OBJECTIVE To investigate the potential mechanism of berberine improving diabetes mellitus type 2 （T2DM） combined with metabolic-associated fatty liver disease （MAFLD） by regulating ceramide. METHODS Thirty-two db/db mice with blood glucose levels＞11.1 mmol/L （T2DM model） were divided into four groups： model group， berberine low- and high-dose groups [100， 200 mg/（kg·d）] and metformin group [300 mg/（kg·d）]， with 8 mice in each group. Additionally， 8 wt/wt mice were selected as the normal control group. Mice in each group were administered the corresponding drug solution or water by gavage once daily for a continuous period of 6 weeks. During the experiment， the body weight of the mice was monitored， and the differences in final body weight were analyzed. After the last administration， the body shape of the mice in each group was observed， and their fasting blood glucose （FBG） and the lipid indicators [total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）] were measured. Fasting serum insulin （FINS） levels were also measured， and the insulin resistance index HOMA-IR） and insulin sensitivity index （ISI） were calculated. Liver weight， liver index and serum liver function indicators [alanine transaminase （ALT）， aspartate transaminase（AST）] were assessed， and hepatic histopathological changes were observed. Additionally， the expression of fatty acid synthesis-related proteins [sterol regulatory element-binding protein 1 （SREBP1）， fatty acid synthase （FASN）， acetyl-CoA carboxylase 1 （ACC1）] in liver tissue was examined. Serum samples from the normal control group， model group， and berberine high-dose group were collected for non-targeted lipidomics analysis and validation. RESULTS Compared with the model group， the pathological changes， including disordered liver tissue cell arrangement and lipid vacuoles， were significantly improved in the berberine low- and high-dose groups. The significant decreases or down-regulations were observed in body weight in the last week， as well as FBG， TC， TG， and LDL-C levels， HOMA-IR （except for the berberine low-dose group）， liver weight， liver index， AST and ALT levels， and protein expressions of SREBP1， FASN and ACC1. Additionally， HDL-C levels， FINS （except for the berberine high-dose group）， and ISI （except for the berberine low-dose group） were significantly increased （P＜0.05）. A total of 21 potential differential metabolites， including multiple types of ceramides， were identified； these metabolites were primarily enriched in sphingolipid metabolism and glycerophospholipid metabolism pathways. Verification experiments confirmed that high-dose berberine significantly reduced the serum content of ceramide in model mice （P＜0.05）. CONCLUSIONS Berberine reduces insulin resistance， improves liver damage and lipid accumulation in the T2DM combined with MAFLD mice， and these effects may be related to the reduction of ceramide content.

Objective:To investigate the related factors of cognitive impairment in middle-aged and old-aged patients with type 2 diabetes mellitus(T2DM).Methods:A total of 970 patients with T2DM(585 middle-aged group and 385 old-aged group)were selected from residents of a large community in Beijing from September to December 2018.The Mini-Mental State Examination(MMSE)was used to assess the cognitive func-tion.Multivariate logistic regression was used to analyze the related factors.Results:The detection rates of cognitive impairment were 12.0％and 13.5％in middle-aged and old-aged patients with T2DM,respectively.Among mid-dle-aged patients with T2DM,work(OR=0.22,95％CI:0.03-0.77)and education at the junior college or un-dergraduate level and above(OR=0.18,95％CI:0.04-0.55)were protective factors for cognitive impair-ment.Myocardial infarction(OR=4.13,95％CI:1.26-13.63)was a risk factor for cognitive impairment.Among old-aged patients with T2DM,drinking tea 1-2 times a week(OR=0.11,95％CI:0.01-0.58)and education at the junior college or undergraduate level and above(OR=0.19,95％CI:0.05-0.54)were protective factors for cognitive impairment.Stroke(OR=3.64,95％CI:1.55-8.39)and good sleep self-assessment(OR=2.75,95％CI:1.13-7.35)were risk factors for cognitive impairment.Conclusion:Cognitive impairment in middle-aged pa-tients with T2DM is related to work,education level and myocardial infarction,and cognitive impairment in old-aged patients with T2DM is related to lifestyle,education level and stroke.

Objective:To investigate the related factors of cognitive impairment in middle-aged and old-aged patients with type 2 diabetes mellitus(T2DM).Methods:A total of 970 patients with T2DM(585 middle-aged group and 385 old-aged group)were selected from residents of a large community in Beijing from September to December 2018.The Mini-Mental State Examination(MMSE)was used to assess the cognitive func-tion.Multivariate logistic regression was used to analyze the related factors.Results:The detection rates of cognitive impairment were 12.0％and 13.5％in middle-aged and old-aged patients with T2DM,respectively.Among mid-dle-aged patients with T2DM,work(OR=0.22,95％CI:0.03-0.77)and education at the junior college or un-dergraduate level and above(OR=0.18,95％CI:0.04-0.55)were protective factors for cognitive impair-ment.Myocardial infarction(OR=4.13,95％CI:1.26-13.63)was a risk factor for cognitive impairment.Among old-aged patients with T2DM,drinking tea 1-2 times a week(OR=0.11,95％CI:0.01-0.58)and education at the junior college or undergraduate level and above(OR=0.19,95％CI:0.05-0.54)were protective factors for cognitive impairment.Stroke(OR=3.64,95％CI:1.55-8.39)and good sleep self-assessment(OR=2.75,95％CI:1.13-7.35)were risk factors for cognitive impairment.Conclusion:Cognitive impairment in middle-aged pa-tients with T2DM is related to work,education level and myocardial infarction,and cognitive impairment in old-aged patients with T2DM is related to lifestyle,education level and stroke.

Objective:To study the relationship between hemoglobin glycation index (HGI) and blood lipid indices such as low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and plasma atherogenic index (AIP).Methods:This cross-sectional study included 16 049 participants from the Beijing Apple Garden community between December 2011 and August 2012. The subjects were divided into three groups based on the HGI quartile: low ( n=5 388), medium ( n=5 249), and high ( n=5 412). The differences in blood lipid indicators between different HGI groups were compared and multivariate logistic regression model was established to analyze the association between HGI and dyslipidemia. And multivariate logistic regression model was established to analyze the relationship between HGI and blood lipid indicators in different glucose metabolism populations. Results:There were 16 049 participants in all (mean age: 56 years), including 10 452 women (65.1%). They were classified into normal glucose tolerance (9 093 cases), prediabetes (4 524 cases), and diabetes (2 432 cases) based on glucose tolerance status. In the general population, with the increase of HGI, LDL-C, non-HDL-C, and AIP gradually increased (all P values for trends were <0.05), and the proportion of abnormalities increased significantly ( χ2=101.40, 42.91, 39.80; all P<0.001). A multivariate logistic regression model was established, which suggested a significant correlation between HGI and LDL-C, non-HDL-C, and AIP (all P<0.05), after adjusting for factors such as age, sex, fasting blood glucose, hypertension, body mass index, smoking, and alcohol consumption. In the overall population, normal glucose tolerance group, and diabetes group, HGI had the highest correlation with non-HDL-C ( OR values of 1.325, 1.678, and 1.274, respectively); in the prediabetes group, HGI had a higher correlation with LDL-C ( OR value: 1.510); and in different glucose metabolism groups, AIP and HGI were both correlated ( OR: 1.208-1.250), but not superior to non-HDL-C and LDL-C. Conclusion:HGI was closely related to LDL-C, non HDL-C, and AIP in the entire population and people with different glucose metabolism, suggesting that HGI may be a predictor of atherosclerotic cardiovascular disease.

Background:Esophageal neuroendocrine neoplasms(E-NENs)are rare and highly aggressive malignancies.Although endoscopic resection(ER)has demonstrated efficacy in managing gastrointestinal neuroendocrine tumors,ER for E-NENs lacks systematic evidence.Aims:To evaluate the feasibility and safety of ER in E-NENs,establish risk-stratified follow-up strategies based on tumor grade,invasion depth,and margin status,and define indications for ER.Methods:A retrospective analysis was conducted for 8 E-NEN patients treated with ER at the Endoscopy Center,Zhongshan Hospital,Fudan University from November 2017 to July 2021.The clinicopathological data,procedural parameters,adverse events,and follow-up outcomes were collected to summarize the diagnostic and therapeutic insights.Results:The cohort included 8 patients,with male-to-female ratio of 1:1;the mean age was(71.4±8.5)years.Half of the cases were incidentally detected during asymptomatic endoscopic screening.All tumors were confined to the submucosa:4 were small cell neuroendocrine carcinomas(SCNECs),and 4 were mixed neuroendocrine-non-neuroendocrine neoplasms(MiNENs).Endoscopic submucosal dissection(ESD)was performed in 6 cases and submucosal tunneling endoscopic resection(STER)in 2 cases.Self-limiting fever was reported in one case.One cases required additional surgery due to horizontal margin involving(no recurrence over 67 months follow-up).The median hospitalization was 4.5 days.With a median follow-up of 66 months,the recurrence and all-cause mortality rates were both 25.0%(2/8).Conclusions:MiNENs≤2.5 cm with complete ER exhibit favorable prognoses,whereas SCNECs with high mitotic indices or elevated Ki-67 proliferation indices correlate with poorer outcomes.Post-ER surveillance for E-NENs should meet or exceed esophageal squamous cell carcinoma standards.As the largest single-center ER cohort for E-NENs,this study provides critical evidence for minimally invasive management,though multicenter validation is needed.

Background:Esophageal neuroendocrine neoplasms(E-NENs)are rare and highly aggressive malignancies.Although endoscopic resection(ER)has demonstrated efficacy in managing gastrointestinal neuroendocrine tumors,ER for E-NENs lacks systematic evidence.Aims:To evaluate the feasibility and safety of ER in E-NENs,establish risk-stratified follow-up strategies based on tumor grade,invasion depth,and margin status,and define indications for ER.Methods:A retrospective analysis was conducted for 8 E-NEN patients treated with ER at the Endoscopy Center,Zhongshan Hospital,Fudan University from November 2017 to July 2021.The clinicopathological data,procedural parameters,adverse events,and follow-up outcomes were collected to summarize the diagnostic and therapeutic insights.Results:The cohort included 8 patients,with male-to-female ratio of 1:1;the mean age was(71.4±8.5)years.Half of the cases were incidentally detected during asymptomatic endoscopic screening.All tumors were confined to the submucosa:4 were small cell neuroendocrine carcinomas(SCNECs),and 4 were mixed neuroendocrine-non-neuroendocrine neoplasms(MiNENs).Endoscopic submucosal dissection(ESD)was performed in 6 cases and submucosal tunneling endoscopic resection(STER)in 2 cases.Self-limiting fever was reported in one case.One cases required additional surgery due to horizontal margin involving(no recurrence over 67 months follow-up).The median hospitalization was 4.5 days.With a median follow-up of 66 months,the recurrence and all-cause mortality rates were both 25.0%(2/8).Conclusions:MiNENs≤2.5 cm with complete ER exhibit favorable prognoses,whereas SCNECs with high mitotic indices or elevated Ki-67 proliferation indices correlate with poorer outcomes.Post-ER surveillance for E-NENs should meet or exceed esophageal squamous cell carcinoma standards.As the largest single-center ER cohort for E-NENs,this study provides critical evidence for minimally invasive management,though multicenter validation is needed.

Humans ; Nitric Oxide ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms ; Lung ; Nitric Oxide Synthase ; Macrophages, Alveolar ; Pulmonary Alveoli

Objective To investigate the efficacy of continuous hepatic arterial infusion chemotherapy (HAIC) with the FOLFOX regimen and its multimodality therapeutic regimen in the treatment of patients with advanced hepatocellular carcinoma, as well as the influencing factors for prognosis. Methods A retrospective analysis was performed for the clinical data of 66 patients with advanced hepatocellular carcinoma who received continuous HAIC with FOLFOX regimen in Nanfang Hospital, Southern Medical University, from September 2018 to November 2021. The patients were observed in terms of objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) after treatment, and treatment-related adverse reactions were recorded. For the patients with portal vein tumor thrombus, the effect of the treatment on portal vein tumor thrombus was assessed. The Kaplan-Meier method was used for survival analysis, and the Cox regression analysis was used to investigate the influencing factors for prognosis. Results According to the RECIST1.1 criteria, FOLFOX-HAIC and its multimodality therapeutic regimen achieved an ORR of 33.3% (22/66) and a DCR of 86.4% (57/66) in the treatment of 66 patients with advanced hepatocellular carcinoma, with an mPFS time of 8.2 months and an mOS time of 22.1 months. Among the 39 patients with portal vein tumor thrombus, 2 achieved complete remission, 8 achieved partial remission, 24 achieved stable disease, and 5 had disease progression, with an ORR of 25.6% (10/39) and a DCR of 87.2% (34/39). The main adverse reactions included gastrointestinal reactions (16.7%, 11/66), pyrexia (12.1%, 8/66), liver area pain (10.6%, 7/66), bone marrow suppression (3.0%, 2/66), and contrast agent allergy (3.0%, 2/66), and there were no grade > Ⅳ toxic or side effects or deaths caused by such complications. The Cox regression analysis showed that extrahepatic metastasis (hazard ratio [ HR ]=2.668, 95% confidence interval [ CI ]: 1.357-5.245, P < 0.05) and prothrombin time (PT) ( HR =1.282, 95% CI : 1.080-1.630, P < 0.05) were independent risk factors for PFS, and aspartate aminotransferase level ( HR =1.008, 95% CI : 1.002-1.013, P < 0.05) and PT ( HR =1.303, 95% CI : 1.046-1.630, P < 0.05) were independent risk factors for OS. Conclusion FOLFOX-HAIC and its multimodality therapeutic regimen has a certain clinical effect with controllable adverse reactions in the treatment of advanced hepatocellular carcinoma.

Objective:To explore the value of the aMAP risk score (age, male, albumin -bilirubin, and platelets) to predict early recurrence within one year after microwave ablation in patients with small hepatocellular carcinoma. Methods:This was a retrospective study that enrolled 142 patients diagnosed with hepatocellular carcinoma who were treated with microwave ablation in the Department of Hepatology Unit of Nanfang Hospital, Southern Medical University from July 2016 to July 2021. The cohort enrolled 121 male and 21 female patients, including 110 patients that were <60 years old. All the patients were followed-up after microwave ablation to evaluate residual tumor and recurrence of tumor by computed tomography or magnetic resonance imaging. The observation indices mainly included general data and imaging data of patients. Using the X-tile tools, patients were divided into two groups: a high aMAP score group and a low aMAP score group. Multivariate Cox regression analysis was conducted for comparison of independent risk factors.Results:Multivariate Cox regression showed that high aMAP score, maximum tumor diameter >20 mm, and high AFP were the independent risk factors of early recurrence (all P<0.05). Kaplan-Meier survival curves showed that the median recurrence-free survival was 25.5 months in the low aMAP score group and 6.1 months in the high aMAP score group ( P=0.001). Conclusions:The aMAP score could predict the early recurrence within 1 year of small hepatocellular carcinoma after microwave ablation. Patients with high aMAP score should undergo rigorous postoperative follow-up evaluations..

Objective:To investigate the influence of hemoglobin glycation index (HGI) on the risk of incident chronic kidney disease (CDK) among nondiabetic patients.Methods:Prospective cohort study. At baseline, a total of 7 407 nondiabetic patients without a history of CKD from Pingguoyuan Community of the Shijingshan District in Beijing were included from December 2011 to August 2012, who were then divided into three groups according to the tertiles of their baseline HGI levels. The CKD incidence rate was compared among the different HGI groups at last follow-up. Cox multivariable regression was applied to evaluate whether HGI measures predicted CKD risk. Test for trend across tertiles were examined using ordinal values in separate models.Results:The mean age of the subjects was (56.4±7.5) years, and 4 933 (66.6%) were female. At mean follow-up of 3.23 years, 107 (1.4%) individuals developed CKD. The incidence of CKD was gradually increasing from the low to high HGI groups [1.1% (28/2 473) vs. 1.2% (31/2 564) vs. 2.0% (48/2 370), P=0.016]. In the multivariate Cox regression analysis, after adjustment for potential confounders, the high HGI group had a 68.5% increased risk of CKD compared with the low HGI group ( HR=1.685, 95% CI 1.023 to 2.774). CKD risk increased with increasing HGI tertiles ( P for trend=0.028). Conclusion:High HGI is associated with an increased risk for CKD in the nondiabetic population, indicating that HGI may help identify individuals at high risk for CKD.