight isolates as Bacillus thuringiensis and the others as Bacillus spp. The nprR phylogenetic tree does not match with the 16S rRNA phylogenetic tree. This confirms that nprR is not a molecular marker for evolution. Most of the new isolates have the same NprR sequence (WTSDIVG). However, the SKPDIVG is the most common NprR sequence in thuringiensis species.展开更多
The atmospheric corrosion monitoring(ACM)technique has been widely employed to track the real-time corrosion behavior of metal materials.However,limited studies have applied ACM to the corrosion protection properties ...The atmospheric corrosion monitoring(ACM)technique has been widely employed to track the real-time corrosion behavior of metal materials.However,limited studies have applied ACM to the corrosion protection properties of organic coatings.This study compared a bare epoxy coating with one containing zinc phosphate corrosion inhibitors,both applied on ACM sensors,to observe their corrosion protection properties over time.Coatings with artificial damage via scratches were exposed to immersion and alternating dry and wet environments,which allowed for monitoring galvanic corrosion currents in real-time.Throughout the corrosion tests,the ACM currents of the zinc phosphate/epoxy coating were considerably lower than those of the blank epoxy coating.The trend in ACM current variations closely matched the results obtained from regular electrochemical tests and surface analysis.This alignment highlights the potential of the ACM technique in evaluating the corrosion protection capabilities of organic coatings.Compared with the blank epoxy coating,the zinc phosphate/epoxy coating showed much-decreased ACM current values that confirmed the effective inhibition of zinc phosphate against steel corrosion beneath the damaged coating.展开更多
The DDR(DNA damage response)is an essential cellular mechanism that detects and repairs DNA lesions to maintain genomic stability.Dysregulation of DDR pathways is frequently observed in human tumors,leading to increas...The DDR(DNA damage response)is an essential cellular mechanism that detects and repairs DNA lesions to maintain genomic stability.Dysregulation of DDR pathways is frequently observed in human tumors,leading to increased genomic instability and promoting tumor progression.Consequently,targeting DDR mechanisms has emerged as a promising therapeutic strategy in oncology.This review provides an overview of the major DDR pathways,highlighting the roles of key proteins involved in various DDR processes.A detailed understanding of these molecular mechanisms has paved the way for the development of targeted antitumor agents,including inhibitors of PARP1,ATM,ATR,CHK1,CHK2,DNA-PK,and WEE1.Additionally,the significant challenges in the development of DDR inhibitors are examined,including tumor microenvironment heterogeneity,resistance mechanisms,issues with selectivity and toxicity,and the complexities associated with clinical trial design.Finally,future directions and emerging strategies to improve DDR-targeted therapies are discussed.These strategies include biomarker-driven precision medicine,novel combination therapies,advanced drug delivery systems,and the potential application of artificial intelligence to optimize treatment outcomes.展开更多
Objectives:Monitoring of Cancer Antigen 125(CA125)during ovarian cancer(OC)maintenance treatment with poly(ADP-ribose)polymerase inhibitors(PARPis)may be insufficient when using Gynecologic Cancer Intergroup(GCIG)bioc...Objectives:Monitoring of Cancer Antigen 125(CA125)during ovarian cancer(OC)maintenance treatment with poly(ADP-ribose)polymerase inhibitors(PARPis)may be insufficient when using Gynecologic Cancer Intergroup(GCIG)biochemical progression criteria.This study aimed to evaluate the usefulness of CA125 monitoring in detecting OC recurrence during PARPis maintenance treatment.Methods:This multicenter retrospective cohort study included patients with primary OC who achieved complete or partial response after first-line platinum-based chemotherapy followed by PARPis maintenance treatment.Progressionwas defined using Response EvaluationCriteria in Solid Tumors(RECIST)and GCIG biochemical criteria.New biochemical progression definitions,based on CA125 nadir determined using receiver operating characteristic(ROC)curve analysis,were proposed.Concordance between radiological and biochemical progression was assessed.Results:Of 142 patients,progression was detected in 54(38.03%)and 29(20.42%)using RECIST and GCIG criteria,respectively.The sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)of the GCIG criteria were 53.70%[95%confidence interval(CI):39.61%–67.38%],100.00%[95%CI:95.91%–100.00%],100.00%[95%CI:88.10%–100.00%]and 77.88%[95%CI:72.54%–82.43%],respectively.A cut-off of 1.59×nadir achieved 88.90%sensitivity and 87.20%specificity[Area Under Curve(AUC):91.10%,95%CI:84.70%–97.40%]with a false positive rate(FPR)of 12.67%.Defining biochemical progression as an increase in CA125 of≥3×nadir achieved sensitivity,specificity,PPV,NPV,and FPR of 79.63%[95%CI:66.47%–89.37%],98.86%[95%CI:93.83%–99.97%],97.73%[95%CI:85.91%–99.67%],88.78%[95%CI:82.35%–93.06%],and 1.14%,respectively.Diagnostic accuracy was higher using the≥3×nadir criterion compared with GCIG definition(91.55%vs.82.39%).Conclusion:GCIG biochemical progression criteria during PARPis maintenance treatment after first-line chemotherapymissed 46.3%of progressing patients.Anewcriterion—CA125≥3×nadir—improves sensitivity and NPV,while maintaining high specificity,offering a simple and practical approach for clinical implementation.展开更多
A pyrimidine derivative,6-phenyl-2-thiouracil(PT),was synthesized for developing a corrosion inhibitor(CI)applied in the protection of the nickel−aluminum bronze(NAB)in seawater.The anti-corrosion effect of PT was eva...A pyrimidine derivative,6-phenyl-2-thiouracil(PT),was synthesized for developing a corrosion inhibitor(CI)applied in the protection of the nickel−aluminum bronze(NAB)in seawater.The anti-corrosion effect of PT was evaluated by the mass loss experiment,electrochemical tests and surface analysis.The results show that PT exhibits excellent inhibition performance and the maximum inhibition efficiency of PT reaches 99.6%.The interaction mechanism was investigated through X-ray photoelectron spectroscopy(XPS)and molecule dynamics simulation based on the density functional theory(DFT).The S-Cu,Al-N and Cu-N bonds are formed by the chemical interactions,leading to the adsorption of PT on the NAB surface.The diffusion of corrosive species is hindered considerably by the protective PT film with composition of(PT-Cu)_(ads)and(PT-Al)_(ads)on the PT/NAB interface.The degree of suppression is increased with the addition of more PT molecules.展开更多
BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-rel...BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-related adverse events,including potentially life-threatening myocarditis.Moreover,ICI-induced myocarditis can be asymptomatic,necessitating early diagnosis.Specific risk factors and biomarkers for esophageal cancer remain poorly characterized.AIM To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers.METHODS A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024.RESULTS Older age,male gender,and elevated creatine kinase isoenzymes(CK-MB)and CK levels were found to be significant risk factors for asymptomatic myocarditis.The myocarditis occurrence group had higher CK-MB(3.05 ng/mL vs 5.02 ng/mL;P<0.001)and CK levels(187.29 U/L vs 212.25 U/L;P=0.005),and the predictive value of age,gender,CK,and CK-MB was low[are under the receiver operating characteristic curve(AUC)=0.579-0.608].However,their combination in a predictive model showed improved diagnostic capability,with an AUC of 0.808.CONCLUSION Age,gender,and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer.The integration of these factors into a predictive model enhances early diagnosis,facilitating personalized risk management.展开更多
Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor ...Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC_(50)=5.41 nM)than that of tubastatin A(TubA)(IC_(50)=15.11 nM),along with a favorable subtype selectivity profile(selectivity index z 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC_(50)=2.59 mM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.展开更多
文摘Piericidin A1, 3’-rhamnopiericidin A1, and a novel compound piericidin E, a new quorum-sensing (QS) inhibitor against Chromobacterium violaceum CV026, were isolated from the culture broth of Streptomyces sp. QS is well known as a microbial signaling system and controls certain types of gene expression resulting in bioluminescence, biofilm formation, swarming motility, antibiotic biosynthesis, and virulence factor production. C. violaceum CV026 is commonly used to determine qualitative and quantitative QS activity. The structures of piericidin derivatives were characterized, and their QS activities were determined.
基金supported by the National Natural Science Foundation of China(Grant No:82474158)the Natural Science Foundation of Sichuan Province,China(Grant No.:2024NSFSC0708).
文摘The rising prevalence of multidrug-resistant pathogens poses a substantial threat to global healthcare systems,demanding urgent therapeutic interventions.Microorganisms exhibit diverse resistance mechanisms against various classes of antibiotics,highlighting the urgent need to discover novel antimicrobial agents for combating bacterial infections.Anti-virulence therapy has emerged as a promising therapeutic strategy that neutralizes pathogens by targeting their virulence determinants.The strategies for screening virulence arresting drugs(VADs)in bacteria represent a multifaceted approach that involves elucidating molecular pathogenesis mechanisms of bacterial pathogenicity,identifying evolutionarily conserved virulence factors across different pathogens,and employing integrated approaches combining in silico prediction with experimental validation.Recent technological advancements have established standardized protocols for effective identification and validation of anti-virulence compounds.This review systematically examines contemporary screening methodologies,primarily focusing on quorum-sensing disruption and biofilm suppression strategies,including in silico screening,activity-based screening with bioassays,in vitro and in vivo models.Additionally,we emphasize the imperative for standardized preclinical validation through physiologically relevant animal models,while proposing framework recommendations for developing next-generation VAD screening platforms.This synthesis not only outlines current best practices but also proposes innovative avenues for future antimicrobial discovery research.
基金financially supported by National Key Research and Development Program of China (No.2021YFD1800900)National Natural Science Foundation of China (No.82073790)+2 种基金Special Fund for Youth Team of Southwest University (No.SWUXJLJ202306)Chongqing Science and Technology Commission (Nos.CSTB2022TIAD-LUX0001,CSTB2023NSCQ-JQX0002)Innovation Research 2035 Pilot Plan of Southwest University (No.SWUXDPY22007)。
文摘Chitosan(CS),a natural polymer derived from chitin found in the exoskeletons of crustaceans,has garnered significant interest in the pharmaceutical field due to its unique properties,including biocompatibility and biodegradability.In recent years,various studies have reported that CS can affect drug bioavailability,and interestingly,it works as an oral absorption enhancer and inhibitor.This review offers an in-depth analysis of the mechanisms underlying such a phenomenon and supports its application as a pharmaceutical excipient.CS enhances oral drug absorption through various mechanisms,such as interaction with the intestinal mucosa,tight junction modulation,inhibition of efflux transporters,enzyme inhibition,solubility and stability enhancement,and complexation.On the other side,CS exhibits the ability to inhibit the absorption of certain drugs by adsorbing to lipids and sterols,modulating bile acids and gut microbiota,altering drug-cell interaction at the polar interface,and mucus-mediated entrapment and interference.Future potential pharmaceutical research in this field includes elucidating the underneath absorption relevant mechanisms,rational use in formulations as excipient,exploring functional CS derivatives,and developing CS-based drug delivery systems.This comprehensive review highlights CS's versatile and significant role in enhancing and inhibiting oral drug absorption,providing insights into the complexities of drug delivery and the potential of CS to improve therapeutic outcomes.
基金financially supported by the Ministry of Science,Technological Development and Innovation of the Republic of Serbia(Nos.451-03-66/2024-03/200026,451-03-65/2024-03/200135)。
文摘The effect of low concentrated green inhibitors based on Ce-adipate and Ce-chloride on the corrosion of 7075 aluminum alloy in neutral NaCl electrolyte was studied.Corrosion studies were carried out using electrochemical impedance spectroscopy(EIS)and linear sweep voltammetry(LSV)while scanning electron microscopy(SEM)and X-ray photoelectron spectroscopy(XPS)were used to conduct surface studies of the alloy upon immersion in the corrosion media.The electrochemical experiments reveal a better inhibitory effect of Ce-adipate than Ce-chloride owing to a higher polarization resistance value(about two times),and a lower corrosion current density.However,both inhibitors act as cathodic inhibitors,show high resistance to pitting corrosion,and enable sufficient protection during prolonged immersion(240 h)in corrosion media.The XPS analysis confirms the presence of cerium in the oxidation states of Ce(III)and Ce(IV)together with the carboxylate-COO−groups and C-C and C-H bonds on the tested specimen with Ce-adipate inhibitor,which are connected to the increased anti-corrosion efficiency.
基金financially supported by the China Postdoctoral Science Foundation(No.2022M712153)The National Natural Science Foundation of China(Nos.22367007 and 82304384)+1 种基金The Fundamental Research Funds for Hainan University(No.KYQD(ZR)23002)Hainan Provincial Natural Science Foundation of China(No.824RC500)。
文摘Alzheimer's disease(AD)is a common neurodegenerative disorder among the elderly population.There are currently no effective therapeutic drugs available,the multi-target-directed ligands(MTDLs)strategy has been considered as the promising approach.Given the structural diversity of natural products,Rivastigmine's pharmacophore was integrated with diverse natural product scaffolds to construct a combinatorial compound library.This library was subsequently screened and optimized to identify a novel butyrylcholinesterase(Bu Ch E)inhibitor,compound 3c.The results showed that compound 3c exhibited favorable Bu Ch E inhibitory activity(half-maximal inhibitory concentration(IC_(50))=0.43μmol/L),potential anti-inflammatory potency,good Aβ_(1-42) aggregation inhibitory capacity and remarkable neuroprotective effects.The in vivo study exhibited that 3c significantly ameliorated AlCl_(3)-induced zebrafish AD model and scopolamine-induced memory impairment.Collectively,compound 3c was the artificial intelligence(AI)-driven promising multifunctional agent with Bu Ch E inhibition for the treatment of AD.
基金Supported by Open Project of Jiangsu Province Key Laboratory of Integrated Traditional Chinese and Western Medicine for the Prevention and Treatment of Geriatric Diseases,No.202232.
文摘BACKGROUND Post-stroke depression(PSD)is associated with hypothalamic-pituitary-adrenal(HPA)axis dysfunction and neurotransmitter deficits.Selective serotonin reuptake inhibitors(SSRIs)are commonly used,but their efficacy is limited.This study investigated whether combining SSRIs with traditional Chinese medicine(TCM)Free San could enhance their therapeutic effects.AIM To evaluate the clinical efficacy and safety of combining SSRIs with Free San in treating PSD,and to assess its impact on HPA axis function.METHODS Ninety-two patients with PSD were enrolled and randomly divided into control groups(n=46)and study groups(n=46).The control group received the SSRI paroxetine alone,whereas the study group received paroxetine combined with Free San for 4 weeks.Hamilton Depression Scale and TCM syndrome scores were assessed before and after treatment.Serum serotonin,norepinephrine,cortisol,cor-ticotropin-releasing hormone,and adrenocorticotropic hormone were measured.The treatment responses and adverse reactions were recorded.RESULTS After treatment,the Hamilton Depression Scale and TCM syndrome scores were significantly lower in the study group than in the control group(P<0.05).Serum serotonin and norepinephrine levels were significantly higher in the study group than in the control group,whereas cortisol,corticotropin-releasing hormone,and adrenocorticotropic hormone levels were significantly lower(P<0.05).The total efficacy rates were 84.78%and 65.22%in the study and control groups,respectively(P<0.05).No significant differences in adverse reactions were observed between the two groups(P>0.05).CONCLUSION Combining SSRIs with Free San can enhance therapeutic efficacy,improve depressive symptoms,and regulate HPA axis function in patients with PSD with good safety and clinical application value.
文摘Acute myeloid leukemia(AML)remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes.The development of menin inhibitors represents a promising shift,particularly for patients harboring KMT2A rearrangements(KMT2Ar)and NPM1 mutations(NPM1m).This manuscript reviews the molecular rationale of menin inhibition for aberrant homeobox/myeloid ectopic insertion site 1(HOX/MEIS1)-driven gene expression and leukemogenesis,clinical trial outcomes,and safety data for menin inhibitors,with a focus on recently FDA-approved revumenib and several other agents in development,ziftomenib(KO-539),bleximenib(JNJ-75276617),and icovamenib(BMF-219).We also focused our discussion on future directions to include resistance mechanisms,biomarker identification and monitoring strategies,and combination therapies.Menin inhibition is now being clinically integrated into relapsed/refractory and frontline treatment settings.
文摘Tumor survival,genomic stability,and therapy resistance are dictated by the DNA damage response(DDR).Although poly(ADP-ribose)polymerase(PARP)inhibitors have established the DDR as a therapeutic target,many tumors evade first-generation drugs by rewiring their adaptive repair pathways and imposing microenvironmental constraints.This review synthesizes recent discoveries in key DDR pathways,such as PARP,ataxia telangiectasia and Rad3-related kinase(ATR),ataxia telangiectasia mutated kinase(ATM),checkpoint kinase 1(CHK1),WEE1 G2 checkpoint kinase(WEE1),and DNA-dependent protein kinase(DNA-PK),and describes the next-generation inhibitors designed to increase selectivity and circumvent resistance.We also analyze the role of hypoxia,stromal remodeling,inflammatory cytokines,and immune-cell plasticity in the tumor microenvironment in determining DDR dependency and response.Special attention is paid to cGAS-STING,immunogenic signaling via damage-associated molecular patterns(DAMPs),and mechanisms that convert a cold tumor into a hot one.Lastly,we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics,target resistant tumor niches,and expand the possibilities for combinatorics with immunotherapy and radiotherapy.Collectively,these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate,durable,and context-specific cancer therapy.
文摘As a representative insensitive high explosive,3-nitro-1,2,4-triazol-5-one(NTO)has garnered significant attention due to its ability to substantially reduce the risk of accidental detonation in munitions.However,its inherent acidity induces severe interfacial corrosion of metal casings,thereby limiting its engineering applications.Based on the micro-corrosion mechanism of NTO on carbon steel(CS),this study designs an arginine-derived corrosion inhibitor,N2-[(phenylamino)thioxomethyl]-arginine(PTA).Electrochemical tests reveal that PTA exhibits an outstanding corrosion inhibition efficiency of 98.0%in NTO solution.Density functional theory(DFT)and molecular dynamics(MD)simulations elucidate the inhibition mechanism of PTA,demonstrating that it not only co-adsorbs with NTO^(−) onto the CS surface to form a dense and stable protective film but also disrupts the strong interactions between NTO^(−) and Fe,thereby suppressing nitro group-induced reduction,decomposition,and excessive surface oxidation.Furthermore,a PTA-loaded mesoporous silica(mSiO_(2))nanoparticles(NPs)-reinforced epoxy resin(EP)composite coating was constructed.Benefiting from the enhanced barrier properties of PTA@mSiO_(2) NPs and the synergistic effect between PTA and NTO^(−),the low-frequency impedance of the composite coating remained as high as 1.29×10^(9)Ω·cm^(2) after 30 days of immersion in NTO solution,exhibiting a two-order-of-magnitude improvement compared to the pure EP coating.This study proposes an effective corrosion control strategy to mitigate NTO-induced corrosion,providing insights into the development of advanced corrosion protection strategies for broader applications.
文摘Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.
基金supported by the National Key Research and Development Program of China for International Science and Innovation Cooperation Major Project between Governments(No.2016YFE0118800)the Shenzhen Science and Technology Development Funding-Fundamental Research Plan(No.JCYJ20150331151358156)
文摘The detection of acyl homoserine lactones（AHLs） in activated sludge is essential for clarifying their function in wastewater treatment processes. An LC–MS/MS method was developed for the detection of AHLs in both the aqueous and solid phases of activated sludge. In addition, the effects of proteases and extracellular polymeric substances（EPS） on the detection of AHLs were evaluated by adding protease inhibitors and extracting EPS,respectively. Recoveries of each AHL were improved by adding 50 μL of protease inhibitor,and recoveries were also improved from 0 to 56.9% to 24.2%–105.8% by EPS extraction.Applying the developed method to determine the type and concentration of AHLs showed that C4-HSL, C6-HSL, C8-HSL and 3-oxo-C8-HSL were widely detected in a suspended activated sludge system. The dominant AHL was C8-HSL, with a highest concentration of304.3 ng/L. C4-HSL was mainly distributed in the aqueous phase, whereas C6-HSL, C8-HSL and 3-oxo-C8-HSL were preferentially distributed in the sludge phase.
文摘Background:Urinary tract infections(UTIs)caused by uropathogenic E.coli(UPEC)pose a global health challenge,largely due to UPEC bioflms that drive persistent infections and antibiotic resistance.Materials and methods:To explore the role of UPEC bioflms in antibiotic-resistant UTIs and summarize emerging therapeutic strategies,this study conducted a systematic review adhering to PRISMA guidelines and registered in PROSPERO(CRD420251040212).A structured search of Pub Med,Google Scholar,Scopus,and Web of Science identifed English-language studies published up to 2024,with 57 eligible studies selected after three-stage screening and analyzed via thematic synthesis.Results:This study explored UPEC bioflms enhance resistance through extracellular matrix barriers,persister cell formation,efflux pump upregulation,and horizontal gene transfer;emerging therapies including bacteriophage therapy,quorum-sensing inhibitors,and nanoparticle-based drug delivery effectively target bioflms by penetration,signaling disruption,and improved drug effcacy.Additional approaches such as antibioflm peptides,probiotics,and immunotherapy also demonstrate potential.Conclusions:The UPEC bioflms are key to chronic UTIs,and novel targeted therapies offer promising solutions,but clinical validation,regulatory hurdles,and combination therapy optimization are critical for translation to clinical practice.
文摘Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. In Gram-positive bacteria, oligopeptides (called autoinducers) are the signaling molecules to elicit quorum sensing. In Bacillus thuringiensis, NprR is a transcriptional regulator whose activity depends on the NprX signalling peptide. Bacillus thuringiensis is closely related to Bacillus cereus and Bacillus anthracis. The principal difference between them is that Bacillus thuringiensis is the only one that produced Cry protein. The aim of this study is to explore the relation of nprR and 16S rRNA genes in Bacillus thurin-giensis. Phylogenetic trees of nucleotide sequences of nprR and 16S rRNA genes were built. Sequences of fourteen new isolates from Papaloapan region were included in those phylo-genetic trees. In order to identify the isolates, a simple and fast methodology considering the Cry protein formation was used. The 16S rRNA phylogenetic tree allows identify eight isolates as Bacillus thuringiensis and the others as Bacillus spp. The nprR phylogenetic tree does not match with the 16S rRNA phylogenetic tree. This confirms that nprR is not a molecular marker for evolution. Most of the new isolates have the same NprR sequence (WTSDIVG). However, the SKPDIVG is the most common NprR sequence in thuringiensis species.
基金financially supported by the National Natural Science Foundation of China(No.52371049)the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology(YESS,No.2020QNRC001)the National Science and Technology Resources Investigation Program of China(Nos.2021FY100603 and 2019FY101404)。
文摘The atmospheric corrosion monitoring(ACM)technique has been widely employed to track the real-time corrosion behavior of metal materials.However,limited studies have applied ACM to the corrosion protection properties of organic coatings.This study compared a bare epoxy coating with one containing zinc phosphate corrosion inhibitors,both applied on ACM sensors,to observe their corrosion protection properties over time.Coatings with artificial damage via scratches were exposed to immersion and alternating dry and wet environments,which allowed for monitoring galvanic corrosion currents in real-time.Throughout the corrosion tests,the ACM currents of the zinc phosphate/epoxy coating were considerably lower than those of the blank epoxy coating.The trend in ACM current variations closely matched the results obtained from regular electrochemical tests and surface analysis.This alignment highlights the potential of the ACM technique in evaluating the corrosion protection capabilities of organic coatings.Compared with the blank epoxy coating,the zinc phosphate/epoxy coating showed much-decreased ACM current values that confirmed the effective inhibition of zinc phosphate against steel corrosion beneath the damaged coating.
文摘The DDR(DNA damage response)is an essential cellular mechanism that detects and repairs DNA lesions to maintain genomic stability.Dysregulation of DDR pathways is frequently observed in human tumors,leading to increased genomic instability and promoting tumor progression.Consequently,targeting DDR mechanisms has emerged as a promising therapeutic strategy in oncology.This review provides an overview of the major DDR pathways,highlighting the roles of key proteins involved in various DDR processes.A detailed understanding of these molecular mechanisms has paved the way for the development of targeted antitumor agents,including inhibitors of PARP1,ATM,ATR,CHK1,CHK2,DNA-PK,and WEE1.Additionally,the significant challenges in the development of DDR inhibitors are examined,including tumor microenvironment heterogeneity,resistance mechanisms,issues with selectivity and toxicity,and the complexities associated with clinical trial design.Finally,future directions and emerging strategies to improve DDR-targeted therapies are discussed.These strategies include biomarker-driven precision medicine,novel combination therapies,advanced drug delivery systems,and the potential application of artificial intelligence to optimize treatment outcomes.
文摘Objectives:Monitoring of Cancer Antigen 125(CA125)during ovarian cancer(OC)maintenance treatment with poly(ADP-ribose)polymerase inhibitors(PARPis)may be insufficient when using Gynecologic Cancer Intergroup(GCIG)biochemical progression criteria.This study aimed to evaluate the usefulness of CA125 monitoring in detecting OC recurrence during PARPis maintenance treatment.Methods:This multicenter retrospective cohort study included patients with primary OC who achieved complete or partial response after first-line platinum-based chemotherapy followed by PARPis maintenance treatment.Progressionwas defined using Response EvaluationCriteria in Solid Tumors(RECIST)and GCIG biochemical criteria.New biochemical progression definitions,based on CA125 nadir determined using receiver operating characteristic(ROC)curve analysis,were proposed.Concordance between radiological and biochemical progression was assessed.Results:Of 142 patients,progression was detected in 54(38.03%)and 29(20.42%)using RECIST and GCIG criteria,respectively.The sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)of the GCIG criteria were 53.70%[95%confidence interval(CI):39.61%–67.38%],100.00%[95%CI:95.91%–100.00%],100.00%[95%CI:88.10%–100.00%]and 77.88%[95%CI:72.54%–82.43%],respectively.A cut-off of 1.59×nadir achieved 88.90%sensitivity and 87.20%specificity[Area Under Curve(AUC):91.10%,95%CI:84.70%–97.40%]with a false positive rate(FPR)of 12.67%.Defining biochemical progression as an increase in CA125 of≥3×nadir achieved sensitivity,specificity,PPV,NPV,and FPR of 79.63%[95%CI:66.47%–89.37%],98.86%[95%CI:93.83%–99.97%],97.73%[95%CI:85.91%–99.67%],88.78%[95%CI:82.35%–93.06%],and 1.14%,respectively.Diagnostic accuracy was higher using the≥3×nadir criterion compared with GCIG definition(91.55%vs.82.39%).Conclusion:GCIG biochemical progression criteria during PARPis maintenance treatment after first-line chemotherapymissed 46.3%of progressing patients.Anewcriterion—CA125≥3×nadir—improves sensitivity and NPV,while maintaining high specificity,offering a simple and practical approach for clinical implementation.
基金supported by the National Natural Science Foundation of China(No.52171069).
文摘A pyrimidine derivative,6-phenyl-2-thiouracil(PT),was synthesized for developing a corrosion inhibitor(CI)applied in the protection of the nickel−aluminum bronze(NAB)in seawater.The anti-corrosion effect of PT was evaluated by the mass loss experiment,electrochemical tests and surface analysis.The results show that PT exhibits excellent inhibition performance and the maximum inhibition efficiency of PT reaches 99.6%.The interaction mechanism was investigated through X-ray photoelectron spectroscopy(XPS)and molecule dynamics simulation based on the density functional theory(DFT).The S-Cu,Al-N and Cu-N bonds are formed by the chemical interactions,leading to the adsorption of PT on the NAB surface.The diffusion of corrosive species is hindered considerably by the protective PT film with composition of(PT-Cu)_(ads)and(PT-Al)_(ads)on the PT/NAB interface.The degree of suppression is increased with the addition of more PT molecules.
文摘BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-related adverse events,including potentially life-threatening myocarditis.Moreover,ICI-induced myocarditis can be asymptomatic,necessitating early diagnosis.Specific risk factors and biomarkers for esophageal cancer remain poorly characterized.AIM To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers.METHODS A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024.RESULTS Older age,male gender,and elevated creatine kinase isoenzymes(CK-MB)and CK levels were found to be significant risk factors for asymptomatic myocarditis.The myocarditis occurrence group had higher CK-MB(3.05 ng/mL vs 5.02 ng/mL;P<0.001)and CK levels(187.29 U/L vs 212.25 U/L;P=0.005),and the predictive value of age,gender,CK,and CK-MB was low[are under the receiver operating characteristic curve(AUC)=0.579-0.608].However,their combination in a predictive model showed improved diagnostic capability,with an AUC of 0.808.CONCLUSION Age,gender,and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer.The integration of these factors into a predictive model enhances early diagnosis,facilitating personalized risk management.
基金funded by Central Guidance on Local Science and Technology Development Fund of Hebei Province,China(Grant No.:226Z2605G)the Key Project from Hebei Provincial Department of Science and Technology,China(Grant No.:21372601D)+6 种基金Graduate Student Innovation Grant Program of Hebei Medical University,China(Grant No.:XCXZZB202303)Science Research Project of Hebei Education Department,China(Grant Nos.:BJ2025046,and CYZD202501)Program for Young Scientists in the Field of Natural Science of Hebei Medical University,China(Program Nos.:CYCZ2023010,CYCZ2023011,CYQD2021011,CYQD2021015 and CYQD2023012)Traditional Chinese Medicine Administration Project of Hebei Province,China(Project No.:2025427)National Natural Science Foundation of China(Grant No.:32100771)the Hebei Provincial Medical Science Research Project Plan,China(Project Nos.:20240241 and 20220200)Shijiazhuang Science and Technology Bureau,China(Grant Nos.:241200487A,and 07202204).
文摘Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC_(50)=5.41 nM)than that of tubastatin A(TubA)(IC_(50)=15.11 nM),along with a favorable subtype selectivity profile(selectivity index z 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC_(50)=2.59 mM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.
