Objective:To investigate impacts of paeoniflorin on inflammation and nuclear transcription factor-κB(NF-κB)/nucleotide-binding oligomeric domain-like receptor protein 3(NLRP3)signal pathway in knee osteoarthritis(KOA)model rats.Meth-ods:SD rats were randomly grouped into model group,glucosamine group,paeoniflorin low-dose group,paeoniflorin high-dose group,paeoniflorin high-dose+phorbol ester(PMA)(NF-κB activator)group,with 10 rats in each group,another 10 rats were regarded as control group,and only knee joint capsule was cut,after treatment with glucosamine,paeoniflorin and PMA,joint pain symptoms of rats were detected by mechanical stimulation method and thermal radiation method;knee joint width,joint swelling and synovial thick-ness were measured;HE staining was applied to detect joint tissue structure and morphology of rats in each group;levels of inflamma-tory factors IL-1β,monocyte chemoattractant protein 1(MCP-1)and IL-9 in joint fluid and serum of rats were detected by ELISA;and Western blot was applied to detect expressions of NF-κB/NLRP3 signal pathway related proteins in rat joint tissue.Results:Com-pared with control group,joint tissue structure of model group was significantly damaged,mechanical pain threshold and thermal sen-sitivity pain threshold were significantly lower(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expression of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were higher(P<0.05).Compared with model group,joint tissue damage of rats in glucosamine group,paeoniflorin low-dose group and paeoniflorin high-dose group was reduced,mechanical pain threshold and thermal sensitivity pain threshold were higher(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expressions of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were lower(P<0.05);joint tissue injury of rats in paeoniflorin high-dose group was further reduced compared with paeoniflorin low-dose group,mechanical pain threshold and thermal sensitivity pain threshold were further higher(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expression of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were further lower(P<0.05).Compared with paeoniflorin high-dose group,joint tissue damage of rats in paeoniflorin high-dose+PMA group was increased,mechanical pain threshold and thermal sensitivity pain threshold were lower(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expression of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were higher(P<0.05);there was no significant change in all indexes of rats in glucosamine group(P>0.05).Conclusion:Paeoniflorin can play an anti-inflammatory role by down-regulating the NF-κB/NLRP3 signal pathway,thus alleviating joint injury and joint pain symptoms of KOA rats.

BACKGROUND:Stachydrine has anti-inflammatory,antioxidant,and antiplatelet properties that promote angiogenesis and has potential benefits on the cardiovascular system and central nervous system.Recently,it has been found that stachydrine effectively reverses homocysteine-induced endothelial dysfunction and ameliorates endothelial dysfunction by increasing the expression of guanosine triphosphate cyclase hydrolase and dihydrofolate reductase,but the role of stachydrine in atherosclerosis is yet unclear.OBJECTIVE:To explore the effect and molecular mechanism of stachydrine on atherosclerosis induced by a high-fat diet in ApoE mice.METHODS:A total of 48 ApoE-/-mice were randomly divided into blank control group,model group,stachydrine group and atorvastatin group,with 12 mice in each group.Mice in the latter three groups were fed with high-fat diet for 12 weeks to establish animal models of atherosclerosis.After successful modeling,the stachydrine group was treated with stachydrine(30 mg/kg)by gavage,the atorvastatin group was treated with atorvastatin(2.6 mg/kg)by gavage,and the blank control group and the model group were treated with the same volume of sodium carboxymethyl cellulose by gavage once a day for 30 days.After administration,hematoxylin-eosin staining was used to observe the pathological changes of the aortic root.Oil red O staining was used to detect lipid deposition in aortic plaques and the aortic root.Real-time fluorescent quantitative PCR was used to detect mRNA expression of adhesion molecules(intercellular adhesion molecule 1,vascular cell adhesion molecule 1,and selectin E)and chemokines(CXCL1,CXCL4,and monocyte chemotactic protein 1)in the aorta.RNA sequencing was used to analyze differential expression of genes between groups of aortic tissues and enrich for significantly upregulated signaling pathways.Western blot was used to detect the expression levels of autophagy marker proteins,autophagy microtubule-associated protein light chain β3 antibody(LC3BⅡ/LC3BⅠ),SQSTM1,phosphorylated AMp-activated protein kinase α and silent information regulator.Autophagy-lysosome changes were observed under transmission electron microscope.RESULTS AND CONCLUSION:Compared with the blank control group,the model group had increased aortic plaques and lipid deposition,and increased mRNA expression of adhesion molecules and chemokines(P＜0.05).Compared with the model group,the stachydrine group or atorvastatin group had reduced aortic plaques and lipid deposition,and decreased mRNA expression of adhesion molecules and chemokines(P＜0.05).RNA sequencing analysis showed that 972 genes were up-regulated and 781 genes were down-regulated in the stachydrine group compared with the model group.KEGG enrichment analysis of the up-regulated genes showed that autophagy signaling pathway and AMPK signaling pathway were significantly up-regulated.Western blot results showed that compared with the model group,the stachydrine group had a significantly increased LC3BⅡ/LC3BⅠ ratio and protein expression of phosphorylated AMp-activated protein kinase α and silent information regulator(P＜0.05),and a significantly decreased protein level of SQSTM1.Transmission electron microscope analysis of mouse aorta showed that the stachydrine group had a significantly increased number of autophagolysosomes compared with the model group.To conclude,stachydrine may activate autophagy by up-regulating AMp-activated protein kinase/silent information regulator signaling pathway,thereby alleviating vascular endothelial inflammation and plaque deposition in atherosclerosis mice.

Objective To investigate the risk factors for postoperative anastomotic stenosis in esophageal cancer patients.Methods A total of 200 patients who underwent radical esophageal cancer resection at the First Affiliated Hospital of Dali University from July 2015 to June 2024 were selected as subjects.The patients were divided into stenosis group(n=100)and non-stenosis group(n=100)based on whether they had benign anastomotic stenosis.Comparative analyses were conducted regarding the first feeding time,surgical duration,use of non-linear anastomotic devices,and anastomotic leakage in both groups.The independent risk factors for benign postoperative anastomotic stenosis were systematically evaluated.Results Delayed initial postoperative feeding,non-linear anastomotic devices,anastomotic leakage,and persistent postoperative hypoxemia were identified as risk factors for anastomotic stenosis in esophageal cancer patients after neck anastomosis.Balloon dilation-induced bleeding and early postoperative feeding within 12h served as protective factors(P＜0.05).Conclusion The development of anastomotic stenosis in esophageal cancer patients following neck anastomosis may be associated with delayed initial feeding,non-linear anastomotic devices,anastomotic leakage,and persistent hypoxemia.

Objective:To study the outcomes of the modified Devine + Shiraki surgical approach in the treatment of severe concealed penis.Methods:A retrospective analysis was conducted on the clinical data of initially treated patients with severe concealed penis admitted to the Department of Urology, Henan Provincial People’s Hospital from March 2020 to September 2022. The therapeutic effects of three surgical approaches (Devine, Shiraki, and modified Devine + Shiraki) were analyzed and compared. The Devine approach mainly focuses on eliminating the pathological morphology of the concealed penis, thoroughly releasing the penile shaft, and correcting the concealed state; the Shiraki approach emphasizes the rational distribution of skin flaps; the key of the modified Devine + Shiraki approach lies in combining the advantages of the two approaches, achieving both complete correction of the concealed state and rational distribution of skin flaps. Improvements were made to the conventional surgical sequence: skin flap distribution was pre-designed before correcting the concealed penis to avoid difficulties in skin flap arrangement caused by degloving, thereby preventing postoperative complications such as stricture rings, lymphedema, or erectile pain. Three months after the operation, follow-up was performed to assess incision healing, presence of lymphedema or stricture rings, satisfaction with penile exposure, recurrence of the concealed state, urination patency, presence of urethral injury, and normal erectile function. A patient satisfaction survey was conducted 6 months after the operation. Measurement data with normal distribution were expressed as Mean± SD, and one-way analysis of variance was used for comparison among the three groups; categorical variables were expressed as case numbers and percentages, and chi-square test was used for comparison among the three groups. Results:Eighty, fifty, and forty-five male children were enrolled in the Devine + Shiraki group, Devine group, and Shiraki group, respectively. There were no statistically significant differences in age and body mass index (BMI) among the three groups [age: (7.6±4.5) years vs. (7.2±4.4) years vs. (6.7±4.2) years, F=0.61, P=0.546; BMI: (17.4±3.1) kg/m 2 vs. (17.7±3.2) kg/m 2 vs. (18.0±3.3) kg/m 2,F=0.57, P=0.565]. During surgery, all concealed penile shafts were completely released, and the penile skin was rationally distributed. The postoperative follow-up period ranged from 3 months to 18 months, with an average follow-up time of 13.6 months. At the 3-month postoperative follow-up, all three groups showed satisfactory wound healing with no signs of infection or skin flap necrosis; penile skin coverage was adequate, and all children demonstrated unobstructed urination without evidence of urethral injury; normal erectile function was preserved in all cases, with no reports of erectile dysfunction or pain. The recurrence rate of the concealed penis in the Devine + Shiraki group was significantly lower than that in the Devine group and Shiraki group, with a statistically significant difference [0 (0/80) vs. 6.0% (3/50) vs. 31.1% (14/45), χ2=32.88, P<0.001]; the proportion of patients without postoperative lymphedema and stricture rings in the Devine + Shiraki group was higher than that in the Devine group and Shiraki group, with a statistically significant difference [97.5% (78/80) vs. 70.0% (35/50) vs. 86.7% (39/45), χ2=20.39, P<0.001]. The Devine+ Shiraki, Devine, and Shiraki groups reported postoperative satisfaction in 76 (95.0%), 35 (70.0%), and 31 (68.9%) cases, respectively. Conclusion:The modified Devine + Shiraki surgical approach has definite efficacy, good safety, and a low incidence of complications, and can be used as an option for the treatment of severe concealed penis.

Objective:To investigate impacts of paeoniflorin on inflammation and nuclear transcription factor-κB(NF-κB)/nucleotide-binding oligomeric domain-like receptor protein 3(NLRP3)signal pathway in knee osteoarthritis(KOA)model rats.Meth-ods:SD rats were randomly grouped into model group,glucosamine group,paeoniflorin low-dose group,paeoniflorin high-dose group,paeoniflorin high-dose+phorbol ester(PMA)(NF-κB activator)group,with 10 rats in each group,another 10 rats were regarded as control group,and only knee joint capsule was cut,after treatment with glucosamine,paeoniflorin and PMA,joint pain symptoms of rats were detected by mechanical stimulation method and thermal radiation method;knee joint width,joint swelling and synovial thick-ness were measured;HE staining was applied to detect joint tissue structure and morphology of rats in each group;levels of inflamma-tory factors IL-1β,monocyte chemoattractant protein 1(MCP-1)and IL-9 in joint fluid and serum of rats were detected by ELISA;and Western blot was applied to detect expressions of NF-κB/NLRP3 signal pathway related proteins in rat joint tissue.Results:Com-pared with control group,joint tissue structure of model group was significantly damaged,mechanical pain threshold and thermal sen-sitivity pain threshold were significantly lower(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expression of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were higher(P<0.05).Compared with model group,joint tissue damage of rats in glucosamine group,paeoniflorin low-dose group and paeoniflorin high-dose group was reduced,mechanical pain threshold and thermal sensitivity pain threshold were higher(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expressions of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were lower(P<0.05);joint tissue injury of rats in paeoniflorin high-dose group was further reduced compared with paeoniflorin low-dose group,mechanical pain threshold and thermal sensitivity pain threshold were further higher(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expression of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were further lower(P<0.05).Compared with paeoniflorin high-dose group,joint tissue damage of rats in paeoniflorin high-dose+PMA group was increased,mechanical pain threshold and thermal sensitivity pain threshold were lower(P<0.05),knee joint width,joint swelling and synovial thickness,levels of IL-1β,MCP-1 and IL-9 in joint fluid and serum,and expression of p-NF-κB p65/NF-κB p65 and NLRP3 proteins in joint tissue were higher(P<0.05);there was no significant change in all indexes of rats in glucosamine group(P>0.05).Conclusion:Paeoniflorin can play an anti-inflammatory role by down-regulating the NF-κB/NLRP3 signal pathway,thus alleviating joint injury and joint pain symptoms of KOA rats.

Objective:To study the outcomes of the modified Devine + Shiraki surgical approach in the treatment of severe concealed penis.Methods:A retrospective analysis was conducted on the clinical data of initially treated patients with severe concealed penis admitted to the Department of Urology, Henan Provincial People’s Hospital from March 2020 to September 2022. The therapeutic effects of three surgical approaches (Devine, Shiraki, and modified Devine + Shiraki) were analyzed and compared. The Devine approach mainly focuses on eliminating the pathological morphology of the concealed penis, thoroughly releasing the penile shaft, and correcting the concealed state; the Shiraki approach emphasizes the rational distribution of skin flaps; the key of the modified Devine + Shiraki approach lies in combining the advantages of the two approaches, achieving both complete correction of the concealed state and rational distribution of skin flaps. Improvements were made to the conventional surgical sequence: skin flap distribution was pre-designed before correcting the concealed penis to avoid difficulties in skin flap arrangement caused by degloving, thereby preventing postoperative complications such as stricture rings, lymphedema, or erectile pain. Three months after the operation, follow-up was performed to assess incision healing, presence of lymphedema or stricture rings, satisfaction with penile exposure, recurrence of the concealed state, urination patency, presence of urethral injury, and normal erectile function. A patient satisfaction survey was conducted 6 months after the operation. Measurement data with normal distribution were expressed as Mean± SD, and one-way analysis of variance was used for comparison among the three groups; categorical variables were expressed as case numbers and percentages, and chi-square test was used for comparison among the three groups. Results:Eighty, fifty, and forty-five male children were enrolled in the Devine + Shiraki group, Devine group, and Shiraki group, respectively. There were no statistically significant differences in age and body mass index (BMI) among the three groups [age: (7.6±4.5) years vs. (7.2±4.4) years vs. (6.7±4.2) years, F=0.61, P=0.546; BMI: (17.4±3.1) kg/m 2 vs. (17.7±3.2) kg/m 2 vs. (18.0±3.3) kg/m 2,F=0.57, P=0.565]. During surgery, all concealed penile shafts were completely released, and the penile skin was rationally distributed. The postoperative follow-up period ranged from 3 months to 18 months, with an average follow-up time of 13.6 months. At the 3-month postoperative follow-up, all three groups showed satisfactory wound healing with no signs of infection or skin flap necrosis; penile skin coverage was adequate, and all children demonstrated unobstructed urination without evidence of urethral injury; normal erectile function was preserved in all cases, with no reports of erectile dysfunction or pain. The recurrence rate of the concealed penis in the Devine + Shiraki group was significantly lower than that in the Devine group and Shiraki group, with a statistically significant difference [0 (0/80) vs. 6.0% (3/50) vs. 31.1% (14/45), χ2=32.88, P<0.001]; the proportion of patients without postoperative lymphedema and stricture rings in the Devine + Shiraki group was higher than that in the Devine group and Shiraki group, with a statistically significant difference [97.5% (78/80) vs. 70.0% (35/50) vs. 86.7% (39/45), χ2=20.39, P<0.001]. The Devine+ Shiraki, Devine, and Shiraki groups reported postoperative satisfaction in 76 (95.0%), 35 (70.0%), and 31 (68.9%) cases, respectively. Conclusion:The modified Devine + Shiraki surgical approach has definite efficacy, good safety, and a low incidence of complications, and can be used as an option for the treatment of severe concealed penis.

BACKGROUND:Stachydrine has anti-inflammatory,antioxidant,and antiplatelet properties that promote angiogenesis and has potential benefits on the cardiovascular system and central nervous system.Recently,it has been found that stachydrine effectively reverses homocysteine-induced endothelial dysfunction and ameliorates endothelial dysfunction by increasing the expression of guanosine triphosphate cyclase hydrolase and dihydrofolate reductase,but the role of stachydrine in atherosclerosis is yet unclear.OBJECTIVE:To explore the effect and molecular mechanism of stachydrine on atherosclerosis induced by a high-fat diet in ApoE mice.METHODS:A total of 48 ApoE-/-mice were randomly divided into blank control group,model group,stachydrine group and atorvastatin group,with 12 mice in each group.Mice in the latter three groups were fed with high-fat diet for 12 weeks to establish animal models of atherosclerosis.After successful modeling,the stachydrine group was treated with stachydrine(30 mg/kg)by gavage,the atorvastatin group was treated with atorvastatin(2.6 mg/kg)by gavage,and the blank control group and the model group were treated with the same volume of sodium carboxymethyl cellulose by gavage once a day for 30 days.After administration,hematoxylin-eosin staining was used to observe the pathological changes of the aortic root.Oil red O staining was used to detect lipid deposition in aortic plaques and the aortic root.Real-time fluorescent quantitative PCR was used to detect mRNA expression of adhesion molecules(intercellular adhesion molecule 1,vascular cell adhesion molecule 1,and selectin E)and chemokines(CXCL1,CXCL4,and monocyte chemotactic protein 1)in the aorta.RNA sequencing was used to analyze differential expression of genes between groups of aortic tissues and enrich for significantly upregulated signaling pathways.Western blot was used to detect the expression levels of autophagy marker proteins,autophagy microtubule-associated protein light chain β3 antibody(LC3BⅡ/LC3BⅠ),SQSTM1,phosphorylated AMp-activated protein kinase α and silent information regulator.Autophagy-lysosome changes were observed under transmission electron microscope.RESULTS AND CONCLUSION:Compared with the blank control group,the model group had increased aortic plaques and lipid deposition,and increased mRNA expression of adhesion molecules and chemokines(P＜0.05).Compared with the model group,the stachydrine group or atorvastatin group had reduced aortic plaques and lipid deposition,and decreased mRNA expression of adhesion molecules and chemokines(P＜0.05).RNA sequencing analysis showed that 972 genes were up-regulated and 781 genes were down-regulated in the stachydrine group compared with the model group.KEGG enrichment analysis of the up-regulated genes showed that autophagy signaling pathway and AMPK signaling pathway were significantly up-regulated.Western blot results showed that compared with the model group,the stachydrine group had a significantly increased LC3BⅡ/LC3BⅠ ratio and protein expression of phosphorylated AMp-activated protein kinase α and silent information regulator(P＜0.05),and a significantly decreased protein level of SQSTM1.Transmission electron microscope analysis of mouse aorta showed that the stachydrine group had a significantly increased number of autophagolysosomes compared with the model group.To conclude,stachydrine may activate autophagy by up-regulating AMp-activated protein kinase/silent information regulator signaling pathway,thereby alleviating vascular endothelial inflammation and plaque deposition in atherosclerosis mice.

Objective To investigate the risk factors for postoperative anastomotic stenosis in esophageal cancer patients.Methods A total of 200 patients who underwent radical esophageal cancer resection at the First Affiliated Hospital of Dali University from July 2015 to June 2024 were selected as subjects.The patients were divided into stenosis group(n=100)and non-stenosis group(n=100)based on whether they had benign anastomotic stenosis.Comparative analyses were conducted regarding the first feeding time,surgical duration,use of non-linear anastomotic devices,and anastomotic leakage in both groups.The independent risk factors for benign postoperative anastomotic stenosis were systematically evaluated.Results Delayed initial postoperative feeding,non-linear anastomotic devices,anastomotic leakage,and persistent postoperative hypoxemia were identified as risk factors for anastomotic stenosis in esophageal cancer patients after neck anastomosis.Balloon dilation-induced bleeding and early postoperative feeding within 12h served as protective factors(P＜0.05).Conclusion The development of anastomotic stenosis in esophageal cancer patients following neck anastomosis may be associated with delayed initial feeding,non-linear anastomotic devices,anastomotic leakage,and persistent hypoxemia.

DNMT3A encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells. Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells. However, sensitive cells became resistant when DNMT3A was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells. Mechanistically, DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition. Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6. Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells. These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers. Together, our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.

Objective To examine the compliance of and factors affecting target attainment of serum trough concentration of norvancomycin in ICU patients,and the effects of different trough concentrations on clinical efficacy and renal impairment.Methods Adult patients admitted to the Department of Critical Care Medicine of Huangshan People's Hospital and receiving intravenous infusion of norvancomycin from January 2020 to December 2022 were included.The dosing regimens and steady-state trough concentrations of norvancomycin were analyzed.The clinical efficacy and renal impairment were compared between different trough concentration levels.The compliance of trough concentration in critically ill patients with different renal functions was examined.Logistic regression analysis was performed to profile the factors possibly affecting the trough concentration of norvancomycin.Results A total of 97 patients were included.The target serum trough concentration(10-20 mg/L)was reached in only 33.0％(32/97)of the critically ill patients.The serum trough concentration was below the target in 51.5％(50/97)of the patients,above the target in 15.5％of the patients.The clinical cure rate and incidence of renal impairment were significantly different among the three groups of patients with different trough concentrations(P＜0.05).The compliance with target serum trough concentration varied with different renal function tests(P＜0.05).Augmented renal clearance and normal renal function were associated with trough concentrations lower than the target.As renal dysfunction got worse,serum trough concentration was more probably higher than the target(P＜0.05).Univariate analysis showed that daily dose,age,gender,height,weight,body mass index(BMI),APACHE Ⅱ score,sequential organ failure assessment(SOFA)score,blood creatinine,urea nitrogen,procalcitonin,concomitant septic shock,and use of norepinephrine were significantly correlated with trough concentrations of norvancomycin(P＜0.05).Multivariate logistic regression analysis indicated that age,SOFA score,blood urea nitrogen,gender,and norepinephrine use were independent factors affecting the serum trough concentration of norvancomycin(P＜0.05).Conclusions The serum trough concentration of norvancomycin varied with renal function states in ICU patients.It is difficult to achieve the steady-state target trough concentration(10-20 mg/L).The clinical cure rate is lower when the trough concentration is lower than the target.As the trough concentration increases,the incidence of renal impairment increases.Age,SOFA score,urea nitrogen,gender,and norepinephrine use are independent factors affecting the serum trough concentrations of norvancomycin.