OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

OBJECTIVE: Recaticimab (SHR-1209) significantly reduces low-density lipoprotein cholesterol levels. However, its effect on glucose metabolism remains unclear. This study aimed to evaluate its effect on glycemic parameters in a Chinese population. METHODS: Recaticimab versus placebo was administered in a 5:1 ratio to 110 hyperlipidemia patients who were followed up for 24 weeks. Glycated hemoglobin (HbA1c) levels were measured at baseline every 12 weeks. Fasting plasma glucose (FPG) levels were measured at baseline at week 1, 3, 5, 8, 12, 16, 20, and 24. Repeated-measures mixed-effects models were used to determine the longitudinal association between reacticimab and FPG and HbA1c levels. RESULTS: Among the 81 participants with normal glucose metabolism, HbA1c levels significantly decreased ( F = 4.568, P = 0.036). In the 29 participants with abnormal glucose metabolism, a significant time effect was observed for FPG levels ( F = 2.492, P = 0.016). For participants with normal and abnormal glucose metabolism, no significant group × time interaction effects on FPG or HbA1c levels were identified. CONCLUSION Recaticimab showed no adverse glycemic effects in participants with normal or abnormal glucose metabolism, indicating its safety in patients with or without diabetes.
Humans ; Male ; Female ; Blood Glucose/drug effects* ; Middle Aged ; Double-Blind Method ; Hyperlipidemias/blood* ; Antibodies, Monoclonal, Humanized/therapeutic use* ; PCSK9 Inhibitors ; Glycated Hemoglobin ; Aged ; Adult ; Proprotein Convertase 9

The introduction of non-vitamin K antagonist oral anticoagulant (NOAC) into clinical use heralds a new age for anticoagulation therapy in patients with atrial fibrillation (AF).However,anticoagulation-related bleeding is currently a major challenge in the anticoagulation process.Assessing the risk of anticoagulation-related bleeding is an important part for the management of patients with AF.Clinical risk factor scores have moderate ability to predict the risk of anticoagulation-related bleeding.To improve the anticoagulation safety of NOACs,additional clinical and biological markers and genetic polymorphisms should be considered to enhance the predictive capability for anticoagulation-related bleeding.This review summarizes the challenges in the management of anticoagulation therapy,with emphases on the bleeding risk scores,biomarkers,clinical indicators,and genetic loci currently used to guide the risk assessment of anticoagulation-related bleeding in AF patients.This review is expected to provide research insights and reference frameworks for predicting and evaluating the bleeding risk associated with NOACs.
Humans ; Atrial Fibrillation/drug therapy* ; Anticoagulants/therapeutic use* ; Hemorrhage/chemically induced* ; Risk Assessment ; Administration, Oral ; Risk Factors

Objective To explore the relationships of cognitive impairment with cardiovascular death and all-cause death in menopausal women with hypertension.Methods A total of 4 595 natural-menopausal women with hypertension screened in Wuyuan County of Jiangxi Province from July to August 2018 were selected as the research subjects,and a follow-up investigation of death information was completed from June to August 2022.According to the baseline mini-mental state examination(MMSE)score,all subjects were allocated into a normal cognitive function group and a cognitive impairment group.The basic characteristics and the cumulative risk of death evaluated by the Kaplan-Meier curve were compared between two groups.The multivariate Cox regression model was adopted to analyze the effect of cognitive function on death,and the relationship between MMSE score and death was fitted by the restricted cubic spline.Results A total of 4 595 subjects with the mean age of(65.1±8.4)years were included in this study,in which and 1 859(40.5%)patients with cognitive impairment were detected.During a mean follow-up period of(3.9±0.4)years,199 all-cause deaths were collected,including 102 cardiovascular deaths.The normal cognitive function group and the cognitive impairment group had the cumulative all-cause death rates of 2.6%and 6.9%and the cumulative cardiovascular death rates of 1.0%and 4.0%,respectively.The Kaplan-Meier curve showed that the cumulative risks of all-cause death(χ²=47.287,P<0.001)and cardiovascular death(χ²=45.169,P<0.001)in the cognitive impairment group were higher than those in the normal cognitive function group.The results of multivariate Cox regression analysis indicated that compared with the normal cognitive function group,the cognitive impairment group had increased risks of all-cause death(HR=1.75,95%CI=1.28-2.39,P<0.001)and cardiovascular death(HR=2.56,95%CI=1.61-4.09,P<0.001).The results of the restricted cubic spline curve fitting showed that the MMSE score had linearly negative correlations with the risk of all-cause death(P_all<0.001, P n o n - l i n e a r i t y=0.519)and cardiovascular death(P_all<0.001, P n o n - l i n e a r i t y=0.195).Conclusion Cognitive impairment is an independent risk factor for all-cause death and cardiovascular death in menopausal women with hypertension,and early identification of cognitive impairment in this population is essential for timely intervention.
Humans ; Female ; Cognitive Dysfunction ; Hypertension/complications* ; Aged ; Middle Aged ; Menopause ; Proportional Hazards Models ; Risk Factors ; Cardiovascular Diseases/mortality* ; Cause of Death ; Kaplan-Meier Estimate

Objective To analyze the epidemiological distribution,microbiological characteristics,drug-resistance status,and risk factors for mortality in adult intensive care unit(ICU)patients with Klebsiella pneumoniae infection.Methods This multi-center prospective cohort study included ICU patients with suspected infection from 67 hospitals across 16 Chinese provinces/municipalities between July 1,2021 and December 31,2022.Clinical data and microbiological results were collected,and patients were divided into survival and non-survival groups according to their survival status and drug-resistance situation.Risk factors for mortality and drug resistance in ICU patients with Klebsiella pneumonia infection were determined through univariate and multivariate logistic regression analyses.Results A total of 2964 ICU-infected patients were enrolled,with 12 175 microbial specimens submitted for testing.Among these,487 specimens tested positive for Klebsiella pneumoniae.Ultimately,314 patients with Klebsiella pneumoniae infection were identified,primarily from lung infections,with a drug-resistance rate of 78.3%.The in-hospital mortality rate of ICU patients infected with Klebsiella pneumoniae was 19.8%.Univariate and multivariate logistic regression analyses revealed that older age(P=0.027),high drug-resistance rate(P=0.028),and low clinical-effectiveness rate(P<0.001)were independent risk factors for mortality in ICU patients infected with Klebsiella pneumoniae.Drug-resistance analysis showed that,compared with non-resistant cases,ICU patients with drug-resistant Klebsiella pneumoniae infection had lower pathogen-clearance rates(P=0.003),clinical-effectiveness rates(P=0.004),and antibiotic-effectiveness rates(P<0.010),and higher mortality rates(P=0.006).Patients with Klebsiella pneumoniae abdominal infection(P=0.003)and urinary tract infection(P=0.007)had higher drug-resistance incidences.There were no statistically significant differences in clinical-effectiveness rate,Klebsiella pneumoniae clearance,drug-resistance incidence,mortality rate,or hospital-stay length between patients with lung infection and those with non-lung infection of Klebsiella pneumoniae(P>0.05).Compared with patients with non-bloodstream infection,patients with bloodstream infection of Klebsiella pneumoniae had lower clinical-effectiveness rates(P=0.027)and higher mortality rates(P=0.021).Conclusions Older age,high drug-resistance rate,and low clinical-effectiveness rate are independent risk factors for mortality in ICU patients infected with Klebsiella pneumoniae.ICU patients with bloodstream infection of Klebsiella pneumoniae may have lower clinical-effectiveness rates and higher mortality rates.ICU patients with abdominal and urinary tract infections caused by Klebsiella pneumoniae are more likely to develop drug resistance.

Objective To investigate the clinical and pathological characteristics of adrenal cortical carcinoma(ACC),compare differences between hypercortisolism and non-functional ACC,and assess the diagnostic value of indicators such as Ki-67 index.Methods The clinical data of 57 ACC patients admitted to the First Medical Center of Chinese PLA General Hospital from January 2015 to March 2025 were retrospectively analyzed.According to the results of endocrine function assessment,47 of these patients were divided into hypercortisolism group(n=19)and non-functional group(n=28).The differences in clinical and pathological characteristics between the two groups were compared,and non-parametric tests and Spearman correlation analysis were used to explore the relationship between Ki-67 index and tumor stage as well as imaging features.Results Among the 57 patients,there were 20 males and 37 females,with a male-to-female ratio of 1:1.85.The age ranged from 16 to 76 years,and the age at diagnosis was(48.7±13.3)years.The tumor diameter was(10.53±4.14)cm.The tumors were located on the right side in 12 cases(21.1%),on the left side in 34 cases(59.6%),and bilaterally in 11 cases(19.3%).Among them,16 cases(28.1%)were complicated with glucose metabolism disorders,31 cases(54.3%)had hypertension,and 20 cases(35.1%)had hypokalemia.According to ENSAT staging,there were 0 cases in stage Ⅰ,15 cases(26.3%)in stage Ⅱ,24 cases(42.1%)in stage Ⅲ,and 18 cases(31.6%)in stage Ⅳ.Endocrine function assessment was completed in 47 of the 57 patients,including 28 cases(59.6%)of non-functional ACC and 19 cases(40.4%)of hypercortisolism(including 1 case of hypercortisolism combined with increased sex hormone secretion).Compared with non-functional group,hypercortisolism group had a significantly higher prevalence of hypertension(P=0.014),later ENSAT stage(P=0.010),and a higher proportion of hypervascularization(P=0.048).The median Ki-67 index was 20%(10%-40%),showing no significant correlation with either the maximum tumor diameter or SUVmax value,but it was related to ENSAT staging,with Ki-67 index in stageⅣ patients being significantly higher than that in stage Ⅱ(P=0.032).Immunohistochemistry results showed that the positive rate of Inhibin-α was 84.8%,and the positive rate of Melan-A was 40.9%.Conclusions ACC is a rare malignant endocrine tumor.ACC patients with hypercortisolism are more likely to be complicated with hypertension,have later staging,and more common hypervascular manifestations.Clinically,their endocrine function should be prioritized for assessment,and more active treatment strategies should be adopted.Diagnosis should be combined with imaging characteristics(such as hypervascularization)and immunohistochemical indicators(Ki-67,Inhibin-α,Melan-A).The significant increase in Ki-67 is in the advanced stage can serve as an important prognostic indicator to guide individualized treatment.

Objective To investigate the application value of peripheral blood soluble human leukocyte antigen-G(sHLA-G)combined with immune cytokines in the differential diagnosis of renal transplant rejection.Methods This case-control study retrospectively analyzed 81 renal transplant patients hospitalized in the Department of Organ Transplantation,the Second Affiliated Hospital of Naval Medical University from April 2020 to December 2023,due to elevated serum creatinine.Among them,32 patients were diagnosed with acute rejection(acute rejection group),29 with chronic rejection(chronic rejection group),and 20 with elevated creatinine due to non-rejection causes(non-rejection group).Fifty renal transplant inpatients and outpatients with normal and stable serum creatinine were selected as control group during the same period.Clinical data such as gender,age,serum creatinine,estimated glomerular filtration rate(eGFR),and urine protein positive rate,etc.were collected.Peripheral blood of patients was sampled to measure the levels of plasma sHLA-G and immune cytokines[interferon-γ(IFN-γ),tumor necrosis factor-β(TNF-β),interleukin(IL)-2,IL-4,IL-10,IL-5,IL-6,IL-17]using enzyme-linked immunosorbent assay(ELISA).Stratify and compare the differences in sHLA-G levels among different groups and all renal transplant inpatients by gender.Results Compared with control group,serum creatinine levels and urine protein positive rate were significantly higher in acute rejection group,chronic rejection group,and non-rejection group,while eGFR was significantly lower,serum creatinine levels in chronic rejection group and non-rejection group were higher than those in acute rejection group,while eGFR was lower than that in acute rejection group,with statistically significant differences(P<0.05).No statistically significant differences were observed in gender,age,blood type,body mass index,transplantation duration,and immunosuppressive agent use among acute rejection,chronic rejection,non-rejection,and control groups(P>0.05).Plasma sHLA-G levels in acute rejection and chronic rejection groups were significantly lower than those in control group[(19.665±11.233)U/ml vs.(24.785±21.668)U/ml vs.(44.918±39.898)U/ml,P<0.05].The sHLA-G/IL-2 ratio in chronic rejection group was significantly higher than that in acute rejection group(5.844±6.248 vs.1.825±1.574,P<0.05),and the sHLA-G/IFN-γ ratio in non-rejection group was significantly higher than that in chronic rejection group(3.452±3.283 vs.1.543±2.030,P<0.05).Among 131 renal transplant inpatients,female sHLA-G levels were significantly higher than male(P<0.05).Within each group,female sHLA-G levels in chronic rejection group were significantly higher than male(P<0.05).Although female sHLA-G levels in acute rejection,non-rejection,and control groups were higher than those of male,the gender difference was not statistically significant(P>0.05).Conclusions Peripheral blood sHLA-G levels are correlated with renal transplantation rejection.The application of sHLA-G/IL-2 and sHLA-G/IFN-γ ratios has potential value in the diagnosis and differentiation of elevated creatinine caused by acute/chronic rejection,chronic rejection and non-rejection causes,respectively.

Objective To analyze the clinical characteristics,treatment,and prognosis of immune checkpoint inhibitor-related diabetes mellitus(ICI-DM).Methods The clinical characteristics,laboratory examinations,treatment regimens,and follow-up outcomes of 10 ICI-DM patients who were diagnosed and treated in the First Medical Center of Chinese PLA General Hospital between July 2019 and December 2024 were retrospectively analyzed.Relevant literatures were retrieved from domestic and foreign databases such as PubMed,CNKI,and VIP.The clinical characteristics of ICI-DM were summarized based on the literature results.Results All 10 patients were PD-1 inhibitor users,including 5 males and 5 females,with a median age of 54.5(51.3,64.0)years and a body mass index(BMI)of(22.0±2.15)kg/m2.Among them,9 cases(90.0%)were fulminant type 1 diabetes mellitus(FT1DM);9 cases(90.0%)had a severity of adverse events reaching grade 3-4 according to the Common Terminology Criteria for adverse events(CTCAE).The median time from PD-1 inhibitor treatment to the occurrence of the classic diabetes symptoms referred to as"three more and one less"(polyuria,polydipsia,polyphagia,and weight loss)in all patients was 145.5(110.5,204.8)days,and the medication duration was 6.0(4.3,7.8)cycles.The average blood glucose level of the 10 patients at the time of consultation was 25.3(10.0-41.4)mmol/L,and the glycated hemoglobin(HbA1c)level was 8.0%(6.6%-10.9%).Eight patients had fasting and 2-hour C-peptide levels<0.1 ng/ml(fasting C-peptide from<0.010 to 0.067 ng/ml,2-hour C-peptide from<0.010 to 0.077 ng/ml).Nine of the 10 patients were negative for diabetes autoantibodies,while 1 was not tested.All 10 patients were successfully treated with insulin and other therapies.During the follow-up after discharge,all patients still relied on insulin treatment,and no significant recovery of pancreatic islet β cell function was observed compared with that at discharge.Literature review revealed that ICI-DM was more common in PD-1 inhibitor users,with clinical mainly manifested as diabetic ketoacidosis(DKA)(65.4%)and diabetic ketosis(13.1%).Patients had severely impaired pancreatic islet function and required long-term insulin treatment,and some cases were complicated by thyroid or pituitary dysfunction.Conclusions ICI-DM typically presents as FT1DM,often manifesting with DKA or diabetic ketosis at onset.It is characterized by severe and irreversible loss of pancreatic islet function,necessitating lifelong insulin therapy.To enable early detection and prompt treatment,close monitoring of blood glucose is essential during ICI treatment.