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.

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.

Chronic kidney disease (CKD) is a major public health problem worldwide. When CKD patients progress to the stage of kidney failure, kidney replacement therapy (KRT) or conservative treatment (palliative or non-dialysis treatment) will be needed. The risk prediction models of chronic kidney failure have been developed in recent years. These models, focusing on demographic indicators, clinical indicators, and laboratory data, are used to predict the likelihood of progression to kidney failure and requiring KRT. This article will retrieve prediction models for chronic kidney failure as an outcome, demonstrate the current research progress, and hope that it may be helpful for the strategies of preventing chronic kidney failure.

Chronic kidney disease (CKD) is a major public health problem worldwide. When CKD patients progress to the stage of kidney failure, kidney replacement therapy (KRT) or conservative treatment (palliative or non-dialysis treatment) will be needed. The risk prediction models of chronic kidney failure have been developed in recent years. These models, focusing on demographic indicators, clinical indicators, and laboratory data, are used to predict the likelihood of progression to kidney failure and requiring KRT. This article will retrieve prediction models for chronic kidney failure as an outcome, demonstrate the current research progress, and hope that it may be helpful for the strategies of preventing chronic kidney failure.

Objective To investigate the distribution and antibiotic resistance profiles of the bacterial strains isolated from urine samples in a tertiary Traditional Chinese Medicine hospital in Shanghai in the 12-year period from 2010 through 2021 for better empirical antibiotic use in clinical practice.Methods The clinical data of patients with urinary tract infection,including the species and antibiotic resistance of the bacterial strains isolated from urine samples from January 2010 to December 2021 were retrospectively analyzed.Results A total of 5 231 nondupliate bacterial strains were isolated,among which E.coli was the most common(52.8％),followed by Enterococcus spp(19.1％)and Klebsiella spp(11.1％).Most of the urinary isolates(76.0％)were isolated from the elderly aged 60-89,and only 3.1％of the strains were isolated from the young people aged under 44.Most of the bacterial strains were isolated from female patients(75.8％),however,more P.aeruginosa and A.baumannii were isolated from male patients compared to female patients(55.3％vs 44.7％and 67.7％vs 32.3％).About 13.7％of the strains were collected from the Department of Nephrology,more than the strains from any other clincial department.In intensive care unit(ICU),the proportion of E.coli was the lowest,while the proportion of Enterococcus spp was the highest.Enterobacterales showed lower resistance raets to carbapenems,cephamycin,amikacin,cefepime,and β-lactam/β-lactamase inhibitor combinations.P.aeruginosa showed higher susceptibility rates to carbapenems,aminoglycosides and β-lactam/β-lactamase inhibitor combinations compared to A.baumannii(≥54.6％vs≤39.8％).Gram-positive cocci were highly sensitive to glycopeptide antibiotics.No SS.aureus or E.faecalis isolates were found resistant to vancomycin.About 2.7％of the E.faecium isolates were resistant to vancomycin.The prevalence of drug-resistant bacteria was the highest in elderly patients,and in the strains isolated from ICU and emergency department.Conclusions Compared with general hospitals,a high proportion of elderly patients were treated in this hospital.It should be more cautious in the treatment of patients with urinary tract infection.The major bacterial species isolated from urine were E.coli,Enterococcus,and K.pneumoniae.Empirical treatment should be prescribed considering patient age and gender as well as the species and distribution of pathogenic bacteria.Urine culture and antibiotic susceptibility testing should be performed proactively.Appropriate antimicrobial agents should be selected according to the results of antimicrobial susceptibility testing.Antimicrobial ressitance surveillance should also be strengthened.

Autophagy is essential for the maintenance of cellular homeostasis and its dysfunction has been linked to various diseases. Autophagy is a membrane driven process and tightly regulated by membrane-associated proteins. Here, we summarized membrane lipid composition, and membrane-associated proteins relevant to autophagy from a spatiotemporal perspective. In particular, we focused on three important membrane remodeling processes in autophagy, lipid transfer for phagophore elongation, membrane scission for phagophore closure, and autophagosome-lysosome membrane fusion. We discussed the significance of the discoveries in this field and possible avenues to follow for future studies. Finally, we summarized the membrane-associated biochemical techniques and assays used to study membrane properties, with a discussion of their applications in autophagy.

Objective:To investigate the clinical value of short segment fusion and long segment fusion combined with posterior pedicle screw system internal fixation in the treatment of degenerative scoliosis.Methods:74 patients with degenerative scoliosis who were treated in the Affiliated Hospital of Southwest Medical University from January 2014 to February 2018 were enrolled in the study. The patients were divided into group A and group B with a random number table of 37 cases each. Group A was treated with short segment fusion and posterior pedicle screw system internal fixation, while group B was with long segment fusion and posterior pedicle screw system internal fixation. The Cobb angle of scoliosis, the balance of coronal and sagittal plane of spine were observed before operation, 1 week after operation, 3 months after operation and 6 months after operation, and the incidence of early and long-term complications were counted.Results:The Cobb angle of scoliosis in group B was lower than that of group A at 1 week, 3 months and 6 months after operation ( P<0.05). There was no significant difference in the balance of coronal plane and sagittal plane between the two groups at 1 week and 3 months after operation ( P>0.05). There was significant difference in the balance of coronal plane and sagittal plane between the two groups at 6 months after operation ( P<0.05). There was no significant difference in the incidence of early postoperative complications between the two groups ( P>0.05). Conclusions:Long segment fusion and posterior pedicle screw system internal fixation can improve the Cobb angle and reduce the incidence of postoperative scoliosis, but it is easy to appear the imbalance of coronal and sagittal planes, which can be selected according to the actual situation.

Objective To explore the effect of oridonin on the endoplasmic reticulum stress (ERS) in colonic epithelium of ulcerative colitis (UC) mice.Methods The UC mice model was established by sodium dextran sulfate (DSS),and the intervention group of oridonin and sulfasalazine was set up,the disease activity index (DAD was measured,the colonic tissue was evaluated by histopathologidscore (HPS),and RT-qPCR was used to detect the expression of inflammatory cytokines tumor factor-α (TNF-α),interleukin 6 (IL-6),cyclooxygenase 2 (COX-2),glucose-regulated protein 78 (GRP78),transcription factor EBP homologous protein (CHOP),activator transcription factor 6 (ATF6),protein kinase R like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme 1α (IRE1α).Results The expression of TNF-α,IL-6,COX-2,GRP78,ATF6,CHOP,PERK and IRE1α mRNA in the colonic epithelium of the model group were all up-regulated obviously as compared with the healthy control group(P＜0.05,P＜0.01).When compared with the model group,DAI and HPS in oridonin-treated group were significantly decreased (P＜0.05,P＜0.01),which the curative effect was similar to that of the sulfasalazine group(P＞0.05,P＜0.01).The expression of TNF-α,IL-6,COX-2,GRP78,CHOP,ATF6 and PERK mRNA levels were significantly reduced in oridonin-treated group(P＜ 0.05,P＜0.01).Conclusion Oridonin can alleviate colonic inflammation induced by DSS and its mechanism may be related to ERS of colonic epithelial tissue.

Objective To investigate the drug resistance situation and Staphylococcal cassette chromosome mec(SCCmec) genotypes of methicillin resistant Staphylococcus aureus (M RSA ) strains isolated from Shang-hai Putuo District People′s Hospital in order to provide a theoretical basis for predicting the trend of drug re-sistant bacterial strains and clinical treatment and prevention of MRSA .Methods Three hundreds and eighty clinically isolated MRSA strains in this hospital were collected from January 2012 to December 2016 .The in vitro drug susceptibility test was performed by adopting the broth microdilution method .The SCCmec geno-types were examined by adopting the multiplex polymerase chain reaction .Results All strains were sensitive to linezolid and vancomycin ,the sensitivity rate was 100 .0％ ;the resistance rates to rifampicin and cotrimox-azole were lower ,which were 5 .0％ and 7 .6％ respectively ;but the strains were highly resistant to erythromy-cin ,levofloxacin and tetracycline ,with the resistance rate of 100 .0％ ,94 .2％ ,93 .4％ and 90 .0％ .The resist-ance rate to penicillin was 100 .0％ .Among 380 strains of MRSA ,there were 281 strains(73 .9％ ) of SCCmecⅡ ,59 strains (15 .5％ ) of SCCmecⅢand 5 strains (1 .3％ ) of SCCmecⅣa ,other 35 strains(9 .2％ ) of MRSA could not be classified .Conclusion M RSA strains isolated in the Shanghai Putuo District People′s Hospital are mainly the type SCCmecⅡ ,w hich has the multi-drug resistant characteristics ,and the drug resistance spec-trum of different SCCmec genotypes is different .

Aim To explore the behavior and CBS /H2 S levels of hippocampus in post traumatic stress dis-order (PTSD)rats and study the effect of exogenous H2 S on PTSD rats.Methods Single prolonged stress paradigm was adopted to prepare PTSD animal model. Morris water maze test was adopted to test space learn-ing and memory ability.CBS /H2 S content in hippo-campus tissue sample was measured using Western blot and methylene blue method.In vivo extracellular single unit recording was used to examine the frequency of spontaneous discharges of hippocampus neurons.Re-sults ① Escape latency increased and quadrant time (%)and platform crossing times decreased in Morris water maze test of PTSD group compared with normal group(P <0.01 ).CBS /H2 S level in hippocampus tis-sue of PTSD group also decreased compared with nor-mal group (P <0.01 ,P <0.05 ).② Escape latency decreased and quadrant time(%)and platform cross-ing times increased in Morris water maze test of NaHS+PTSD group compared with PTSD group(P <0.01 ).③ L-cysteine increased the frequency of spontaneous discharges of hippocampus neurons(P < 0.01 ).Con-clusions Learning and memory ability decrease in PTSD model rats owing to the inhibition of CBS /H2 S content in hippocampus tissue.The mechanism of be-havior improvement of H2 S on PTSD model rat is possi-bly related to the excitation of H2 S on frequency of spontaneous discharges of hippocampus neurons.