1.Outcomes of the modified Devine + Shiraki approach in the treatment of severe concealed penis
Xuejun HUANGFU ; Zhiqiang FAN ; Jia ZHENG ; Zhonghua LIU ; Xinglei HONG ; Yifan WANG
Chinese Journal of Plastic Surgery 2025;41(11):1152-1158
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.
2.Risk factors of anastomotic stenosis after esophageal cancer surgery
Wenrong YANG ; Aimin LI ; Lijie YANG ; Zhonghua LI ; Zheng SONG ; Wanchun YANG ; Jianyuan CHA
China Modern Doctor 2025;63(23):24-27
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.
3.Impacts of paeoniflorin on inflammation and NF-κB/NLRP3 signal pathway in knee osteoarthritis model rats
Zhongbo ZHANG ; Fuzeng ZHENG ; Shangzeng WANG ; Dongliang SHI ; Zhonghua GUO ; Yunfei WANG ; Zhentao WANG
Chinese Journal of Immunology 2025;41(8):1826-1832
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.
4.Mechanism of stachydrine-induced autophagy in improving atherosclerosis in high-fat-fed mice
Jun YANG ; Peng YIN ; Zhonghua ZHENG
Chinese Journal of Tissue Engineering Research 2025;29(24):5140-5147
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.
5.Impacts of paeoniflorin on inflammation and NF-κB/NLRP3 signal pathway in knee osteoarthritis model rats
Zhongbo ZHANG ; Fuzeng ZHENG ; Shangzeng WANG ; Dongliang SHI ; Zhonghua GUO ; Yunfei WANG ; Zhentao WANG
Chinese Journal of Immunology 2025;41(8):1826-1832
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.
6.Outcomes of the modified Devine + Shiraki approach in the treatment of severe concealed penis
Xuejun HUANGFU ; Zhiqiang FAN ; Jia ZHENG ; Zhonghua LIU ; Xinglei HONG ; Yifan WANG
Chinese Journal of Plastic Surgery 2025;41(11):1152-1158
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.
7.Mechanism of stachydrine-induced autophagy in improving atherosclerosis in high-fat-fed mice
Jun YANG ; Peng YIN ; Zhonghua ZHENG
Chinese Journal of Tissue Engineering Research 2025;29(24):5140-5147
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.
8.Risk factors of anastomotic stenosis after esophageal cancer surgery
Wenrong YANG ; Aimin LI ; Lijie YANG ; Zhonghua LI ; Zheng SONG ; Wanchun YANG ; Jianyuan CHA
China Modern Doctor 2025;63(23):24-27
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.
9.DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer.
Jiayu ZHANG ; Yingxi ZHAO ; Ruijuan LIANG ; Xue ZHOU ; Zhonghua WANG ; Cheng YANG ; Lingyue GAO ; Yonghao ZHENG ; Hui SHAO ; Yang SU ; Wei CUI ; Lina JIA ; Jingyu YANG ; Chunfu WU ; Lihui WANG
Acta Pharmaceutica Sinica B 2024;14(12):5219-5234
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.
10.Berberine regulates polarization of macrophages:a mechanistic study based on PI3K/Akt1 signaling pathway
Yushan CHEN ; Tingting WANG ; Zhonghua MENG ; Shasha SHANG ; Junmeng ZHENG ; Yonghua ZONG ; Chunying SI ; Yazhou LIANG ; Huaimin GUAN
Chinese Journal of Geriatric Heart Brain and Vessel Diseases 2024;26(6):694-698
Objective To explore the effect and possible mechanism of berberine on the macro-phage polarization of human myeloid leukemia monocytic cell line THP-1 induced by oxidized low-density lipoprotein(ox-LDL).Methods THP-1 cells were induced into macrophages by PMA,and then according to different concentrations of berberine,the cells were divided into con-trol group,and 5,10,20,40 and 50 μmol/L berberine groups.After intervention for 24 or 48 h,CCK8 assay was used to detect cell viability for optimal concentration and time of berberine treat-ment.PMA-induced THP-1 macrophages were assigned into blank group,model group(ox-LDL),berberine group,inhibitor group(phosphatidyl inositol 3-kinase(PI3K)inhibitor LY294002)and berberine+inhibitor group(berberine+LY294002).The contents of inducible nitric oxide syn-thase(iNOS)and TGF-β1 were detected by ELISA.qPCR was employed to measure the mRNA expression of TNF-α,arginase 1(Arg1),PI3K and protein kinase B Akt1,and Western blotting was applied to detect the protein levels of Akt1 and phosphorylated protein kinase B antibody(p-Akt1).Results In 24 h after intervention,the macrophage activity was significantly lower in the 40 and 50 μmol/L berberine groups than the control group(P<0.05),and after 48 h,the ac-tivity in all the 5 doses of berberine groups was obviously lower than that in the control group[(0.89±0.02)%,(0.82±0.03)%,(0.71±0.02)%,(0.62±0.03)%and(0.53±0.02)%vs(1.01±0.01)%,P<0.05].Berberine treatment of 20 μmol/L for 24 h had little effect on cell viability,and the dose and the time were regarded as the best concentration and time.Compared with the blank group,iNOS content and TNF-α mRNA level were increased in the model group,while TGF-β1 content,mRNA levels of Arg1,PI3K and Akt1,and p-Akt1/Akt1 protein levels were de-creased(P<0.05).iNOS content and TNF-α mRNA level were decreased,while TGF-β1 content,mRNA levels of Arg1,PI3K and Akt1 and protein levels of p-Akt1/Akt1s were increased in the berberine group than the model group(P<0.05).Compared with the berberine group,iNOS con-tent and TNF-α mRNA level were increased,while mRNA levels of Arg1,PI3K and Akt1 and protein levels of p-Akt1/Akt1 were decreased in the berberine+inhibitor group(P<0.05).Con-clusion Berberine can inhibit the inflammatory response of THP-1 macrophages induced by ox-LDL by activating PI3K/Akt1 pathway,and inhibit the M1 polarization and promote the M2 polarization of macrophages.

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