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 (IC₅₀ = 5.41 nM) than that of tubastatin A (TubA) (IC₅₀ = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 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 (IC₅₀ = 2.59 μM). 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.

Objective To evaluate the efficacy and safety of amoxicillin-clavulanate(10∶1)for injection in the treatment of community-acquired pneumonia(CAP)in adult patients.Methods Eligible patients were randomized to receive amoxicillin-clavulanate(10∶1)2.2 g or ampicillin-sulbactam(2∶1)3.0 g via intravenous infusion q12h or q8h for 7 to 14 days.The primary endpoint was to the clinical efficacy 7-14 days after discontinuation of treatment.The secondary endpoints included microbiological efficacy and safety.Results All enrolled patients(n=324)were included in the full analysis set(FAS),specifically 165 patients receiving amoxicillin sodium-clavulanate potassium(10∶1)and 159 patients receiving ampicillin sodium-sulbactam sodium(2∶1).The clinical cure rate was 78.8％(130/165)for amoxicillin-clavulanate(10∶1)and 77.4％(123/159)for ampicillin-sulbactam 7-14 days after end of treatment(P＞0.05).The clinical cure rate was 87.5％(126/144)for amoxicillin-clavulanate(10∶1)and 87.4％(111/127)for ampicillin-sulbactam(2∶1)in per protocol set(P＞0.05).Therefore,amoxicillin-clavulanate(10∶1)was non-inferior to ampicillin-sulbactam in the primary endpoint in the treatment of CAP in adult patients.The overall bacterial eradication rate was 94.4％(34/36)for amoxicillin-clavulanate(10∶1)and 89.3％(25/28)for ampicillin-sulbactam(P＞0.05).The common study drug-related clinical adverse event were abnormalities of hepatic function in both the amoxicillin-clavulanate(10∶1)group(4.8％,8/165)and ampicillin-sulbactam group(3.1％,5/159)(P＞0.05).Conclusions Amoxicillin-clavulanate(10∶1)2.2 g Ⅳ infusion q12h or q8h for 7-14 days was noninferior to ampicillin-sulbactam in terms of clinical and microbiological efficacy in the treatment of CAP in adult patients.The safety of the two dosing regimens was comparable.

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(IC50=5.41 nM)than that of tubastatin A(TubA)(IC50=15.11 nM),along with a favorable subtype selectivity profile(selectivity index ≈ 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(IC50=2.59 μM).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.

This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Nav1.7,Nay1.8,and Nay1.9 and Kv7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Nav1.7,Nav1.8,and Nav1.9 channels with a particularly low half maximal inhibitory concentration(ICs0)for Nay1.9 by promoting sodium channel inactivation,and also effectively increased Kv7.2/73,Kv7.2,and Kv7.5 channels,excluding Kv7.1 by promoting potassium channel acti-vation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alle-viated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe thera-peutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.

Objective To develop a rapid and accurate ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)method for the detection of etomidate,metomidate,propoxate,and isopropoxate in human hair.Methods Hair samples containing etomidate,metomidate,propoxate,and isopropoxate were extracted with methanol containing the internal standard orthoxine,filtered with a 0.22 μm organic filter membrane and detected vio UPLC-MS/MS.All components were separated by using a gradient elution procedure consisting of 0.01％formic acid(1 mmol/L ammonium acetate)and acetonitrile.Positive electrospray ionization was performed using multiple reaction monitoring(MRM)mode.Results The linear relationships of etomidate,metomidate,propoxate,and isopropoxate were good in the range of 0.01～1 ng/mg(r ≥ 0.997 9),with recovery rates ranging from 87.9％to 101.5％.The accuracy was between 80.0％and 110.0％.The intra-day and inter-day relative standard deviations(RSD)were 2.9％～9.6％and 3.6％～19.9％.Conclusion This method is easy to operate and has high recovery efficiencies.It is sufficiently simple and sensitive to be applied to detect etomidate,metomidate,propoxate,and isopropoxate in hair.

Vascular cognitive impairment (VCI), caused by cerebrovascular dysfunction, severely impacts the quality of life in the elderly population, yet effective therapeutic approaches remain limited. Mitophagy, a selective mitochondrial quality-control mechanism, has emerged as a critical focus in neurological disease research. Accumulating evidence indicates that mitophagy modulates oxidative stress, neuroinflammation, and neuronal apoptosis. Key signaling pathways associated with mitophagy—including PINK1/Parkin, BNIP3/Nix, FUNDC1, PI3K/Akt/mTOR, and AMPK—have been identified as potential therapeutic targets for VCI. This review summarizes the mechanistic roles of mitophagy in VCI pathogenesis and explores emerging therapeutic strategies targeting these pathways, aiming to provide novel insights for clinical intervention and advance the development of effective treatments for VCI.

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Objective:To prepare the nanodrug paclitaxel dimer(PTX2)-loaded nanoparticles(NPs)using the block copolymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000,(DSPE-PEG2000),and to explore the killing effect of PTX2 NPs on the human lung cancer A549 cells and its influence on apop to tis.Methods:The PTX2 NPs were prepared using nanoprecipitation method.Dynamic light scattering(DLS)was employed to determine the particle size distribution,and transmission electron microscope(TEM)was used to observe the ultrastructure of the nanoparticles.After treatment of 0 and 10 mmol·L-1 dithiothreitol(DTT),dialysis method was used to evaluate the in vitro drug release profile of PTX2 NPs.The cell counting kit-8(CCK-8)method was used to assess the survival rates of the A549 cells after treated with PTX2 and PTX2 NPs with different concentrations(0.000 1,0.001 0,0.010 0,0.100 0,and 1.000 0 μmol·L-1).The A549 cells were divided into control group,PTX2 group,and PTX2 NPs group.Live/dead staining method was used to detect the survival of the A549 cells in various groups,and flow cytometry was used to detect the apoptotic rates of the A549 cells in various groups.Results:The mean hydrodynamic diameter of PTX2 NPs was determined to be 144.7nmbyDLS.TheTEM imaging confirmed uniform spherical morphology of PTX2 NPs.In a reductive environment,the PTX2 NPs exhibited continuous drug release with total paclitaxel(PTX)release of 84％within 72 h.The results of CCK-8 method showed that both PTX2 and PTX2 NPs inhibited the proliferation of A549 cells in a dose-dependent manner.When the concentrations of PTX＜0.01 μmol·L-1,compared with PTX2 group,the survival rates of A549 cells in PTX2 NPs group were significantly decreased(P＜0.01 or P＜0.001).The live/dead staining results showed that compared with PTX2 group,the number of red fluorescence-labeled dead cells in PTX2 NPs group was increased.The flow cytometry results demonstrated that compared with control group and PTX2 group,the apoptotic rates of the A549 cells in PTX2 NPs group were significantly increased(P＜0.05 orP＜0.01).Conclusion:The PTX2-loaded nanoparticles PTX2 NPs are successfully prepared which exhibits responsive drug release and demonstrates a more significant killing effect on the human lung cancer A549 cells compared to PTX2.

Extensive tissue and organ defects caused by major trauma and burns are common problems in clinical practice. Recombinant human collagen biomaterials, with advantages including impeccable biocompatibility, customization, stable amino acid sequence, low immunogenicity, and inherent biodegradation, have been widely used in the field of tissue engineering and have broad clinical application prospects. This paper briefly summarizes the design and preparation methods, processing techniques of recombinant human collagen biomaterials and their application in the field of tissue engineering, as well as the latest research advances.