Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality globally. Elevated levels of serum LDL-C (low-density lipoprotein cholesterol) represent a significant risk factor for atherosclerosis. LDLR (low-density lipoprotein receptor) plays a critical role in LDL-C uptake and clearance, with its recycling to the cell surface being essential for maintaining LDLR availability. However, the molecular mechanisms underlying LDLR homeostasis and recycling remain poorly defined. SNX (sorting nexin) proteins and Rab (Ras-associated binding protein) GTPases are key regulators of vesicle transport and endosomal sorting and are implicated in LDLR endocytosis, recycling, and subsequent cholesterol metabolism. This review aims to summarize the data on the roles of SNX17, Rab11, and Rab5 in LDLR recycling and endosomal dynamics, highlighting their potential as therapeutic targets for managing dyslipidemia and associated diseases.

Atherosclerosis, a leading cause of cardiovascular disease, is driven by a complex interplay of dyslipidemia, inflammation, and arterial plaque formation and progression. Animal models are indispensable to elucidate the pathogenesis and develop novel therapies. Rodent models are widely utilized due to their cost-effectiveness, reproducibility, and rapid disease progression. However, notable species differences exist in lipoprotein composition and lipid metabolism pathways. Mice and rats exhibit an HDL-dominant profile, whereas Syrian golden hamsters express cholesteryl ester transfer protein (CETP) and display a higher LDL fraction, but lower than that of humans, offering a model closer to human metabolically. Divergent CETP activity across species further complicates the translational relevance of the findings from these models for atherosclerosis and related metabolic disorders. This review systematically examines the key factors in rodent model selection and optimization, with consideration on the roles of sex and age. We focus on three commonly used and well-characterized rodent strains prone to atherosclerosis: C57BL/6J mice, Sprague-Dawley (SD) rats, Wistar rats, and golden hamsters. On Apoe-/- or Ldlr-/- backgrounds, male C57BL/6 mice, owing to their pronounced hypercholesterolemia and extended survival with high-fat diet, are preferentially used in late-stage plaque stability studies. In contrast, male SD or Wistar rats develop atherosclerosis slowly with limited lesion progression, while hamsters, despite their human-like lipid metabolism, exhibit substantial individual variability and lesions that typically arrest at early fatty streaks with poor reproducibility. Therefore, rats and hamsters are better suited for studies focusing on early disease mechanisms and human-mimetic lipid metabolism.

Background: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid -lowering effects. Objective: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. Methods: Differential metabolites in Curtn-treated HepG2 cells were identified via LC -MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high -fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. Results: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. Conclusion: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.

Curcumin nicotinate (Curtn) is a synthesized ester derivative of curcumin and niacin. Our previous study has shown that Curtn lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE-/- mice and promotes LDL-C uptake into HepG2 cells in vitro. The present study was to test the hypothesis that Curtn decreases serum LDL-C levels through decreased expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and subsequent increase in LDL receptor expression. Male Wistar rats on high-fat diet (HFD) were treated with Curtn or rosuvastatin. Curtn or rosuvastatin treatment significantly decreased serum levels of total cholesterol (TC) and LDL-C in rats on HFD with increased liver LDL receptor expression. LDL-C-lowering effect of Curtn was not observed in LDL receptor deficient (LDLR-/-) mice on HFD, while rosuvastatin still decreased serum lipid levels in LDLR-/- mice, indicating that the reduction of serum LDL-C levels by Curtn treatment was LDL receptor-dependent. Curtn treatment also significantly decreased the protein expression of PCSK9 in Wistar rats and LDLR-/- mice. In HepG2 cells with overexpression of human PCSK9, Curtn treatment significantly increased LDL-C uptakes into hepatocytes, and increased LDL receptor distribution on cell surface in association with decreased PCSK9 protein expression. RNAi-LDLR significantly attenuated the effect of Curtn on LDLR distribution on cell surface. These data indicates that Curtn would decrease serum LDL-C level at least partially through inhibition of PCSK9 expression, and subsequent increase in LDL receptor expression and distribution in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.

Endothelial cell (EC) dysfunction is one of the initiating factors of atherosclerosis. EC dysfunction is primarily caused by oxidative damage and inflammation. As a classic non-specific antioxidant and anti-inflammatory drug, curcumin has been widely used in studies of lipid metabolism disorders. However, whether curcumin is able to alleviate H2O2-induced EC damage and its related mechanisms has remained to be elucidated. The present study confirmed the protective effects of curcumin on human umbilical vein endothelial cells (HUVECs). A HUVEC injury model was established using H2O2 and the optimal concentrations and time of curcumin to achieve therapeutic effects were explored. Curcumin was observed to inhibit H2O2-induced pyroptosis by inhibiting the activation of NOD-, LRR- and pyrin domain-containing protein 3. In addition, curcumin improved HUVEC function by restoring αvβ3 and reducing endothelin-1 expression. In conclusion, the results of the present study revealed the mechanism through which curcumin inhibits pyroptosis and indicated that curcumin may have a potential utility in treating diseases of EC dysfunction.

The aim of this study was to explore the effects of ethanol extracts from Portulaca oleracea L. (ePO) on joint inflammation and to explain the underlying mechanisms. A joint inflammation mouse model was constructed by injecting zymosan, and the Von Frey method was employed and the joint thickness measured. The numbers of leukocytes, neutrophils, and monocytes were counted in the joint cavity and the infiltration of inflammatory cells was assessed by joint histopathological analysis. The mRNA levels of inflammatory cytokines were determined by quantitative RT-PCR and their secretion levels were determined by specific ELISAs. Pre-treatment with ePO inhibited articular mechanical hyperalgesia and edema and ameliorated the recruitment of mononuclear neutrophils and leukocytes. In addition, pre-treatment with ePO improved pathological alternations in the joint tissues by reducing the number of inflammatory cells. Pre-treatment with ePO regulated the nuclear factor erythroid 2-related factor 2 (Nrf2)-related proteins and thereby inhibited oxidative stress. In addition, ePO inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome-related genes (NLRP3, ASC, pro-caspase-1 and pro-IL-1ß), modulated inflammatory cytokines and the activation of NF-κB. ePO attenuated zymosan-induced joint inflammation by regulating oxidative stress, NLRP3 inflammasome, and NF-κB. Keywords L. , zymosan , inflammation , Nrf2 , NLRP3

•Stimulants such as oxidation and endoplasmice stress, DNA damage, epigenetic modification, etc., stimulate.•Stress response, classical senescence proteins, CCHOP, calcineurin/CaMKII, etc.,•Promoting senescence and dead cells accumulation, endocardium remodeling.•Accelerating contractile dysfunction, impaired left ventricular ejection fraction and HF in aging population.•However, attenuating senescence and dead cell retention prevents cardiac aging and HF development.

Vascular diseases (VDs) including pulmonary arterial hypertension (PAH), atherosclerosis (AS) and coronary arterial diseases (CADs) contribute to the higher morbidity and mortality worldwide. Apolipoprotein A-I (Apo A-I) binding protein (AIBP) and Apo-AI negatively correlate with VDs. However, the mechanism by which AIBP and apo-AI regulate VDs still remains unexplained. Here, we provide an overview of the role of AIBP and apo-AI regulation of vascular diseases molecular mechanisms such as vascular energy homeostasis imbalance, oxidative and endoplasmic reticulum stress and inflammation in VDs. In addition, the role of AIBP and apo-AI in endothelial cells (ECs), vascular smooth muscle (VSMCs) and immune cells activation in the pathogenesis of VDs are explained. The in-depth understanding of AIBP and apo-AI function in the vascular system may lead to the discovery of VDs therapy.

目的 明确姜黄素可通过下调低密度脂蛋白受体诱导降解蛋白(IDOL)来升高低密度脂蛋白受体(LD-LR)的表达水平,从而促进肝细胞摄取低密度脂蛋白胆固醇(LDLC).方法 利用过表达IDOL和干扰IDOL慢病毒(OE/RNAi-IDOL)感染HepG2和LO2两种体外培养的肝细胞,倒置荧光显微镜观察病毒感染情况;Western blot检测IDOL及LDLR蛋白表达;油红O染色观察细胞中脂质情况;酶法检测细胞内胆固醇含量;DiI-LDL摄取实验检测肝细胞对LDLC的摄取能力;流式细胞术检测肝细胞膜LDLR分布丰度.结果 与明场比较,暗场下可见胞内呈绿色荧光;与对照组比较,三种不同干扰IDOL慢病毒感染的HepG2和LO2细胞中,仅RNAi-IDOL-2的IDOL蛋白表达显著降低,且相应组的LDLR蛋白表达显著增强(P＜0.01),选择为后续RNAi-IDOL组所用;相反,OE-IDOL慢病毒感染的HepG2和LO2细胞中,IDOL表达显著增高,相应组内LDLR表达减弱;以上结果表明已获得RNAi-IDOL-2及OE-IDOL慢病毒感染的HepG2和LO2细胞模型.与无药物处理的Control组相比,RNAi-IDOL-2及OE-IDOL慢病毒感染的肝细胞内经25 μmol/L姜黄素处理24 h后,油红O染色及胆固醇含量测定结果显示:细胞内脂滴含量和相对胆固醇含量均显著增加(P＜0.01);且DiI-LDL摄取及免疫流式细胞结果显示:肝细胞摄取LDLC的能力增强(P＜0.01);肝细胞膜表面LDLR分布丰度增多(P＜0.01);以上结果与阳性药物对照组的结果趋势一致.结论 姜黄素可以下调肝细胞内IDOL水平,提高细胞膜LDLR分布丰度,从而促进肝细胞摄取LDLC.

在医教协同背景下,加强医学人才培养是深化高等教育综合改革的重要任务.然而,传统的生物化学课堂教学模式已经无法满足当代高素质医学人才的培养.信息化时代促进了线上教学的开展,本文借助泛雅平台构建生物化学优质网络教学课程,运用微信公众平台适时推送课程内容,并通过微信群与学生进行即时沟通互动和答疑,辅助生物化学传统课堂教学,培养学生自主学习能力,实现学生个性化学习.

目的 探究驱动蛋白超家族成员16B(KIF16B)在低密度脂蛋白受体诱导降解蛋白(IDOL)调节肝细胞摄取低密度脂蛋白胆固醇(LD LC)中的作用.方法 干扰/过表达IDOL (RNAi/OE-IDOL)的慢病毒感染HepG2和LO2细胞,通过倒置荧光显微镜来观测病毒感染效果;油红O染色观察细胞内脂质蓄积水平;DiI荧光染料标记的LDL(DiI-LDL)摄取实验检测肝细胞对LDLC的摄取能力,流式细胞术检测肝细胞表面低密度脂蛋白受体(LDLR)丰度;Western blot检测IDOL、KIF16B及LDLR蛋白的表达变化,并免疫共沉淀进一步检测蛋白之间的相互作用.结果 两种感染慢病毒的肝细胞内均显示绿色荧光,提示RNAi/OE-IDOL的慢病毒已感染HepG2和LO2细胞;与无慢病毒感染的Control组比较,OE-IDOL组的细胞内脂质含量显著减少(P＜0.05),LDLC的摄取显著减弱(P＜0.05),且肝细胞表面LDLR丰度显著降低(P＜0.01);RNAi-IDOL组的细胞内脂滴含量显著增加(P＜0.01),LDLC摄取增强,且肝细胞表面LDLR丰度显著增高(P＜0.01);与慢病毒载体的Control组比较,RNAi-IDOL组LDLR蛋白和KIF16B蛋白的表达升高(P＜0.01),且KIF16B与LDLR的相互作用增强;OE-IDOL组LDLR蛋白和KIF16B蛋白的表达降低(P＜0.05),LDLR与KIF16B相互作用随之减弱.结论 IDOL调节的肝细胞摄取LDLC的过程可能与KIF16B跟LDLR之间存在相互作用有关.

目的 观察姜黄素对人肝癌细胞HepG2脂质摄取的影响是否与驱动蛋白16B (KIF16B)有关,探索姜黄素的降脂机制.方法 (1)将体外培养的HepG2细胞分为对照组(姜黄素浓度为0)和20、30、40 μmol/L姜黄素处理组,CCK8法检测细胞活性,以确定合适的姜黄素药物作用浓度.(2)将体外培养的HepG2细胞分为空白对照组、阴性对照组、瑞舒伐他汀(阳性药物)组和姜黄素组.胆固醇检测试剂盒检测HepG2细胞内胆固醇含量;荧光显微镜观察细胞对DiI标记的低密度脂蛋白(DiI-LDL)的摄取情况;Western blot检测细胞内KIF16B和低密度脂蛋白受体(LDLR)的蛋白表达;激光共聚焦显微镜观察细胞内KIF16B与LDLR荧光共定位情况.结果 25 μmol/L姜黄素不影响HepG2细胞生长.与阴性对照组相比,姜黄素组HepG2细胞内总胆固醇和游离胆固醇水平明显增高,细胞摄取DiI-LDL明显增加,细胞内KIF16B、LDLR蛋白表达显著升高,细胞内KIF16B和LDLR蛋白的荧光共定位显著增加(P＜0.05).结论 姜黄素作用于HepG2细胞导致的LDL脂质摄取、LDLR表达增加与KIF16B和LDLR的相互作用有关.

The aim of this study was to explore the effects of ethanol extracts from Portulaca oleracea L. (ePO) on joint inflammation and to explain the underlying mechanisms. A joint inflammation mouse model was constructed by injecting zymosan, and the Von Frey method was employed and the joint thickness measured. The numbers of leukocytes, neutrophils, and monocytes were counted in the joint cavity and the infiltration of inflammatory cells was assessed by joint histopathological analysis. The mRNA levels of inflammatory cytokines were determined by quantitative RT-PCR and their secretion levels were determined by specific ELISAs. Pre-treatment with ePO inhibited articular mechanical hyperalgesia and edema and ameliorated the recruitment of mononuclear neutrophils and leukocytes. In addition, pre-treatment with ePO improved pathological alternations in the joint tissues by reducing the number of inflammatory cells. Pre-treatment with ePO regulated the nuclear factor erythroid 2-related factor 2 (Nrf2)-related proteins and thereby inhibited oxidative stress. In addition, ePO inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome-related genes (NLRP3, ASC, pro-caspase-1 and pro-IL-1ß), modulated inflammatory cytokines and the activation of NF-κB. ePO attenuated zymosan-induced joint inflammation by regulating oxidative stress, NLRP3 inflammasome, and NF-κB.

Heart failure (HF) remains one of the major causes of morbidity and mortality worldwide. Recent studies have shown that stem cells (SCs) including bone marrow mesenchymal stem (BMSC), embryonic bodies (EB), embryonic stem (ESC), human induced pluripotent stem (hiPSC)-derived cardiac cells generation, and transplantation treated myocardial infarction (MI) in vivo and in human. However, the immature phenotypes compromise their clinical application requiring immediate intervention to improve stem-derived cardiac cell (S-CCs) maturation. Recently, an unbiased multi-omic analysis involving genomics, transcriptomics, epigenomics, proteomics, and metabolomics identified specific strategies for the generation of matured S-CCs that may enhance patients’ recovery processes upon transplantation. However, these strategies still remain undisclosed. Here, we summarize the recently discovered strategies for the matured S-CC generation. In addition, cardiac patch formation and transplantation that accelerated HF recuperation in clinical trials are discussed. A better understanding of this work may lead to efficient generation of matured S-CCs for regenerative medicine. Graphical abstract

BACKGROUND Inhibition of plasma cholesteryl ester transfer protein (CETP) can effectively reduce the risk of ath-erosclerotic cardiovascular disease by increasing high-density lipoprotein cholesterol (HDL-C) levels, but the effect of CETP on the distributions of HDL subclasses in patients with coronary heart disease (CHD) is still elusive. METHODS To investigate the correlation between the level of CETP and the distributions of HDL subclasses, 121 healthy controls and 139 patients with CHD were selected as study subjects. The plasma levels of CETP and each HDL subclass were respectively determined by enzyme-linked immunosorbent assay and two-dimensional gel electrophoresis associated with the immunodetection method. At the same time, blood biochemical data from all subjects were collected, including the levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, apoA1, and apoB100. Correlation analysis and multiple regression analysis among the plasma HDL subclass values and biochemical parameters in subjects with CHD were conducted. RESULTS As the plasma level of CETP increases, the contents of TC, TG, and apoB100/A1 were obviously elevated, while the levels of HDL-C and apoA1 decreased significantly. For distributions of HDL subclasses, large-sized HDL2a and HDL2b were markedly decreased in the middle CETP group (p < 0.05) and the high CETP group (p < 0.001) compared to the low CETP group, while the small-sized preβ1-HDL was obviously increased. Intriguingly, when the plasma concentration of TC or TG in patients with CHD was higher, the elevated preβ1-HDL and reduced HDL2a were more dependent on the increase in CETP. Furthermore, correlation analysis and multiple regression analysis also confirmed that plasma CETP was positively correlated with preβ1-HDL levels and negatively correlated with HDL2b levels. CONCLUSIONS The distributions of HDL subclasses were associated with CETP in patients with CHD, especially in those with high levels of TC and TG. CETP levels were associated with an increase in small-sized preβ1-HDL and a decrease in large-sized HDL subclasses, which indicated that CETP might be a limiter of reverse cholesterol transport and HDL maturation.

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.

Oxidative stress induces the formation of oxidized low-density lipoprotein (ox-LDL), which accelerates the development of atherosclerosis and the rupture of atherosclerotic plaques by promoting lipid accumulation and inhibiting autophagy in vascular cells. Lipophagy is known to be involved in maintaining the balance of neutral lipid metabolism; however, the phenomenon of lipophagy deficiency in ox-LDL-treated endothelial cells (ECs) remains to be elucidated. It has been demonstrated that lipid accumulation caused by ox-LDL inhibits autophagy, which promotes apoptosis in ECs. The aim of the present study was to investigate the association between decreased autophagy and lipid accumulation in ECs treated with ox-LDL. Electron microscopy demonstrated that the formation of autolipophagosomes was decreased in ox-LDL-treated human umbilical vein ECs compared with that in the LDL-treated group and was accompanied by a decrease in the autophagy-associated proteins via western blotting analysis. Using laser focal colocalization detection, decreased lipid processing was observed in the lysosomes of ox-LDL-treated ECs, which indicated that lipophagy may be attenuated and subsequently result in lipid accumulation in ox-LDL-treated ECs.

<span id="ChDivSummary" name="ChDivSummary" class="abstract-text">目的明确姜黄素调节PCSK9促进肝细胞摄取LDL的作用。方法利用实验室现有的慢病毒感染HepG2和LO2两种细胞,分别构建过表达PCSK9（RNAi-PCSK9）和干扰PCSK9（OE-PCSK9）细胞模型,通过倒置荧光显微镜检测慢病毒转染效率;Western blot检测蛋白表达;油红O染色分析姜黄素对细胞中脂质摄取情况;酶法检测细胞内胆固醇含量。结果镜下观察细胞内可见清晰绿色荧光。Western blot结果显示干扰PCSK9组降低PCSK9表达,升高LDLR表达;过表达PCSK9组增加PCSK9表达,降低LDLR表达。油红O结果显示姜黄素/瑞舒伐他汀处理24 h后RNAi/OEPCSK9组细胞内脂质含量均增加。胆固醇含量测定姜黄素/瑞舒伐他汀处理24 h后RNAi-PCSK9组总胆固醇（total cholesterol,TC）/游离胆固醇（free cholesterol,FC）含量升高,OEPCSK9组TC/FC含量均下降。结论姜黄素特异性降低PCSK9表达继而促进肝细胞摄取LDL-C。</span>

BACKGROUND:Metabolic syndrome (MS) is characterized by a constellation of metabolic disorders. Hyperglycemia and dyslipidemia are the major risk factors of MS. Here we performed a study to explore the association between glycated hemoglobin A1c (HbA1c) and high-density lipoprotein (HDL) subclasses in patients with MS.METHODS:We included 101 MS patients and 77 healthy subjects in this study. Blood tests were executed to assess the blood glucose and lipid indicators, including HbA1c, fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B100 (apoB100), preβ1-HDL, HDL3b, apoB100/AI, apolipoprotein AI (apoAI), HDL2b and HDL2a. Multivariate linear regression was used to explore potential relationship between HDL subclasses and HbA1c.RESULTS:Compared with control group, the levels of HbA1c, FPG, TG, TC, LDL-C, apoB100, preβ1-HDL, HDL3b, apoB100/AI and LDL-C/HDL-C were significantly increased in MS subjects (p < 0.01), while plasma concentrations of HDL-C, apoAI, HDL2b and HDL2a were significantly decreased in MS subjects (p < 0.01). With the increase of whole blood HbA1c levels in MS subjects, preβ1-HDL was elevated gradually, while HDL2a was decreased gradually.CONCLUSIONS:Blood HbA1c level is associated with the changes in HDL subclass distribution in patients with MS.