BACKGROUND:Spondylolisthesis is a common disease,and there is a lack of effective drugs to treat it.There is still a need to further define the pathogenesis and screen out more suitable therapeutic targets for spondylolisthesis.Mendelian randomization analysis can be used to explore the drugable genes associated with spondylolisthesis and provide valuable guidance for the development of more effective and targeted therapeutic drugs.OBJECTIVE:To explore potential therapeutic targets and effective drugs for spondylolisthesis by means of pharmaceutically available genome-wide Mendelian randomization analysis.METHODS:Using the Finnish database,eQTLGen consortium,drug signature database,drug-gene interaction database,protein-protein interaction database,organic small molecule biological activity database and protein structure database,which contains genome and health information of half a million Finns,data on druggable genes were subjected to two-sample Mendelian randomization analysis and co-localization analysis with data from genome-wide association studies of spondylolisthesis to identify genes highly associated with spondylolisthesis.In addition,GO and KEGG enrichment analysis,protein network construction,drug prediction and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic agents.RESULTS AND CONCLUSION:In this study,we identified 34 potential drug target genes that were significantly associated with spondylolisthesis,particularly the gene APOBEC3G.This gene showed a significant association with spondylolisthesis outcomes through Mendelian analysis and co-localization analysis,suggesting that APOBEC3G may be a priority therapeutic target.As for other potential mechanisms and drugs,we still need to conduct more in-depth research to determine their roles.This study used a database from a European population,which can be used as a reference for the study of population genetics in China.

BACKGROUND:Spondylolisthesis is a common disease,and there is a lack of effective drugs to treat it.There is still a need to further define the pathogenesis and screen out more suitable therapeutic targets for spondylolisthesis.Mendelian randomization analysis can be used to explore the drugable genes associated with spondylolisthesis and provide valuable guidance for the development of more effective and targeted therapeutic drugs.OBJECTIVE:To explore potential therapeutic targets and effective drugs for spondylolisthesis by means of pharmaceutically available genome-wide Mendelian randomization analysis.METHODS:Using the Finnish database,eQTLGen consortium,drug signature database,drug-gene interaction database,protein-protein interaction database,organic small molecule biological activity database and protein structure database,which contains genome and health information of half a million Finns,data on druggable genes were subjected to two-sample Mendelian randomization analysis and co-localization analysis with data from genome-wide association studies of spondylolisthesis to identify genes highly associated with spondylolisthesis.In addition,GO and KEGG enrichment analysis,protein network construction,drug prediction and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic agents.RESULTS AND CONCLUSION:In this study,we identified 34 potential drug target genes that were significantly associated with spondylolisthesis,particularly the gene APOBEC3G.This gene showed a significant association with spondylolisthesis outcomes through Mendelian analysis and co-localization analysis,suggesting that APOBEC3G may be a priority therapeutic target.As for other potential mechanisms and drugs,we still need to conduct more in-depth research to determine their roles.This study used a database from a European population,which can be used as a reference for the study of population genetics in China.

Necroptosis, a form of programmed cell death, initiates a series of biological responses and further culminates in necroinflammatory processes, consequently limiting the efficacy of cytokine antagonists in treating inflammatory diseases. To address this issue, DNAzyme R3-Dz specifically targeting receptor-interacting protein kinase 3 (RIP3) mRNA, a necrosome component, has been successfully developed and studied to elucidate the mechanism in cleaving its target mRNA. Then a polyamidoamine (PAMAM) derivative was constructed through the modification of nucleobase analog (termed AP) to achieve the R3-Dz delivery to macrophages. The AP/R3-Dz nanoparticles effectively downregulated the RIP3 expression, leading to subsequent decrease in the levels of reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), ultimately inhibiting the necroinflammatory processes mediated by the NOD-like receptor family pyrin domain-containing 3 (NLRP3). Finally, AP/R3-Dz nanoparticles and their combination with the NLRP3 inhibitor MCC950 suppressed the necrotic phenotype and ameliorated the disease progression in diverse models, including gouty arthritis, autoimmune hepatitis and rheumatoid arthritis. In summary, the AP/R3-Dz nanoparticles in combination with MCC950 have been demonstrated to achieve the intervention in necroptosis and inflammation by dual disruption of the intricate feedback loop of necroinflammation and thus have promising potential in the treatment of inflammatory diseases.

Objective:To explore the predictive factors for extubation in the operating room after single lung transplantation without the assistance of extracorporeal membrane oxygenation (ECMO) in adult patients with end-stage interstitial lung disease (ILD), as well as their short-term (1-year postoperative) prognosis.Methods:A retrospective analysis was conducted on the clinical data of 78 adult ILD recipients who underwent single lung transplantation without ECMO assistance at the First Affiliated Hospital of Guangzhou Medical University from June 2018 to June 2023. Based on whether extubation was completed in the operating room (OR), patients were divided into the OR group (19 cases) and ICU group (59 cases). Baseline characteristics of donors and recipients, as well as intraoperative events, were compared between the two groups. Univariate logistic regression analysis was used to identify potential predictors, and variables with P<0.2 were included in multivariate logistic regression to determine independent predictors for OR extubation. Receiver operating characteristic (ROC) curves were plotted to evaluate predictive performance. The Kaplan-Meier method was used to analyze survival, and short-term prognosis between groups was compared. Results:The rate of OR extubation after single lung transplantation in ILD recipients was 24%(19/78). Compared with the ICU group, the OR group had shorter operation times, lower fluid volumes, reduced transfusions of red blood cells and plasma, less intraoperative bleeding, and lower lactate levels 15 minutes after pulmonary artery reperfusion (all P<0.05). Univariate logistic regression analysis identified the following factors as significantly associated with OR extubation: recipient age ( P=0.100), operative time ( P=0.001), fluid infusion volume ( P=0.005), red blood cell transfusion volume ( P=0.037), plasma transfusion volume ( P=0.039), blood loss ( P=0.004), oxygenation index at 15 minutes after reperfusion ( P=0.174), and blood lactate at 15 minutes after reperfusion ( P=0.041). Multivariate analysis revealed that intraoperative blood loss was an independent predictor of OR extubation ( OR=0.993, 95% CI: 0.986 - 0.999, P=0.026). ROC curve analysis showed that blood loss had an area under the curve (AUC) of 0.822 in predicting OR extubation, with a sensitivity of 64.4% and specificity of 89.5%. Postoperatively, patients in the OR group had significantly shorter durations of mechanical ventilation [0 vs 5 (3,11) days, P<0.001], ICU stay [7(4,8) vs 9(6,20) days, P=0.012], and overall postoperative hospitalization [19 (15,23) vs 25 (19,39) days, P=0.015]. Within one year after surgery, 2 patients (11%) in the OR group and 19 patients (32%) in the ICU group had died, but the difference in 1-year survival rates between the two groups was not statistically significant. Conclusions:Intraoperative blood loss is an independent predictor of extubation in the operating room. Early extubation in non-ECMO-assisted single lung transplantation for ILD patients is associated with improved short-term outcomes.

Objective To elucidate the mechanistic role of ferrostatin-1(Fer-1)in the pathogenesis of diabetic nephropathy(DN).Methods Twenty spontaneous diabetic mice and ten negative control mice were used for in vivo experiments.The for-mer were randomly divided into a model group and a Fer-1 treatment group,with the treatment group receiving intraperitoneal injections of Fer-1(1 mg/kg).Levels of BUN,Scr,glucose,microalbuminuria,GSH,and iron were measured in the mice.Renal histopathological staining was performed to observe renal morphology.Western blot and immunohistochemistry were used to detect the expression of ferroptosis marker proteins,heat shock factor 1(HSF-1),and heme oxygenase-1(HO-1)in renal tis-sues.Human renal cortical proximal tubular epithelial cells(HK-2)were cultured and divided into three groups during in vitro experiments:control group,high glucose group(30 mmol/L),and Fer-1 treatment group(1μmol/L).Levels of GSH,MDA,4-HNE,and iron content were measured.Immunofluorescence experiment was used to assess the level of reactive oxygen species(ROS).Western blot was performed to detect the expressions of ferroptosis marker proteins,kidney injury molecule-1,neutro-phil gelatinase-associated lipocalin,HO-1,and HSF-1 in HK-2 cells.Results In the model group,renal pathological changes,in-cluding glomerular hypertrophy,mesangial matrix expansion,glycogen accumulation,and fibrosis,were observed.Compared with the control group,levels of BUN,Scr,glucose,and urinary microalbumin were increased,GSH content was decreased,and iron level was elevated in the model group(all P＜0.05).The expression of HSF-1 protein in the kidneys of the model group was lower than that in the control group,while HO-1 protein expression was higher.The Fer-1 treatment group exhibited the oppo-site trend.(both P＜0.05).GSH expression was decreased,and iron content,MDA,and 4-HNE levels were increased in the high glucose group(all P＜0.05).Immunofluorescence result revealed that,compared with the control group,ROS level was higher in the high glucose group(all P＜0.05).Additionally,the high glucose group showed increased expressions of KIM-1,NGAL,and HO-1,along with reduced HSF-1 expression,whereas the Fer-1 treatment group exhibited the opposite trend.(all P＜0.05).Conclusion Both in vivo and in vitro experiments have demonstrated that ferroptosis plays a significant role in the de-velopment and progression of DN.Fer-1 may alleviate DN injury by upregulating ferroptosis through the HSF-1/HO-1 signaling pathway.

BACKGROUND:Monounsaturated fatty acids are mostly recognized as a fatty acid with beneficial effects on human health,and some studies have suggested that they may contribute to non-inflammatory pain at multiple sites in the body.OBJECTIVE:To investigate the effect of monounsaturated fatty acids on the incidence of low back pain and all-cause mortality,thereby providing potential biomarkers and intervention strategies for low back pain management and prevention.METHODS:A Mendelian randomization method was used to analyze the potential association of monounsaturated fatty acids on the incidence of low back pain and all-cause mortality in conjunction with large sample data from the National Health and Nutrition Examination Survey(NHANES)database.Results were validated and sensitivity analyzed using multiple statistical models(e.g.,inverse variance weighting,MR-Egger regression,simple median,weighted median,and weighted median)to enhance the reliability of causal inferences.In the NHANES study,multivariate Cox proportional risk regression models were used to assess the independent predictive values of different fatty acid ratios and to control for confounders.Potential nonlinear relationships between monounsaturated fatty acids and all-cause mortality were assessed using Kaplan-Meier curves,log-rank tests,and restricted cubic spline curves.RESULTS AND CONCLUSION:Elevated monounsaturated fatty acids have been found to be associated with a significantly higher risk of low back pain,suggesting an unfavorable effect of this fatty acid.Also,monounsaturated fatty acids may increase all-cause mortality in patients with low back pain.This provides new insights into the potential effects of monounsaturated fatty acids on low back pain and all-cause mortality,and provides a scientific basis for nutritional interventions for low back pain.The results support the use of dietary modification as one of the strategies for the prevention and management of low back pain in the European population,but further studies are needed to explore the specific biological mechanisms and potential for clinical application,thereby improving guidance for the prevention and treatment of diseases in China.

Objective To observe the effects of tuina of"three methods and three acupoints"on skeletal muscle α-actin,myostatin(MSTN)and atrophy gene 1(Atrogin1)expression of sciatic nerve injury(SNI)rats;To explore the mechanism of tuina therapy on motor dysfunction.Methods Male SD rats were randomly divided into blank group,sham-operation group,model group and tuina group,with 9 rats in each group.SNI model was established by clamp method in rats of the model group and tuina group.The sciatic nerve was exposed without clamping in rats of the sham-operation group,the blank group was not intervened.7 days after the operation,the intelligent tuina manipulation simulator was used to simulate the point method,dial method and knead method,which were applied to the"Yinmen"(BL37),"Chengshan"(BL57)and"Yanglingquan"(GB34)of rats in the tuina group,once a day,for 20 times.The rats in the sham-operation group and the model group were only grasped and restrained.Rats in the blank group did not receive any intervention.The hind limb muscle strength were evaluated by inclined plate test before modeling,after 10 interventions and 20 interventions.After the intervention,the rats were euthanized.The expressions of α-actin in gastrocnemius muscle tissue were detected by immunofluorescence staining,the expressions of MSTN,Atrogin1 mRNA and protein in gastrocnemius muscle tissue were detected by RT-PCR and Western blot.Results Compared with the blank group and sham-operation group,the model group showed a decrease in hind limb muscle strength(P<0.01),a significant decrease in α-actin expression in gastrocnemius muscle tissue(P<0.01),and a significant increase in MSTN,Atrogen1 mRNA and protein expression(P<0.05,P<0.01).Compared with the model group,the hind limb muscle strength in tuina group significantly increased(P<0.01),the expressions of α-actin significantly increased(P<0.01),and the expressions of MSTN,Atrogin1 mRNA and protein significantly decreased(P<0.05,P<0.01).Conclusion"Three methods and three acupoints"tuina can improve hind limb muscle strength and restore motor function of SNI rats,which is related to the down-regulation of MSTN and Atrogin1 as well as increasing the expression of α-actin in gastrocnemius muscles.

Objective:To investigate the impact of body composition and inflammatory nutritional indicators on postoperative complications in patients with obstructive colorectal cancer,and to develop and validate a nomogram model.Methods:This is a retrospective case series study. The clinical data of 293 patients with obstructive colorectal cancer who were treated at the Department of Gastrointestinal Surgery,the Affiliated Hospital of Qingdao University,between January 2016 and January 2024,were retrospectively collected. The cohort included 182 males and 111 females,aged (65.0±12.1) years (range: 18 to 80 years). The dataset was randomly divided into a training group ( n=196) and a validation group ( n=97) with a 7∶3 ratio. Independent sample t test and multivariate logistic regression analysis were employed to identify independent risk factors associated with postoperative complications in patients with obstructive colorectal cancer. A preoperative nomogram model was subsequently developed for predicting postoperative complications,which was further validated using a validation cohort. Results:The training group comprised 119 males and 77 females,with 68 cases experiencing postoperative complications and 128 cases without complications. The validation group included 63 males and 34 females,with 30 cases experiencing postoperative complications and 67 cases without complications.Univariate analysis and multivariate analysis revealed that low skeletal muscle index ( OR=0.867,95% CI: 0.795 to 0.947),high visceral fat index ( OR=1.058,95% CI: 1.028 to 1.089),high systemic immune inflammation index ( OR=1.002, 95% CI: 1.000 to 1.003), low prognostic nutritional index ( OR=0.847,95% CI: 0.782 to 0.917),and preoperative anemia ( OR=2.714,95% CI: 1.161 to 6.344) were independent risk factors for postoperative complications (all P<0.05). A nomogram prediction model based on these five indicators was established. The area under the receiver operating characteristic (ROC) curve for the prediction model was 0.878 (95% CI: 0.829 to 0.928) in the training group and 0.849 (95% CI:0.767 to 0.930) in the validation group. Conclusions:The preoperative nomogram model,which incorporates inflammatory and nutritional indicators,demonstrates a good accuracy in predicting postoperative complications for patients with obstructive colorectal cancer. This model can effectively assist in guiding treatment decisions.

Objective To evaluate the therapeutic effects of ticagrelor combined with traditional Chinese medicine(TCM)in patients with microvascular angina.Methods A retrospective analysis was conducted on 356 patients diagnosed with microvascular angina who were hospitalized in the Department of Cardiology at the First Hospital of Hebei Medical University between January 1,2022,and January 1,2024.Patients were assigned to a conventional treatment group or a combined TCM-Western medicine treatment group.The conven-tional treatment group received standard Western medicine therapy,whereas the combined treatment group received ticagrelor and TCM based on syndrome differentiation.After four weeks of treatment,coronary flow reserve(CFR),Canadian Cardiovascular Society(CCS)angina classification,and incidence of adverse drug reactions were compared between the two groups.Results The combined TCM-Western medicine treatment group had significantly better outcomes in CFR and CCS angina classification than the conventional treat-ment group(P＜0.05).Conclusion The combination of ticagrelor and TCM is safe and effective for treating patients with microvascular angina.

Objective To analyze the clinical characteristics of recipients with interstitial lung disease (ILD) who underwent second lung transplantation and summarize the diagnostic and therapeutic experience. Methods A retrospective analysis was conducted on the clinical data of 14 patients who underwent first and second lung transplants for ILD at the First Affiliated Hospital of Guangzhou Medical University from January 2015 to December 2024. The preoperative conditions, intraoperative events, postoperative treatments and prognoses of the first and second lung transplantation were compared, and the postoperative survival of ILD patients after the second lung transplantation was analyzed. Results Among the 14 recipients of the second lung transplant, 13 underwent the procedure due to chronic lung allograft dysfunction, and 1 due to airway complications. The median interval time from the first to the second lung transplant was 32 (2, 80) months. Before the second transplantation, 2 recipients required endotracheal intubation and mechanical ventilation, and 2 required endotracheal intubation, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) support. The surgical time for the second lung transplantation was longer than that for the first, with increased intraoperative red blood cell and plasma transfusion volumes, the proportion of ECMO support during the second lung transplantation was higher than that during the first (all P<0.05). However, the cold ischemia time for one-sided lung transplant completion in the first lung transplant was similar to that in the second lung transplantation (P>0.05). The median follow-up time after the second lung transplantation was 32 (1, 63) months. The 1-month, 6-month and 1-year survival rates after the second lung transplantation were 79%, 57% and 50%, respectively, with causes of death being infection, multiple organ failure and gastrointestinal bleeding. Conclusions For ILD patients undergoing second lung transplantation after the first lung transplantation, the second lung transplantation is more challenging, with longer surgical time and higher intraoperative blood loss. It requires higher surgical skills and perioperative management. Non-emergency second transplantation may still achieve good results.