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.

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:Surgical site infection (SSI) is the most common infectious complication after emergency abdominal surgery (EAS). To a large extent, most SSI can be prevented, but there are few relevant studies in China. This study mainly investigated the current situation of SSI occurrence after EAS in China, and further explored risk factors for SSI occurrence.Methods:Multi-center cross-sectional study was conducted. Clinical data of patients undergoing EAS in 33 hospitals across China between May 1, 2019 and June 7, 2019 were prospectively collected, including perioperative data and microbial culture results from infected incisions. The primary outcome was the incidence of SSI after EAS, while the secondary outcomes were postoperative hospital stay, ICU occupancy rate, length of ICU stay, hospitalization cost, and mortality within postoperative 30 days. Univariate and multivariate logistic regression models were used to analyze the risk factors of SSI after EAS.Results:A total of 660 EAS patients aged (47.9±18.3) years were enrolled in this study, including 56.5% of males (373/660). Forty-nine (7.4%) patients developed postoperative SSI. The main pathogen of SSI was Escherichia coli [culture positive rate was 32.7% (16/49)]. As compared to patients without SSI, those with SSI were more likely to be older (median 56 years vs. 46 years, U=19 973.5, P<0.001), male [71.4% (35/49) vs. 56.1% (343/611), χ 2=4.334, P=0.037] and diabetes [14.3% (7/49) vs. 5.1% (31/611), χ 2=5.498, P=0.015]; with-lower preoperative hemoglobin (median: 122.0 g/L vs. 143.5 g/L, U=11 471.5, P=0.006) and albumin (median: 35.5 g/L vs. 40.8 g/L, U=9452.0, P<0.001), with higher blood glucose (median: 6.9 mmol/L vs. 6.0 mmol/L, U=17 754.5, P<0.001); with intestinal obstruction [32.7% (16/49) vs. 9.2% (56/611), χ 2=25.749, P<0.001], with ASA score 3-4 [42.9% (21/49) vs. 13.9% (85/611), χ 2=25.563, P<0.001] and with high surgical risk [49.0% (24/49) vs. 7.0% (43/611), χ 2=105.301, P<0.001]. The main operative procedure resulting in SSI was laparotomy [81.6%(40/49) vs. 35.7%(218/611), χ 2=40.232, P<0.001]. Patients with SSI experienced significantly longer operation time (median: 150 minutes vs. 75 minutes, U=25 183.5, P<0.001). In terms of clinical outcome, higher ICU occupancy rate [51.0% (25/49) vs. 19.5% (119/611), χ 2=26.461, P<0.001], more hospitalization costs (median: 44 000 yuan vs. 15 000 yuan, U=24 660.0, P<0.001), longer postoperative hospital stay (median: 10 days vs. 5 days, U=23 100.0, P<0.001) and longer ICU occupancy time (median: 0 days vs. 0 days, U=19 541.5, P<0.001) were found in the SSI group. Multivariate logistic regression analysis showed that the elderly (OR=3.253, 95% CI: 1.178-8.985, P=0.023), colorectal surgery (OR=9.156, 95% CI: 3.655-22.937, P<0.001) and longer operation time (OR=15.912, 95% CI:6.858-36.916, P<0.001) were independent risk factors of SSI, while the laparoscopic surgery (OR=0.288, 95% CI: 0.119-0.694, P=0.006) was an independent protective factor for SSI. Conclusions:For patients undergoing EAS, attention should be paid to middle-aged and elderly patients and those of colorectal surgery. Laparoscopic surgery should be adopted when feasible and the operation time should be minimized, so as to reduce the incidence of SSI and to reduce the burden on patients and medical institutions.

Objective:Surgical site infection (SSI) is the most common infectious complication after emergency abdominal surgery (EAS). To a large extent, most SSI can be prevented, but there are few relevant studies in China. This study mainly investigated the current situation of SSI occurrence after EAS in China, and further explored risk factors for SSI occurrence.Methods:Multi-center cross-sectional study was conducted. Clinical data of patients undergoing EAS in 33 hospitals across China between May 1, 2019 and June 7, 2019 were prospectively collected, including perioperative data and microbial culture results from infected incisions. The primary outcome was the incidence of SSI after EAS, while the secondary outcomes were postoperative hospital stay, ICU occupancy rate, length of ICU stay, hospitalization cost, and mortality within postoperative 30 days. Univariate and multivariate logistic regression models were used to analyze the risk factors of SSI after EAS.Results:A total of 660 EAS patients aged (47.9±18.3) years were enrolled in this study, including 56.5% of males (373/660). Forty-nine (7.4%) patients developed postoperative SSI. The main pathogen of SSI was Escherichia coli [culture positive rate was 32.7% (16/49)]. As compared to patients without SSI, those with SSI were more likely to be older (median 56 years vs. 46 years, U=19 973.5, P<0.001), male [71.4% (35/49) vs. 56.1% (343/611), χ 2=4.334, P=0.037] and diabetes [14.3% (7/49) vs. 5.1% (31/611), χ 2=5.498, P=0.015]; with-lower preoperative hemoglobin (median: 122.0 g/L vs. 143.5 g/L, U=11 471.5, P=0.006) and albumin (median: 35.5 g/L vs. 40.8 g/L, U=9452.0, P<0.001), with higher blood glucose (median: 6.9 mmol/L vs. 6.0 mmol/L, U=17 754.5, P<0.001); with intestinal obstruction [32.7% (16/49) vs. 9.2% (56/611), χ 2=25.749, P<0.001], with ASA score 3-4 [42.9% (21/49) vs. 13.9% (85/611), χ 2=25.563, P<0.001] and with high surgical risk [49.0% (24/49) vs. 7.0% (43/611), χ 2=105.301, P<0.001]. The main operative procedure resulting in SSI was laparotomy [81.6%(40/49) vs. 35.7%(218/611), χ 2=40.232, P<0.001]. Patients with SSI experienced significantly longer operation time (median: 150 minutes vs. 75 minutes, U=25 183.5, P<0.001). In terms of clinical outcome, higher ICU occupancy rate [51.0% (25/49) vs. 19.5% (119/611), χ 2=26.461, P<0.001], more hospitalization costs (median: 44 000 yuan vs. 15 000 yuan, U=24 660.0, P<0.001), longer postoperative hospital stay (median: 10 days vs. 5 days, U=23 100.0, P<0.001) and longer ICU occupancy time (median: 0 days vs. 0 days, U=19 541.5, P<0.001) were found in the SSI group. Multivariate logistic regression analysis showed that the elderly (OR=3.253, 95% CI: 1.178-8.985, P=0.023), colorectal surgery (OR=9.156, 95% CI: 3.655-22.937, P<0.001) and longer operation time (OR=15.912, 95% CI:6.858-36.916, P<0.001) were independent risk factors of SSI, while the laparoscopic surgery (OR=0.288, 95% CI: 0.119-0.694, P=0.006) was an independent protective factor for SSI. Conclusions:For patients undergoing EAS, attention should be paid to middle-aged and elderly patients and those of colorectal surgery. Laparoscopic surgery should be adopted when feasible and the operation time should be minimized, so as to reduce the incidence of SSI and to reduce the burden on patients and medical institutions.

Objective · To analyze the clinical distribution and drug resistance of Acinetobacter junii (A. junii) and Acinetobacter lwoffii (A. lwoffii) from a grade 3A hospital in Shanghai, China, and provide the foundation for prevention and control of infections caused by them. Methods · A. junii and A. lwoffii were collected from the hospital between Aug, 2011 and Aug, 2016. VITEK2 Compact of bioMérieux (French) was used for bacterial identification and antibiotic susceptibility tests, clinical information of each strain was also analyzed. Results · 28 strains of A. junii and 58 strains of A. lwoffii were enrolled. A. junii was mainly from the departments of urology, thoracic surgery and geriatrics, and the samples were mainly sputum and urine. The resistant rates of A. junii to gentamicin, ampicillin sulbactam, piperacillin, piperacillin/tazobactam, ceftazidime, cefepime, imipenem, meropenem, levofloxacin, ciprofloxacin and cotrimoxazole were 35.71%, 3.57%, 10.71%, 3.57%, 3.57%, 3.57%, 3.57%, 3.57%, 0, 3.57% and 35.71%, respectively. A. lwoffii was mainly isolated from the departments of urology, geriatrics, respiratory and renal medicine, and the samples mainly included urine, blood and sputum. The rates of antibiotics (mentioned above) resistance were 29.31%, 13.79%, 13.79%, 6.90%, 20.69%, 18.97%, 12.07%, 15.52%, 18.97%, 31.03% and 31.03%, respectively. The levels of antibiotic resistance of these two strains were constant during the five years. Conclusion · A. junii and A. lwoffii antibiotic resistant rates were much lower than those of reported A. baumannii, the over-all antibiotic resistances of A. junii were lower than those of A. lwoffii. This study provided fundamental data for prevention or control of these two strains by empirical use of antibiotics.

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.

Objective To evaluate the impact of obesity and spleen length on laparoscopic splenectomy combined with pericardial devascularization.Methods We retrospectively analyzed 121 patients with portal hypertension who underwent laparoscopic splenectomy combined with pericardial devascularization in our hospital.Using BMI,these patients were classified as the obesity and the non-obesity groups.Using length of the spleen,the patients were divided into two subgroups:spleen AC diameter ＞ 20 cm and spleen AC diameter ≤20 cm.Results (1) For the Obesity group,the operation time,the rate of conversion to open operation and the complication rate after operation were higher than the non-obesity group [(184.0 ± 49.0) min vs (142.0 ±39.0) min,26.1％ vs 8.0％,26.1％ vs 6.7％,respectively,P＜0.05].However,the differences were not significant for mean blood loss,intraperitoneal drainage and complication rate after operation.For patients with massive splenomegaly,the obesity group had higher rates of conversion into open operation and complication (42.9％ vs 11.7％,33.3％ vs 8.8％,respectively,P ＜0.05).For patients with non-massive splenomegaly,the differences were not significant between the obesity and non-obesity groups (P ＞ 0.05).(2) For obesity patients,the spleen AC diameter ＞ 20 cm group had a longer operation time and a higher rate of conversion to open operation [(224.0 ± 42.0) min vs (152.0 ± 44.0) min,42.9％ vs 12.0％,respectively,P ＜ 0.05].The length of spleen had no effect on the operation and its complication (P ＞ 0.05).Conclusions Obesity extended the operation time and increased the rates of conversion to open operation and complication after operation.The spleen length had a major impact on the rates of conversion to open operation and complication after operation for the groups of obesity patients.

Objective:To observe the efficacy of auricular acupoint sticking based on conventional treatment in treating pain in early-stage extremity trauma.Methods:A hundred eligible patients with acute soft tissue injury or acute closed fracture were randomized into an observation group and a control group by their admission sequence, 50 cases in each group. The two groups both received routine management including routine checking, external fixing, traction, raising up the affected limb, etc., as well as cold compress with Chinese medication (Xiao Zhong Zhi Tong Powder). In addition to the routine management, the control group was given oral administration of amidopyrine and phenacetin compound tablet, 1 tablet per dose, twice a day, which was then taken only when necessary or terminated after pain subsided. The observation group was given auricular acupoint sticking in addition to the routine management. The two groups were compared in terms of numerical rating scale (NRS) score, therapeutic efficacy and adverse reactions after pain was relieved.Results:After the intervention, the NRS scores dropped significantly in both groups (P<0.01); the NRS score in the observation group was significantly lower than that in the control group (P<0.05).The total effective rate in the observation group was superior to that in the control group (P<0.05).There were no severe adverse reactions in the two groups.Conclusion:Based on routine management, auricular acupoint sticking can produce a more significant efficacy in treating pain in early-stage extremity trauma compared to amidopyrine and phenacetin compound tablet; it can effectively reduce pain of the affected limb and prevent complications; it's easy-to-operate and safe; patients can learn and understand it easily; its efficacy is confirmed; it enhances the satisfaction degree of the inpatients. Therefore, this method is worth promoting in clinic.

Objective To investigate the impact of hepatectomy combined with splenectomy on hepatitis B virus (HBV) reactivation in patients with hepatocellular carcinoma (HCC) ≤5 cm and with hypersplenism.Methods This is a retrospective case-control study on 167 patients with HCC ≤5 cm and with hypersplenism who underwent hepatectomy combined with splenectomy at the Shengli Oilfield Central Hospital between May 2008 and June 2015.64 patients underwent hepatectomy combined with splenectomy,and 103 patients hepatectomy alone.The patients were assigned to the hepatectomy combined with splenectomy group (the combined group,n =61) or the hepatectomy alone group (the control group,n =61) using propensity score matching (PSM).Logistic regression was used to evaluate the relative clinical factors associated with HBV reactivation.The stratified Chi-squared test was utilized to determine the impact of the surgical procedure and preoperative anti-viral therapy on postoperative hepatitis B virus reactivation of these patients.Results The serum PLT level,Child-Pugh grading,tumor diameter and surgical procedures were shown to be independent risk factors associated with postoperative HBV reactivation (P ＜ 0.05).To study the impact of preoperative anti-viral therapy on postoperative HBV reactivation:-the incidence of HBV reactivation was higher in the control group than in the combined group (19.7％ vs.6.6％,P ＜ 0.05).In the combined group,there was no significant difference between patients who received anti-viral therapy and those who were treatment-naive (5.3％ vs.7.1％,P ＞0.05).In the control group,a higher incidence of HBV reactivation was found in patients with treatment-na(i)ve than in patients who received anti-viral therapy (26.1 ％ vs.0,P ＜ 0.05).For the patients who received anti-viral therapy,there was no significant difference between the combined group and the control group (5.3％ vs.0,P ＞ 0.05).In patients with treatment-na(i)ve,a higher incidence of HBV reactivation was observed in the control group than the combined group (26.1％ vs.7.1％,P ＜ 0.05).Conclusions In patients who were not treated with antiviral therapy,hepatectomy combined with splenectomy decreased the incidence of postoperative HBV reactivation in patient with HCC ≤5 cm and with hypersplenism.For the patients who received preoperative anti-viral therapy,the incidence of postoperative HBV reactivation was not decreased with hepatectomy combined with splenectomy.