👤 Zhengzhang Guo

This study aimed to investigate the therapeutic effects of minocycline on neuropathic pain by examining its regulatory influence on hippocampal proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels, given the established involvement of neuroinflammation and BDNF dysregulation in the pathogenesis of neuropathic pain and associated neurological dysfunctions. This study used a rat model of neuropathic pain induced by L5 spinal nerve transection (L5-SNT). Forty-eight male Sprague-Dawley rats were divided into four groups: naive, sham-operated, model + saline, and model + minocycline. Minocycline was administered intraperitoneally at 40 mg/kg daily. Mechanical allodynia was assessed using the von Frey test, while real-time reverse transcription and ELISA were employed to quantify hippocampal expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and BDNF at various time points postsurgery. L5-SNT induced significant mechanical allodynia in the model + saline group, which was significantly attenuated by minocycline treatment in the model + minocycline group on days 3, 7, and 11 postsurgery (P < 0.05). Minocycline significantly reduced TNF-α, IL-6, and BDNF levels in the hippocampus, particularly on day 7 post-SNT (P < 0.05); however, minocycline did not significantly affect IL-1β levels. These findings suggest that minocycline's analgesic effects may be mediated through the downregulation of key proinflammatory cytokines and BDNF in the hippocampus. Minocycline administration significantly mitigates mechanical allodynia and modulates hippocampal neuroinflammatory markers in a rat model of neuropathic pain. These results highlight minocycline's potential as a therapeutic option for neuropathic pain, particularly in targeting neuroinflammation within the hippocampus. Show less

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less

The contribution of glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling in brown adipose tissue (BAT) remains underexplored. We studied the acute effects of exogenous acyl-GIP (1 nmol/kg) administration on whole-body lipid handling and fatty acid oxidation, using lipid tolerance tests (LTT) and indirect calorimetry, respectively. We demonstrate that in obese male mice, acute acyl-GIP administration improves lipid tolerance; however, pharmacological inhibition of GIPR, or genetic removal of GIPR globally or with the Myf5-Cre driver, completely abolishes GIP-mediated improvements in lipid tolerance, implicating GIPR in BAT. GIP-mediated improvements in lipid tolerance are associated with an increase in BAT lipid uptake, linked to increases in BAT lipoprotein lipase activity. Our data also reveal that BAT GIPR signalling is necessary for GIP-mediated increases in whole-body fatty acid oxidation, as Myf5-Cre: Gipr mice do not shift substrate oxidation upon GIP administration. Our findings suggest that BAT should be more closely considered in studies examining GIP's effects on whole-body metabolism in rodent models. Show less

Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology. Show less

With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less

The melanocortin receptor accessory protein 2 (MRAP2), which is abundantly expressed in the brain including the hypothalamus, has emerged as a key regulator of melanocortin-4 receptor (MC4R) activity. We sought to delineate the physiological significance of MRAP2 in MC4R neurons, with a particular focus on metabolic, autonomic and cardiovascular functions. Selective deletion of MRAP2 in MC4R neurons causes obesity that was associated with hyperphagia and impairment in glucose homeostasis and insulin sensitivity. MC4R agonist Melatonan II (MTII)-induced anorectic effects were blunted in mice lacking MRAP2 in MC4R neurons, whereas Celastrol retained its efficacy in reducing food intake and body weight. MRAP2 deletion also reduced baseline sympathetic nerve activity (SNA), particularly the SNA subserving the kidney. This was associated with reduced innervation of the kidney. In addition, MTII-induced increases in renal and brown adipose tissue (BAT) SNA as well as hepatic vagal nerve activity were significantly attenuated in MC4R neuron MRAP2-deficient mice. Transynaptic tracing revealed that MC4R neurons projecting to BAT and kidneys were localized to specific brain nuclei including the paraventricular nucleus of the hypothalamus, providing anatomical substrate for MRAP2 regulation of sympathetic outflow. Although the loss of MRAP2 in MC4R neurons did not affect arterial pressure, it caused a significant decrease in heart rate and baroreflex sensitivity. Finally, MRAP2 deficiency in MC4R neurons attenuated MTII-induced increase in arterial pressure and heart rate. These findings demonstrate that in addition to its role in energy balance and glucose homeostasis MRAP2 in MC4R neurons is crucial for cardiovascular autonomic regulation and is required for the development of obesity-associated hypertension and autonomic dysfunction. Show less

Obesity and weight regulation disorders are determined by the combined effects of genetics and environment. Polygenic obesity results from the combination of common variants in several genes which predisposes the individual to obesity and its related complications. In contrast, monogenic obesity results from changes in single genes, especially those in leptin-melanocortin pathway, and presents with early onset severe obesity, with or without other syndromic features. Rare variants in melanocortin 4 receptor are the commonest form of monogenic obesity. In addition, structural variation in small or large segments of chromosomes may also present with syndromic forms of obesity. Prader-Willi Syndrome, caused by imprinting errors in chromosome 15q11-13, is the most prevalent genetic cause of severe hyperphagia and obesity. With the advances in technologies, the past decade has witnessed a revolution in the identification of novel genetic causes of obesity, primarily in genes related to the leptin melanocortin pathway. The availability of safe melanocortin analogs holds the potential for targeted therapies for some of these disorders. This review summarizes known and novel rare genetic forms of obesity, along with approaches for the clinical investigation of copy number and sequence variants. The goal is to provide a reference for practicing clinicians to encourage genetic testing in obesity. IMPACT: What does this article add to the existing literature? Genetic obesity is an expanding frontier with potential to change management. Here, we summarize current information on the genetic causes of obesity and provide guidance for genetic testing. Emerging treatments may provide targeted precise treatment and change management practices. Show less

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with increasing evidence implicating the oral microbiome and tumor microenvironment in its progression. However, the mechanistic impact of OSCC patient-derived saliva on tumor development remains poorly understood. We established an orthotopic OSCC mouse model and topically applied saliva collected from OSCC patients to assess its effects on tumor progression. Multi-omics analyses, including 16 S rRNA sequencing, tumor transcriptomics (RNA-seq), and metabolomics (LC-MS), were performed to explore changes in the oral microbiota, gene expression profiles, and metabolic pathways. Treatment with OSCC patient saliva significantly accelerated tumor growth compared to controls. Saliva application altered the oral microbiota, most notably causing a significant enrichment of the genus Staphylococcus. Tumor transcriptomics revealed upregulation of genes associated with chronic neutrophilic inflammation (Mpo), cancer-associated fibroblast (CAF) activation, and extracellular matrix (ECM) remodeling (Angptl4, Col2a1). Metabolomic analysis demonstrated profound metabolic reprogramming within the tumors, including enhanced amino acid metabolism (tryptophan, glutamate), fatty acid oxidation, and accumulation of the oncometabolite succinate. Integrated analysis showed that Staphylococcus abundance was strongly correlated with these inflammatory and metabolic signatures. This study demonstrates that saliva from OSCC patients promotes tumor progression in vivo through a multifactorial mechanism involving inflammation, stromal remodeling, and metabolic rewiring. These findings highlight the tumor-promoting potential of salivary and microbial components, suggesting new avenues for diagnostic and therapeutic strategies targeting the oral microenvironment in OSCC. Show less

The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its active metabolites have been implicated in muscle development and the transformation of muscle fiber types. However, conventional VA formulations are restricted by poor stability and low bioavailability. In this study, a stable Nano VA was utilized to systematically evaluate its effects on muscle development and exercise performance in mice, as well as to explore its underlying mechanisms. A total of 44 male C57BL/6J mice were randomly divided into four groups: (i) normal control (NC), (ii) 5 mg/kg Nano VA (5 NVA), (iii) 10 mg/kg Nano VA (10 NVA), and (iv) 10 mg/kg VA (10 VA). The 10 NVA group demonstrated significantly improved muscle strength and swimming endurance, compared with the NC group. Further examination suggested a significant increase in myofiber diameter, cross-sectional area, and the content of fast-twitch fibers. Additionally, Nano VA treatment improved glucose tolerance and insulin sensitivity. To elucidate the mechanism by which Nano VA enhances muscle locomotor ability, transcriptomics and metabolomics data identified 111 differentially expressed genes and 253 differential metabolites. Of these, Angptl4, Ppp1r3a, and Cyp26b1 were identified as candidate regulators of muscle development and myofiber type transformation. In conclusion, Nano VA regulates muscle development and promotes muscle fiber type conversion, thus improving muscle strength and endurance in mice. Moreover, Nano VA facilitates mitigating and improving myasthenia gravis-related conditions. Show less

Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Angiopoietin-like 4 (ANGPTL4), a multifunctional protein, has previously been implicated in promoting EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-β (TGF-β) superfamily, also stimulates EVT cell invasion. However, it remains unclear whether GDF-8 regulates ANGPTL4 expression and how this regulation contributes to the invasive behavior of human EVT cells. This study aims to explore the role of ANGPTL4 in GDF-8-induced EVT cell invasion and to uncover the underlying molecular mechanisms. The immortalized EVT cell line HTR-8/SVneo and primary human EVT cells were used as in vitro models. The effects of GDF-8 on ANGPTL4 expression and the underlying signaling mechanisms were investigated using RT-qPCR and Western blot analysis. Cell viability was assessed using the MTT assay, and cell invasiveness was examined using a Matrigel-coated transwell invasion assay. Our results demonstrated that GDF-8 increased ANGPTL4 expression. Mechanistically, we found that activin receptor-like kinases 4 and 5 (ALK4 and ALK5) were required for GDF-8-mediated upregulation of ANGPTL4. Additionally, both SMAD2 and SMAD3 were involved in this regulatory pathway. We further showed that GDF-8 treatment promoted cell invasion without affecting cell viability. The pro-invasive effect of GDF-8 was attenuated by ANGPTL4 knockdown, whereas ANGPTL4 overexpression alone enhanced cell invasiveness. This study reveals a novel role for GDF-8 in regulating ANGPTL4 expression and EVT cell invasion, offering new insights into placental development and potential implications for pregnancy-related disorders. Show less

In this study, we investigated the therapeutic effects and mechanisms of umbilical cord mesenchymal stem cells (UCMSCs) in diabetic nephropathy (DN) ZDF (FA/FA) rats. The therapeutic effects were assessed by renal function tests, the urinary albumin-creatinine ratio, PAS staining, electron microscopy, and TGF- Show less

Angiopoietin-like protein 4 (ANGPTL4) is critical for vascular integrity and reducing inflammation in ischemic and hypoxic brain injuries. However, limited studies have evaluated ANGPTL4's role in acute ischemic stroke (AIS) assessment, and its expression patterns across AIS phases remain unclear. The severity of AIS at admission was assessed using the National Institutes of Health Stroke Scale (NIHSS). The association between serum ANGPTL4 level and the occurrence of AIS was examined using logistic regression analysis. The diagnostic accuracy of serum ANGPTL4 level for AIS severity was assessed using receiver operating characteristic curves. This study included 389 AIS patients and 133 healthy individuals. There was a notable increase in the occurrence of AIS associated with rising serum ANGPTL4 levels (odds ratio [OR] 1.03, 95% confidence interval [CI]: 1.02-1.06; p < 0.001). A higher serum level of ANGPTL4 was also found to be associated with severe AIS, as indicated by an AUC of 0.848. Additionally, we observed significant dynamic changes in ANGPTL4 levels, with a marked decrease at 1 week or 2 weeks after admission compared with the acute phase (the day after admission; both p < 0.001). Our findings suggest a robust association between elevated serum ANGPTL4 levels and the presence and severity of AIS. Importantly, this study is distinguished by its novel focus on the temporal dynamics of ANGPTL4 levels, which underscores its potential as a biomarker for AIS monitoring and provides new insights into AIS pathophysiology. Show less

Hepatocellular carcinoma (HCC) represents a particularly aggressive form of cancer, characterized by its rapid progression and a complex interplay with the surrounding immune cellular environment. The primary objective of this study was to comprehensively investigate the role of ANGPTL4 in the context of HCC, utilizing RNA sequencing (RNA-seq) techniques to explore its impact on the M2 polarization of tumor-associated macrophages (TAM) and to uncover potential mechanisms driving HCC progression. To achieve this, we performed a transcriptome analysis of HCC cell lines, alongside cells obtained after co-culturing these lines with macrophages. By comparing gene expression profiles between the experimental groups exposed to ANGPTL4 and control groups, we aimed to identify specific molecular pathways associated with ANGPTL4's function. In addition to gene expression analysis, we employed flow cytometry to assess the polarization status of TAM. Furthermore, we utilized immunohistochemistry to evaluate the distribution of macrophages within HCC tissues and to quantify the expression levels of M2 macrophage markers. The results derived from RNA-seq analysis were particularly revealing; treatment with ANGPTL4 led to a significant upregulation of genes linked to M2 polarization, notably including CD206 and Arg1. In subsequent experimental observations, it became evident that ANGPTL4 not only facilitated the M2 polarization of macrophages but also enhanced the proliferation and migratory capacity of HCC cells through the upregulation of these same cytokines. Show less

Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality. Show less

Pulmonary nodule with diameters ranging 8-30 mm has a high occurrence rate, and distinguishing benign from malignant nodules can greatly improve the patient outcome of lung cancer. However, sensitive and specific liquid-biopsy methods have yet to achieve satisfactory clinical goals. We enrolled three cohorts and a total of 185 patients diagnosed with benign (BE) and malignant (MA) pulmonary nodules. Utilizing data-independent acquisition (DIA) mass spectrometry, we quantified plasma proteome from these patients. We then performed logistic regression analysis to classify benign from malignant nodules, using cohort 1 as discovery data set and cohort 2 and 3 as independent validation data sets. We also developed a targeted multi-reaction monitoring (MRM) method to measure the concentration of the selected six peptide markers in plasma samples. We quantified a total of 451 plasma proteins, with 15 up-regulated and 5 down-regulated proteins from patients diagnosed as having malignant nodules. Logistic regression identified a six-protein panel comprised of APOA4, CD14, PFN1, APOB, PLA2G7, and IGFBP2 that classifies benign and malignant nodules with improved accuracy. In cohort 1, the area under curve (AUC) of the training and testing reached 0.87 and 0.91, respectively. We achieved a sensitivity of 100%, specificity of 40%, positive predictive value (PPV) of 62.5%, and negative predictive value (NPV) of 100%. In two independent cohorts, the 6-biomarker panel showed a sensitivity, specificity, PPV, and NPV of 96.2%, 35%, 65.8%, and 87.5% respectively in cohort 2, and 91.4%, 54.2%, 74.4%, and 81.3% respectively in cohort 3. We performed a targeted LC-MS/MS method to quantify plasma concentration of the six peptides and applied logistic regression to classify benign and malignant nodules with AUC of the training and testing reached 0.758 and 0.751, respectively. Our study identified a panel of plasma protein biomarkers for distinguishing benign from malignant pulmonary nodules that worth further development into a clinically valuable assay. Show less

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial. Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA. To test the hypothesis that elevated plasma TG levels accelerate AAA development, we used Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified causal relationships between elevated TG-rich lipoproteins, TG metabolism-related proteins/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most These findings identify hypertriglyceridemia as a key contributor to AAA pathogenesis and suggest that targeting TG-rich lipoproteins may be a promising therapeutic strategy for AAA. Show less

Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation Show less

Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets. Show less

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most Show less

To systematically evaluate the causal effects of lipoproteins on ischemic stroke (IS) through a systematic review and meta-analysis of Mendelian randomization (MR) studies. A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science to identify MR studies investigating the relationship between lipoproteins and IS, covering all publications up to November 2024. Relevant data were extracted, followed by a quality assessment. Meta-analyses were performed using RevMan software, with evaluations of heterogeneity and publication bias. A total of 442 studies were evaluated, and 10 were included. Our meta-analysis showed a significant positive correlation between LDL and IS (OR 1.09, 95% CI 1.07-1.12; This meta-analysis provides evidence for a causal relationship between various lipoproteins and ischemic stroke. Most non-HDL lipoproteins (LDL, VLDL, apoB) are associated with an increased risk of IS, while HDL and apoA1 appear to confer a protective effect. The role of Lp(a) in IS remains inconclusive and warrants further investigation. https://www.crd.york.ac.uk/PROSPERO, CRD42024617825. Show less

Dyslipidemia and oxidative stress are key components in the pathophysiology of gestational diabetes mellitus (GDM), yet the contribution of genetic factors to these metabolic disturbances remains unclear. This study aimed to investigate the relationship between two lipid-related genetic polymorphisms, apolipoprotein C1 (apoC1) gene -317H1/H2 (rs1568822) and rs4420638, with GDM risk and lipid profiles and oxidative stress markers in Chinese populations. The apoC1 -317H1/H2 and rs4420638 polymorphisms were genotyped in 734 GDM patients and 1,102 control subjects. Genetic association with GDM risk and related traits were also analyzed. The distribution of genotype and allele in both polymorphisms were similar between the two groups. However, the combined H1H1/AG+GG genotype was significantly more frequent in women with GDM than in the control group. GDM patients who carried H1H1/AG+GG genotype were 1.97-fold increased risk to develop GDM (95% CI: 1.140-3.414, ApoC1 gene polymorphisms associate with GDM risk and affect the lipid profile. The combined H1H1/AG+GG genotype of the apoC1 gene polymorphisms appears to augment the propensity to develop GDM, while the rs4420638 polymorphism links to adverse lipid components in the patients. Further genetic studies to add information beyond the traditional risk factors in GDM and to identify risk genotypes will help in early prediction and identification of at-risk patients. Show less

Emerging evidence suggests that ApoB outperforms LDL-C in predicting cardiovascular risk, especially in cases of discordance with the two. However, the specific type and composition of lipoprotein particles in this situation remain unclear. 375,544 individuals were enrolled from the UK Biobank without baseline cardiovascular disease, not on lipid-lowering therapy, and with available lipid nuclear magnetic resonance (NMR) data. Based on whether the absolute difference in baseline percentile of LDL-C and ApoB level was over 10 units, participants were categorized into concordant, discordantly high ApoB, and discordantly low ApoB group. The primary endpoint was major adverse cardiovascular events (MACE). Cox regression analysis showed the risk of MACE was increased in the discordantly high ApoB group (HR, 1.11; 95% CI, 1.06-1.15) and reduced in the discordantly low ApoB group (HR, 0.87; 95% CI, 0.83-0.93). Similar trends were observed in the NMR data. Compared to the other two groups, the discordantly high ApoB group exhibited the highest concentrations of VLDL-C, VLDL-CE, and VLDL particles. However, the CE content per LDL, IDL, and VLDL particle was lower in this group. Mediation analysis showed that VLDL particles and triglycerides mediated 25.5% and 26.6% of the MACE risk, respectively, in the discordantly high ApoB group (both P < 0.001). ApoB is a more comprehensive marker of cardiovascular risk than LDL-C. The higher cardiovascular risk in discordantly high ApoB individuals was partly mediated by VLDL; however, no conclusive evidence indicated that VLDL provides additional prognostic value beyond triglyceride measurements alone. Show less

Postmenopausal women are at elevated risk for osteoporosis and dysregulated lipid metabolism. While the relationship between conventional lipid markers and bone mineral density (BMD) remains controversial, the association between apolipoprotein B-100 (ApoB-100) (an established independent predictor of atherosclerosis) and bone metabolism in postmenopausal women remains poorly understood. This study investigated the relationship between ApoB-100 and lumbar BMD in postmenopausal women, with specific focus on potential inflammatory and platelet-mediated pathways. We conducted a cross-sectional study of 1,429 postmenopausal women who underwent health screening at the First Affiliated Hospital of Xinxiang Medical University between January 2022 and December 2024. ApoB-100 levels were measured by immunoturbidimetry, and lumbar BMD was assessed using low-dose chest CT imaging. Participants were stratified into tertiles based on ApoB-100 levels. We employed univariate and multivariate regression analyses to evaluate the relationship between lumbar BMD and ApoB-100. Generalized additive models with smooth curve fitting were used to characterize the linear relationship. Subgroup analyses assessed the consistency of associations across different populations, while mediation models quantified the intermediary roles of the neutrophil-to-lymphocyte ratio (NLR) and platelet count. After multivariate adjustment, ApoB-100 demonstrated a significant independent negative correlation with lumbar BMD (β=-6.37, 95%CI: -9.26 to -3.49). This association was more pronounced in women younger than 60 years (β=-10.18, 95%CI: -13.94 to -6.42), those with BMI≥28kg/m² (β=-10.73, 95%CI: -15.31 to -0.86), and those without hypertension (β=-7.3, 95%CI: -10.42 to -4.19). Mediation analysis revealed that NLR accounted for 8.17% of the negative association between ApoB-100 and lumbar BMD, while platelet count showed a suppressive indirect association (20.60%). ApoB-100 exhibits an independent negative association with lumbar BMD in postmenopausal women, partially mediated through inflammatory and platelet pathways. These findings support the potential utility of ApoB-100 as a biomarker for osteoporosis risk assessment in postmenopausal women, particularly within specific high-risk subgroups. Show less

Low-density lipoprotein cholesterol (LDL-C) has now been the primary target for lipid-lowering therapy in the European and US guidelines for the management of dyslipidemia, with increasing interest in apolipoprotein B (ApoB) as a secondary target. The relationship between ApoB and the severity of acute myocardial infarction as well as residual risk still needs to be further determined. Coronary atherosclerosis occurs as a result of a complex set of factors, and there is a strong relationship between insulin resistance and cardiovascular disease. In contrast, there are limited studies on the relationship between TyG index (triglyceride glucose index), an indicator of insulin resistance, and cardiovascular disease. The purpose of this study was to investigate the value of ApoB and TyG index in assessing the severity of myocardial infarction and predicting prognosis. This study included 712 participants with acute myocardial infarction for a 5-year follow-up. Spearman correlation analysis and generalized linear model analysis were used to assess the correlation between ApoB and the severity of coronary atherosclerosis. Risk regression analysis was used to assess the correlation between ApoB and residual risk in patients with acute myocardial infarction, and the C-statistic, net reclassification index (NRI), and integrated discriminant improvement index (IDI) were further calculated to assess the predictive value of ApoB for residual risk after myocardial infarction. Categorizing apoB, LDL-C, and TyG indices according to tertiles, higher levels of ApoB were significantly associated with the severity of coronary artery stenosis in patients with acute myocardial infarction ( ApoB is an independent risk factor for major adverse cardiovascular events (MACE) following myocardial infarction. Elevated ApoB levels are more advantageous than elevated LDL-C levels in assessing the severity of coronary artery stenosis in myocardial infarction patients and predicting residual risk after myocardial infarction. Therefore, in patients with acute myocardial infarction, ApoB can be considered to guide further intensive treatment. However, the TyG index did not demonstrate a significant advantage in predicting cardiovascular residual risk in this study. Show less

Coronary artery disease (CAD) is showing a trend toward earlier onset. Premature CAD (PCAD) is clinically defined as CAD with onset before the age of 55 in males and 65 in females. Notably, many young patients subsequently hospitalized with acute cardiovascular events had undergone annual physical examinations before hospitalization, yet were not identified as high-risk by current risk stratification guidelines or traditional risk assessment tools. This study aims to investigate the diagnostic capacity of novel inflammatory biomarkers (including the monocyte-to-high-density lipoprotein cholesterol ratio (MHR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), apolipoprotein B to apolipoprotein A-1 ratio (apoB/apoA-1), and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LDL-c/HDL-c)) for PCAD, thereby providing the evidence-based foundation for PCAD screening. A total of 1,012 young subjects (male<55 years, female<65 years) undergoing diagnostic coronary angiography (CAG) at the Third Affiliated Hospital of Zunyi Medical University (from January 2022 to February 2023) were retrospectively analyzed. We stratified 1,012 eligible participants into two groups: 521 angiographically confirmed PCAD cases and 491 controls with normal coronary arteries. Comprehensive baseline characteristics, including cardiovascular risk profiles and core laboratory-measured inflammatory markers, were recorded. The Mann-Whitney U test and binary logistic regression analysis were employed to assess the associations between inflammatory biomarkers and PCAD. The areas under the receiver operating characteristic (ROC) curves (AUCs) were calculated to evaluate their diagnostic performance for PCAD. The odds ratio (OR) values for MHR, NLR, LDL-c/HDL-c, and apoB/apoA-1 were 5.592 (95% CI: 2.886-7.836), 1.671 (95% CI: 1.500-1.861), 1.663 (95% CI: 1.419-1.950), and 6.268 (95% CI: 2.765-8.213), respectively (all The apoB/apoA-1 outperformed MHR, NLR, and LDL-c/HDL-c as an inflammatory biomarker in PCAD. Its diagnostic capacity was notably enhanced in ACS subgroups. A comprehensive model combining apoB/apoA-1 with traditional risk factors demonstrated exceptional accuracy. Incorporating this biomarker into routine screening protocols could significantly strengthen preventive strategies. Show less

In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated therapeutic efficacy in dampness constitution (DC) treatment, the material basis underlying its constitutional modulatory effects remains unclear. This study proposes objective indicators for the differentiation and therapeutic evaluation of DC and elucidates the material basis of FLZXD in DC treatment. Serum exosome proteomic profiling was conducted across two independent cohorts to identify DC-related indicators and assess the therapeutic efficacy of FLZXD in DC-associated hyperlipidemia (DC-hyperlipidemia). The bioactive compounds of FLZXD were prioritized through a comprehensive analysis of patent documentation and network pharmacology, with subsequent validation of DC-related targets using enzyme-linked immunosorbent assay (ELISA). Proteomic analysis of serum exosomes revealed signatures that differentiate individuals with a balanced constitution (BC) from those with DC. The differentially expressed proteins (DEPs) were enriched predominantly in pathways related to the complement cascade and cardiovascular diseases. FLZXD demonstrated therapeutic efficacy against DC-hyperlipidemia, as evidenced by the reversal of DEPs expression following treatment, which was supported by the patentable findings and network pharmacology analysis. Through experimental validation and pharmacological evidence, the active herbs of FLZXD (Fuling, Zexie and Baizhu, collectively referred to as FZB) were identified, and a total of 73 putative therapeutic targets involved in the dampness-resolving effects of FZB were revealed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment further confirmed that FLZXD exerts its anti-dampness effects primarily through regulation of the complement and coagulation cascades. Among eight candidate indicators specifically associated with DC, four proteins were validated via ELISA, indicating potential utility for the differentiation of DC. The sensitivity (%), specificity (%), fold change (FC), p-value, and area under the curve (AUC) for each indicator were as follows: apolipoprotein B-100 (APOB) (100.00, 80.00, 0.63, 0.0051, 0.94), complement factor H-related protein 1 (CFHR1) (90.00, 100.00, 0.55, 0.0001, 0.98), alpha-1-acid glycoprotein 1 (ORM1) (100.00, 80.00, 0.71, 0.0043, 0.92), and pigment epithelium-derived factor (SERPINF1) (90.00, 70.00, 0.66, 0.0002, 0.87). The integrative approach, combining proteomic profiling, network pharmacology analysis, and clinical validation, establishes an integrative approach for research on TCM constitutions. This approach provides (1) molecular insights into the differentiation of DC, (2) a foundation for mechanism-based, targeted therapeutic strategies, and (3) enhanced patient stratification to support personalized treatment approaches. Show less

Primary Sjögren's Syndrome (pSS) is a chronic autoimmune condition affecting lacrimal and salivary glands. While previous studies suggest potential associations between dyslipidemia and autoimmune diseases, the causal relationship between lipid-lowering medications and pSS remains unclear. This study employed drug-targeted Mendelian randomization (MR) analysis to assess the impact of lipid-lowering drugs on pSS risk, focusing on genetic targets including HMGCR, PCSK9, NPC1L1, APOB, CETP, and LDLR. Data were sourced from the Global Lipids Genetics Consortium and UK Biobank. Significant single-nucleotide polymorphisms linked to LDL cholesterol were utilized as instrumental variables. Causal effects were estimated using Inverse Variance Weighted, Weighted Median, MR Egger, Simple Mode, and Weighted Mode methods. Robustness was ensured through heterogeneity and sensitivity analyses. The inhibition of HMGCR and CETP genes was found to be significantly associated with an increased risk of developing pSS (HMGCR: OR = 3.602, 95% CI [1.051, 12.344], p = 0.041; CETP: OR = 12.251, 95% CI [2.599, 57.743], p = 0.002). HMGCR and CETP may affect pSS risk via non-lipid pathways, suggesting distinct mechanisms among different lipid-lowering drug targets. This study provides compelling evidence suggesting that lipid-lowering drugs may contribute to the risk of pSS, thus offering new insights for clinical intervention strategies. Show less