Neuropathic pain, a debilitating condition caused by dysfunction of the somatosensory nervous system, remains difficult to treat due to limited understanding of its molecular mechanisms. Bioinformatics analysis identified cerebellin 2 (CBLN2) as highly enriched in human and murine proprioceptive and nociceptive neurons. We found that CBLN2 expression is persistently upregulated in dorsal root ganglia (DRG) following spinal nerve ligation (SNL) in mice. In addition, transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription. SNL also induced SOX11 upregulation, with SOX11 and CBLN2 co-localized in nociceptive neurons. The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. High-throughput sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes, including upregulation of numerous NF-κB downstream targets. Consistently, CBLN2 activated NF-κB signaling, and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity, proinflammatory cytokines and chemokines production, and neuronal hyperexcitability. Together, these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.
Animals ; Neuralgia/metabolism* ; Ganglia, Spinal/metabolism* ; Up-Regulation ; Mice ; NF-kappa B/metabolism* ; SOXC Transcription Factors/genetics* ; Male ; Neuroinflammatory Diseases/metabolism* ; Mice, Inbred C57BL ; Nerve Tissue Proteins/genetics* ; Hyperalgesia/metabolism* ; Signal Transduction ; Spinal Nerves

Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of A ldoa strikingly decreased HCC development in vivo. Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.

OBJECTIVE: Glucocorticoid-induced osteoporosis (GIOP) is a common complication of prolonged glucocorticoid therapy. Chlorogenic acid (CGA), a polyphenol with antioxidant properties that is extracted from traditional Chinese medicines such as Eucommiae Cortex, has potential anti-osteoporotic activity. This study aimed to investigate the possible effects of CGA on GIOP in mice and murine long bone osteocyte Y4 (MLO-Y4) cells and explore the underlying molecular mechanisms. METHODS: The protective effects of CGA were initially evaluated in the GIOP mouse model induced by dexamethasone (Dex). The micro-computed tomography, hematoxylin-eosin staining, silver nitrate staining, and serum detection were used to assess the efficacy of CGA for improving bone formation in vivo. Then, network pharmacology analysis was used to predict the potential targets and molecular mechanisms underlying the therapeutic efficacy of CGA against GIOP. After that, 2',7'-dichlorofluorescein diacetate staining, flow cytometry, real-time quantitative reverse transcription polymerase chain reaction, and Western blotting were used to verify the mechanisms of CGA against GIOP in vitro. RESULTS: Animal experiments showed that CGA treatment effectively attenuated Dex-induced decreases in bone mass and strength and improved disrupted osteocyte morphology in mice. The protein-protein interaction analysis highlighted erb-b2 receptor tyrosine kinase (ERBB2), which is also known as human epidermal growth factor receptor 2 (HER2), caspase-3, kinase insert domain receptor, matrix metallopeptidase 9, matrix metallopeptidase 2, proto-oncogene tyrosine-protein kinase Src, and epidermal growth factor receptor as core targets. The Kyoto Encyclopedia of Genes and Genomes analysis revealed several significantly enriched pathways (P < 0.05), including the ERBB, phosphoinositide 3 kinase-AKT serine/threonine kinase 1 (AKT), and mechanistic target of rapamycin kinase (mTOR) pathways. Cellular experiments verified that CGA enhanced bone formation and promoted autophagy while inhibiting apoptosis in MLO-Y4 cells exposed to Dex, which was associated with the upregulated expression of HER2 and activation of the HER2/AKT/mTOR signaling pathway. CONCLUSION CGA exerted anti-osteoporotic effects against GIOP, partially through targeting osteocytes and modulating the HER2/AKT/mTOR signaling pathway. Please cite this article as: Xie AN, Zhang SZY, Zhang Y, Cao JL, Wang CL, Wang LB, Wu HJ, Zhang J, Dai WW. Chlorogenic acid mitigates glucocorticoid-induced osteoporosis via modulation of HER2/AKT/mTOR signaling pathway. J Integr Med. 2025; 23(6):670-682.
Animals ; Chlorogenic Acid/therapeutic use* ; Osteoporosis/metabolism* ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Mice ; Glucocorticoids/adverse effects* ; Receptor, ErbB-2/metabolism* ; Proto-Oncogene Mas ; Dexamethasone/adverse effects* ; Osteocytes/drug effects* ; Osteogenesis/drug effects* ; Male ; Cell Line ; Mice, Inbred C57BL ; Humans

Lipids,including fats(triglycerides)and lipoids(phospholipids and sterols),not only serve as an energy source for the body but also play a pivotal role throughout the reproductive process,particularly in the establishment and maintenance of early pregnancy.This encompasses the regulate of early embryonic development and uterine tolerance,and the facilitation of embryo implantation.Given the diversity of lipids,this review focuses on extensively studied lipid mediators such as polyunsaturated fatty acids,endocannabinoids,prostaglandins,lysophosphatidic acid,sphingolipids and steroid hormones.It systematically elaborates on the regulatory effects of fatty acid,phospholipid,and cholesterol metabolism on the formation of endometrial receptivity and embryo implantation,as well as the potential underlying mechanisms.The review aims to provide new insights and feasible intervention approaches for predicting and improving the outcomes of natural pregnancy and/or assisted reproductive technology.

Objective:Based on the health ecological model, this paper systematically explores the influencing factors of mild cognitive impairment among the elderly herders in Nanshan pastoral area of Xinjiang, and provides the basis for local medical institutions to formulate prevention and control strategies for mild cognitive impairment among the elderly herders.Methods:A total of 1 145 valid questionnaires were collected, all of them were permanent herdsmen aged over 60 years in Nanshan pastoral area of Xinjiang were selected from June 2022 to February 2023 by stratified cluster random sampling method in a cross-sectional survey. Under the guidance of health ecological model, the research variables were included from five dimensions: physiology, psychology, behavioral lifestyle, social network and medical and health environment, and questionnaires were conducted. SPSS 23.0 was used for chi-square test and binary Logistic regression to analyze the influencing factors of mild cognitive impairment in elderly herders.Results:There were 564 males and 581 females with age of (70.84 ± 5.69) years old in the study. The prevalence rate of mild cognitive impairment among elderly herdsmen in Nanshan pastoral area of Xinjiang was 36.1%(413/1 145). Binary Logistic regression analysis showed that: personal monthly income (1 000-2 999 yuan)( OR = 0.583, 95% CI 0.366 - 0.926, P<0.05), education level (junior high school and above)( OR = 0.479, 95% CI 0.315 - 0.728, P<0.01) were the protective factors for mild cognitive impairment among the elderly herdsmen in Nanshan pastoral area. Hypertension ( OR = 1.842, 95% CI 1.256 - 2.702, P<0.01), dyslipidemia ( OR = 1.449, 95% CI 1.069 - 1.964, P<0.05) and chronic pain ( OR = 1.549, 95% CI 1.082 - 2.216, P<0.05) were the risk factors of mild cognitive impairment in elderly herders in Nanshan pastoral area. Conclusions:The prevalence rate of mild cognitive impairment among elderly herders in Nanshan pastoral area of Xinjiang is high, so it is necessary to carry out mild cognitive impairment screening as soon as possible, especially focusing on people suffering from hypertension, dyslipidemia and chronic pain, and making intervention plans to delay the occurrence and development of mild cognitive impairment and improve the quality of life of elderly herders.

Objective To investigate the results of ambulatory electrocardiographic(ECG)monitoring in a community-based homebound elderly population and to explore the applicability of wearable long-range ambulatory ECG monitor for them.Methods Elderly volunteers were recruited in Shuangbei Community,Shapingba District,Chongqing,from November 2021 to June 2023.A single-lead wearable ambulatory ECG recorder was applied to them to obtain ECG for 7 consecutive days.The adverse reactions,acceptability,monitoring duration,and arrhythmia detection rate during the wearing were described and recorded.Serious arrhythmic events included frequent atrial premature,atrial flutter,atrial fibrillation(AF),frequent ventricular premature,and RR intervals ≥5 s.Results There were 416 individuals enrolled,with a mean age of 71.2±6.6 years,and a male percentage of 36.1％(150 men).Finally,384(92.3％)participants completed the wearing of the ECG monitor for 7 d,with an average time of 159.2±29.4 h.There were 179 participants(48.5％)reporting no discomfort during wearing,and 175 ones(47.4％)feeling itchy at the wearing site.The monitoring results showed that the common arrhythmias were atrial premature contractions(97.1％),premature ventricular contractions(93.3％),atrial tachycardia(84.6％),bradycardia(46.6％),frequent atrial premature contractions(15.1％),ventricular tachycardia(13.2％),and long RR interval(11.8％).Among them,29.1％of the participants experienced serious arrhythmic events,and the detection rate of certain serious arrhythmic events was comparatively higher in the individuals≥70 years of age and those with history of previous cardiac disease.Conclusion The detection rate of common arrhythmias is quite high in the community-based homebound elderly population.A 7-day long-range ambulatory ECG monitoring may be appropriate.

Objective To analyze and construct systolic blood pressure(SBP)fluctuation trajectory in a community population with hypertension and to analyze the factors influencing different trajectories.Methods This is a community-based retrospective cohort study.A latent class trajectory model was used to identify and construct longitudinal trajectories of blood pressure change.Multinomial logistic regression analysis was performed to identify the associated factors of blood pressure trajectories by adjusting for different confounders.Potential confounding factors were identified using a directed acyclic graph based on a priori knowledge.Results A total of 793 patients with hypertension were enrolled in the analysis.They were divided into 3 groups by LCTM-fitted systolic blood pressure trajectories,namely stable low-level group(n=561,70.74％),declining group(n=170,21.44％)and rising group(n=62,7.82％).Significant differences were observed among the 3 trajectories groups in terms of age,frequency of exercise,ways of follow-up,salt intake,compliance behavior,and referral(P＜0.05).Compared to the stable low-level group and adjusting for corresponding confounding factors,the male patients and the patients with"outpatient follow-up"were more likely to be classified into"declining group",with OR and 95％CI of 1.436(1.016～2.030)and 1.702(1.202～2.410),respectively.The participants aged ≥ 65 years,who did not exercise or occasionally exercised,and had moderate and severe salt intake,were more likely to be classified into the"rising group"(OR=1.949,2.284,2.433,4.540,95％CI:1.145～3.317,1.305～3.998,1.272～4.654,1.291～15.963).Conclusion SBP trajectories in community-dwelling hypertensive population can be divided into stable low-level,declining and rising groups.Gender,age,salt intake,exercise frequency,and follow-up methods may be influencing factors for SBP blood pressure trajectory.

Background::Total human immunodeficiency virus (HIV) DNA and integrated HIV DNA are widely used markers of HIV persistence. Droplet digital polymerase chain reaction (ddPCR) can be used for absolute quantification without needing a standard curve. Here, we developed duplex ddPCR assays to detect and quantify total HIV DNA and integrated HIV DNA.Methods::The limit of detection, dynamic ranges, sensitivity, and reproducibility were evaluated by plasmid constructs containing both the HIV long terminal repeat (LTR) and human CD3 gene (for total HIV DNA) and ACH-2 cells (for integrated HIV DNA). Forty-two cases on stable suppressive antiretroviral therapy (ART) were assayed in total HIV DNA and integrated HIV DNA. Correlation coefficient analysis was performed on the data related to DNA copies and cluster of differentiation 4 positive (CD4 +) T-cell counts, CD8 + T-cell counts and CD4/CD8 T-cell ratio, respectively. The assay linear dynamic range and lower limit of detection (LLOD) were also assessed. Results::The assay could detect the presence of HIV-1 copies 100% at concentrations of 6.3 copies/reaction, and the estimated LLOD of the ddPCR assay was 4.4 HIV DNA copies/reaction (95% confidence intervals [CI]: 3.6-6.5 copies/reaction) with linearity over a 5-log 10-unit range in total HIV DNA assay. For the integrated HIV DNA assay, the LLOD was 8.0 copies/reaction (95% CI: 5.8-16.6 copies/reaction) with linearity over a 3-log 10-unit range. Total HIV DNA in CD4 + T cells was positively associated with integrated HIV DNA ( r = 0.76, P <0.0001). Meanwhile, both total HIV DNA and integrated HIV DNA in CD4 + T cells were inversely correlated with the ratio of CD4/CD8 but positively correlated with the CD8 + T-cell counts. Conclusions::This ddPCR assay can quantify total HIV DNA and integrated HIV DNA efficiently with robustness and sensitivity. It can be readily adapted for measuring HIV DNA with non-B clades, and it could be beneficial for testing in clinical trials.

Background: Triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) are reliable surrogate indices of insulin resistance and used for risk stratification and outcome prediction in patients with atherosclerotic cardiovascular disease (ASCVD). Here, we inserted estimated average glucose (eAG) into the TyG (TyAG) and TyG-BMI (TyAG-BMI) as derived parameters and explored their clinical significance in cardiovascular risk prediction. Methods: This was a population-based cohort study of 9,944 Chinese patients with ASCVD. The baseline admission fasting glucose and A1C-derived eAG values were recorded. Cardiovascular events (CVEs) that occurred during an average of 38.5 months of follow-up were recorded. We stratified the patients into four groups by quartiles of the parameters. Baseline data and outcomes were analyzed. Results: Distribution of the TyAG and TyAG-BMI indices shifted slightly toward higher values (the right side) compared with TyG and TyG-BMI, respectively. The baseline levels of cardiovascular risk factors and coronary severity increased with quartile of TyG, TyAG, TyG-BMI, and TyAG-BMI (all P<0.001). The multivariate-adjusted hazard ratios for CVEs when the highest and lowest quartiles were compared from low to high were 1.02 (95% confidence interval [CI], 0.77 to 1.36; TyG), 1.29 (95% CI, 0.97 to 1.73; TyAG), 1.59 (95% CI, 1.01 to 2.58; TyG-BMI), and 1.91 (95% CI, 1.16 to 3.15; TyAG-BMI). The latter two showed statistical significance. Conclusion This study suggests that TyAG and TyAG-BMI exhibit more information than TyG and TyG-BMI in disease progression among patients with ASCVD. The TyAG-BMI index provided better predictive performance for CVEs than other parameters.

Objective To investigate the clinical features and risk factors of primary biliary cholangitis(PBC)comorbid with metabolic associated fatty liver disease(MAFLD)and the interaction between the two diseases.Methods A total of 187 patients who were diagnosed with PBC,MAFLD,or PBC with MAFLD in The First Affiliated Hospital of Kunming Medical University from January 2019 to December 2022 were enrolled and divided into PBC group with 70 patients,PBC+MAFLD group with 38 patients,and MAFLD group with 79 patients.Related data were collected,including general information,clinical symptoms,serological parameters,transient elastography(FibroScan),and non-invasive fibrosis markers,which were compared between the three groups.A one-way analysis of variance or the Kruskal-Wallis H test was used for comparison of continuous data between groups,the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups,and the binary Logistic regression analysis was used for multivariate analysis.Results There were significant differences between the three groups in sex,age,height,weight,body mass index(BMI),and history of autoimmune diseases(P<0.05).In the PBC+MAFLD group,female patients accounted for 89.5%,with a mean age of 57.26±12.72 years and a BMI of 23.35±3.70 kg/m2,and in the PBC group,the detection rate of autoimmune diseases was 25.7%(18 patients).There were significant differences between the three groups in the incidence rates of weakness,poor appetite,pruritus,jaundice,varices,ascites,and splenomegaly(all P<0.05).The PBC+MAFLD group had the common symptoms of weakness in 18 patients(47.4%),poor appetite in 15 patients(39.5%),abdominal pain in 14 patients(36.8%),and abdominal distension in 16 patients(42.1%);the MAFLD group had the common symptoms of abdominal pain in 34 patients(43%)and abdominal distension in 32 patients(40.5%);the PBC group had the common symptoms of weakness in 37 patients(52.9%),poor appetite in 25 patients(35.7%),jaundice in 25 patients(35.7%),abdominal pain in 18 patients(25.7%),abdominal distension in 25 patients(35.7%),varices in 19 patients(27.9%),ascites in 23 patients(32.9%),and splenomegaly in 44 patients(62.9%).The PBC+MAFLD group had a controlled attenuation parameter(CAP),which was higher than that of the PBC group,and the PBC group had significantly higher levels of liver stiffness measurement,aspartate aminotransferase-to-platelet ratio index(APRI),and fibrosis-4(FIB-4)than the MAFLD group(all P<0.05).The factors without multicollinearity were included in the regression analysis,and with the PBC group as the reference group,FIB-4(odds ratio[OR]=0.218,95%confidence interval[CI]:0.069-0.633,P<0.05)and history of autoimmune diseases(OR=0.229,95%CI:0.067-0.810,P<0.05)were influencing factors for the onset of PBC with MAFLD;with the MAFLD group as the reference group,ALT(OR=0.157,95%CI:0.025-1.000,P<0.05)and TBil(OR=0.995,95%CI:0.990-0.999,P<0.05)were influencing factors for the onset of PBC with MAFLD.Conclusion PBC with MAFLD lacks specific clinical manifestations,and PBC patients tend to have more severe clinical manifestations and a higher incidence rate of liver function decompensation.PBC comorbid with MAFLD may not aggravate the disease progression of PBC.