Background/Aims: Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed. Methods: We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models. Results: ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis. Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.

BACKGROUND: The role of inflammation in the development of gestational diabetes mellitus (GDM) has recently become a focus of research. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI), novel indices, reflect the body's chronic immune-inflammatory state. This study aimed to investigate the associations between the SII or SIRI and GDM. METHODS: A prospective birth cohort study was conducted at Beijing Obstetrics and Gynecology Hospital from February 2018 to December 2020, recruiting participants in their first trimester of pregnancy. Baseline SII and SIRI values were derived from routine clinical blood results, calculated as follows: SII = neutrophil (Neut) count × platelet (PLT) count/lymphocyte (Lymph) count, SIRI = Neut count × monocyte (Mono) count/Lymph count, with participants being grouped by quartiles of their SII or SIRI values. Participants were followed up for GDM with a 75-g, 2-h oral glucose tolerance test (OGTT) at 24-28 weeks of gestation using the glucose thresholds of the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Logistic regression was used to analyze the odds ratios (ORs) (95% confidence intervals [CIs]) for the the associations between SII, SIRI, and the risk of GDM. RESULTS: Among the 28,124 women included in the study, the average age was 31.8 ± 3.8 years, and 15.76% (4432/28,124) developed GDM. Higher SII and SIRI quartiles were correlated with increased GDM rates, with rates ranging from 12.26% (862/7031) in the lowest quartile to 20.10% (1413/7031) in the highest quartile for the SII ( Ptrend <0.001) and 11.92-19.31% for the SIRI ( Ptrend <0.001). The ORs (95% CIs) of the second, third, and fourth SII quartiles were 1.09 (0.98-1.21), 1.21 (1.09-1.34), and 1.39 (1.26-1.54), respectively. The SIRI findings paralleled the SII outcomes. For the second through fourth quartiles, the ORs (95% CIs) were 1.24 (1.12-1.38), 1.41 (1.27-1.57), and 1.64 (1.48-1.82), respectively. These associations were maintained in subgroup and sensitivity analyses. CONCLUSION The SII and SIRI are potential independent risk factors contributing to the onset of GDM.
Humans ; Female ; Pregnancy ; Diabetes, Gestational/immunology* ; Prospective Studies ; Adult ; Inflammation/immunology* ; Glucose Tolerance Test ; Birth Cohort

Mesenchymal stem cells(MSCs)have become a key focus in the development of cell-based therapeutic products due to their wide availability,lack of ethical constraints,and potential for immune privileges.However,the transition from basic MSC transplantation techniques to fully devel-oped therapeutic drugs presents numerous challenges given the current regulatory framework in China and from the perspective of drug development and review.This article summarizes the problems faced in this transition,particularly the challenges posed by theheterogeneity of MSC sources,the complexity of unique manufacturing processes,and the complexities of quality characterization.The article also offers suggestions and countermeasures in the hopes of advancing the research,development,and registration of MSC-based therapeutic products.

Mesenchymal stem cells(MSCs)have become a key focus in the development of cell-based therapeutic products due to their wide availability,lack of ethical constraints,and potential for immune privileges.However,the transition from basic MSC transplantation techniques to fully devel-oped therapeutic drugs presents numerous challenges given the current regulatory framework in China and from the perspective of drug development and review.This article summarizes the problems faced in this transition,particularly the challenges posed by theheterogeneity of MSC sources,the complexity of unique manufacturing processes,and the complexities of quality characterization.The article also offers suggestions and countermeasures in the hopes of advancing the research,development,and registration of MSC-based therapeutic products.

Objective:To investigate the association of time in range(TIR) with the severity of coronary artery disease and acute coronary syndrome in patients with type 2 diabetes mellitus.Methods:A total of 216 patients with type 2 diabetes mellitus and coronary heart disease were recruited and undergone anthropometric and biochemical measurements, continuous glucose monitoring, and calculation of SYNTAX score. TIR was defined as the percentage of time within the glucose range of 3.9-10.0 mmol/L during 24 h. Spearman correlation analysis and multivariate linear regression analysis were used to evaluate the correlation factors of SYNTAX score. Multivariate logistic regression analysis was used to analyze the association of TIR with the severity of coronary artery disease and acute coronary syndrome. Results:Compared with patients with mild coronary artery disease, TIR in patients with moderate to severe coronary artery disease was lower[(69.4±17.3)% vs (60.8±17.8)%, t=3.0, P=0.003], and HbA 1C of patients with moderate to severe coronary artery disease was higher [(9.6±1.7)% vs (8.8±1.6)%, t=3.3, P=0.001]. SYNTAX score was negatively correlated with TIR ( r=-0.251, P<0.01) and positively correlated with HbA 1C ( r=0.249, P<0.01). Moreover, compared with HbA 1C (standardized coefficients=0.181, P=0.007), TIR (standardized coefficients=-0.192, P=0.004) had a greater influence on SYNTAX score. Multivariate linear regression analysis showed that TIR, HbA 1C, duration of diabetes and smoking were independently correlated with SYNTAX score. Multivariate logistic regression analysis revealed that compared with TIR Q1, Q3 and Q4 were independent protective factors for moderate to severe coronary artery disease (respectively, OR=0.61 and 0.59, 95% CI 0.39-0.96 and 0.38-0.94, P=0.014 and 0.009) and acute coronary syndrome (respectively, OR=0.51 and 0.39, 95% CI 0.32-0.95 and 0.26-0.75, P=0.022 and 0.008). Conclusion:TIR was significantly and independently correlated with the severity of coronary artery disease and acute coronary syndrome in type 2 diabetes mellitus after controlling confounding factors. When TIR level was decreased, the severity of coronary artery disease was aggravated, and SYNTAX score and the risk of acute coronary syndrome was increased.

Objective To investigate the effect of astragalus injection combined with beta-adrenoceptor antagonist on serum levels of brain natriuretic peptide ( BNP) , interleukin1β( IL-1β) , IL-6 and tumor necrosis factorα( TNF-α) in the treatment of elderly patients with heart failure. Methods 78 elderly patients with heart failure from April 2013 to April 2015 in department of cardiology of the second hospital of Yuhang district were selected and divided into control group and experimental group with 39 cases in each group.All patients received correction of the electrolyte and acid-base balance and other conventional treatment.The control group received carvedilol by oral, the experimental group received astragalus injection on the basis of control group, with a course of 30 days.The serum BNP,IL-1β,IL-6 and TNF-αlevels pre-and post-treatment in two groups were compared. Results Compared with pre-treatment, the serum IL-1β,IL-6,TNF-α,and BNP levels post-treatment in two groups were lower(P<0.05).Compared with the control group post-treatment, the IL-1β,IL-6,TNF-αand BNP levels in experimental group were lower(P <0.05).Conclusion Astragalus injection combined with beta-adrenoceptor antagonist could significantly improve the clinical sign of elderly patients with heart failure, the mechanism may be reducing the serum levels of IL-1β,IL-6,TNF-αand BNP.