👤 Kenneth Yu

Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD. RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity. In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD. Show less

To elucidate the mechanisms of angiopoietin-like 4 (ANGTPL4) in neovascularization (NV) in retinopathy of prematurity (ROP). We compared ANGPTL4 expression levels of aqueous humour and vitreous fluid samples in infants with acute-phase ROP and control group. ANGPTL4 Show less

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1-the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen-is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary. Show less

Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy. Show less

High altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant mortality risk. Despite its clinical relevance, the molecular mechanisms underlying HAPE are not well understood. We conducted whole-transcriptome RNA sequencing on blood samples from 6 pairs of HAPE patients and healthy controls to identify differentially expressed (DE) mRNAs, miRNAs, circRNAs, lncRNAs, along with alternative splicing (AS) events, gene fusions, and novel transcripts. To explore the regulatory dynamics, we constructed ceRNA networks and analyzed immune cell infiltration patterns, further annotating the biological functions of these transcripts. For empirical validation, we selected five circRNAs from the ceRNA network and conducted RT-qPCR on 50 paired samples. Additionally, we assessed the correlations between circRNA expression levels and clinical data to evaluate their diagnostic potential. We observed 2,023 differentially expressed mRNAs (DEmRNAs), 84 DEmiRNAs, 200 DEcircRNAs, and 3,573 DElncRNAs. A total of 139 'A3SS' events, 103 'A5SS' events, 545 'MXE' events, 14 'RI' events, and 1,482 'SE' events were identified in the AS events analysis between the two groups. Two ceRNA networks were constructed. T cells, follicular helper, and Macrophages M1 cells exhibited the strongest positive correlation (R=0.82), while naive B cells and memory B cells demonstrated the strongest negative correlation (R=-0.62). In total, the expression of three circRNAs was significantly different in a larger cohort. Hsa_circ₀₀₅₈₄₉₇, hsa_circ₀₀₈₁₀₀₆, and hsa_circ₀₀₈₃₂₂₀ demonstrated consistent with the RNA sequencing results. These three circRNAs strongly correlate with clinical indicators and exhibit potential as diagnostic biomarkers. Finally, we verified five genes (CXCR4, HSD17B2, ANGPTL4, TIMP3, N4BP3) that were differentially expressed in endothelial cells under normoxia and hypoxia through bioinformatics and RT-qPCR analyses. This study elucidates the differential expression of coding and non-coding RNAs (ncRNAs) in HAPE, identifies new transcripts and genes, and enhances our understanding of the transcriptional characteristics of HAPE. Moreover, it highlights the potential role of circRNAs in advancing the diagnosis and treatment of HAPE. Show less

The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. ANGPTL4 could be a potential marker and therapeutic target for DKD treatment. Show less

Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM. We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transition (EMT) program and facilitates the development of LM, the results of cell-based This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT. Show less

ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation. To better understand the role of intracellular ANGPTL8 in adipocytes and assess whether it may play a role in adipocyte differentiation, we knocked down its expression in normal mouse subcutaneous preadipocytes. ANGPTL8 knockdown reduced adipocyte differentiation, cellular TG accumulation and also isoproterenol-stimulated lipolysis at day 7 of differentiation. RNA-Seq analysis of ANGPTL8 siRNA or control siRNA transfected SC preadipocytes on days 0, 2, 4 and 7 of differentiation showed that ANGPTL8 knockdown impeded the early (day 2) expression of adipogenic and insulin signaling genes, PPARγ, as well as genes related to extracellular matrix and NF-κB signaling. Insulin mediated Akt phosphorylation was reduced at an early stage during adipocyte differentiation. This study based on normal primary cells shows that ANGPTL8 has intracellular actions in addition to effects in the extracellular space, like modulating LPL activity. Preadipocyte ANGPTL8 expression modulates their differentiation possibly via changes in insulin signaling gene expression. Show less

Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation. Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence. We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived. Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated "Endothelial-Monocyte-Neutrophil" axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD. Show less

A high-fat diet (HFD) is recognized as an important contributor to inflammatory bowel disease (IBD). However, the precise underlying mechanism of HFD on IBD remains elusive. This study aimed to investigate the potential mechanism by which HFD affects IBD using 16S rRNA-sequencing and RNA-seq technology. Results indicated that HFD-treated mice exhibited notable alternations in the structure and composition of the gut microbiota, with some of these alternations being associated with the pathogenesis of IBD. Analysis of the colon transcriptome revealed 11 hub genes and 7 hub pathways among control, DSS-induced colitis, and HFD + DSS-treated groups. Further analysis explores the relationship between the hub pathways and genes, as well as the hub genes and gut microbiota. Overall, the findings indicate that the impact of HFD on DSS-induced colitis may be linked to intestinal dysbiosis and specific genes such as Show less

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF) are Philadelphia chromosome-negative myeloproliferative neoplasms. These conditions share overlapping clinical presentations; however, their prognoses differ significantly. Current morphological diagnostic methods lack reliability in subtype differentiation, underlining the need for improved diagnostics. The aim of this study was to investigate the multi-omics alterations in bone marrow biopsies of patients with ET and pre-PMF to improve our understanding of the nuanced diagnostic characteristics of both diseases. We performed proteomic analysis with 4D direct data-independent acquisition and microbiome analysis with 2bRAD-M sequencing technology to identify differential protein and microbe levels between untreated patients with ET and pre-PMF. Laboratory and multi-omics differences were observed between ET and pre-PMF, encompassing diverse pathways, such as lipid metabolism and immune response. The pre-PMF group showed an increased neutrophil-to-lymphocyte ratio and decreased high-density lipoprotein and cholesterol levels. Protein analysis revealed significantly higher CXCR2, CXCR4, and MX1 levels in pre-PMF, while APOC3, APOA4, FABP4, C5, and CFB levels were elevated in ET, with diagnostic accuracy indicated by AUC values ranging from 0.786 to 0.881. Microbiome assessment identified increased levels of Mycobacterium, Xanthobacter, and L1I39 in pre-PMF, whereas Sphingomonas, Brevibacillus, and Pseudomonas_E were significantly decreased, with AUCs for these genera ranging from 0.833 to 0.929. Our study provides preliminary insights into the proteomic and microbiome variations in the bone marrow of patients with ET and pre-PMF, identifying specific proteins and bacterial genera that warrant further investigation as potential diagnostic indicators. These observations contribute to our evolving understanding of the multi-omics variations and possible mechanisms underlying ET and pre-PMF. Show less

Platelets are small anucleate cells that play a key role in thrombosis and hemostasis. Our group previously identified apolipoprotein A-IV (apoA-IV) as an endogenous inhibitor of thrombosis by competitive blockade of the αIIbβ3 integrin on platelets. ApoA-IV inhibition of platelets was dependent on the N-terminal D5/D13 residues, and enhanced with absence of the C-terminus, suggesting it sterically hinders its N-terminal platelet binding site. The C-terminus is also the site of common apoA-IV polymorphisms apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). Interestingly, both are linked with an increased risk of cardiovascular disease, however, the underlying mechanism remains unclear. Here, we generated recombinant apoA-IV and found that the Q360H or T347S polymorphisms dampened its inhibition of platelet aggregation in human platelet-rich plasma and gel-filtered platelets, reduced its inhibition of platelet spreading, and its inhibition of P-selectin on activated platelets. Using an ex vivo thrombosis assay, we found that Q360H and T347S attenuated its inhibition of thrombosis at both high (1800s Show less

The aim of this study is to explore the potential modulatory role of quercetin against Endotoxin or lipopolysaccharide (LPS) induced septic cardiac dysfunction. Specific pathogen-free chicken embryos ( They demonstrated that the heart presented inflammatory responses after LPS induction. The LPS-induced higher mRNA expressions of inflammation-related factors (TLR4, TNFα, MYD88, NF-κB1, IFNγ, IL-1β, IL-8, IL-6, IL-10, p38, MMP3, and MMP9) were blocked by quercetin with three dosages. Quercetin significantly decreased immunopositivity to TLR4 and MMP9 in the treatment group when compared with the LPS group. Quercetin significantly decreased protein expressions of TLR4, IFNγ, MMP3, and MMP9 when compared with the LPS group. Quercetin treatment prevented LPS-induced increase in the mRNA expression of Claudin 1 and ZO-1, and significantly decreased protein expression of claudin 1 when compared with the LPS group. Quercetin significantly downregulated autophagy-related gene expressions (PPARα, SGLT1, APOA4, AMPKα1, AMPKα2, ATG5, ATG7, Beclin-1, and LC3B) and programmed cell death (Fas, Bcl-2, CASP1, CASP12, CASP3, and RIPK1) after LPS induction. Quercetin significantly decreased immunopositivity to APOA4, AMPKα2, and LC3-II/LC3-I in the treatment group when compared with the LPS group. Quercetin significantly decreased protein expressions of AMPKα1, LC3-I, and LC3-II. Quercetin significantly decreased the protein expression to CASP1 and CASP3 by immunohistochemical investigation or Western blotting in treatment group when compared with LPS group. Quercetin alleviates cardiac inflammation induced by LPS through modulating autophagy, programmed cell death, and myocardiocytes permeability. Show less

Apolipoprotein A4 (Apo-A4) is considered as a prospective molecular biomarker for diagnosis of depression due to its neurosynaptic toxicity. We develop a proximity hybridization-induced DNAzyme-driven bipedal DNA walker strategy for Apo-A4 quantification based on rolling circle amplification (RCA) triggered by poly adenine binding to Ag nanoparticles (AgNPs). With the help of DNAzyme, the free-running bipedal DNA walker can quickly and sequentially shear a molecular beacon that acts as a primer to initiate the RCA process, producing a large number of long DNA strands containing numerous adenines. The long repetitive adenine strands then absorb large amounts of AgNPs on the electrode interface, which is then electrochemically stripped of the AgNPs. The method has a linear detection range of 0.001 ∼ 100 ng mL Show less

Apolipoprotein A4 has a wide range of synaptic toxicity and can be used as a reliable molecular biomarker for the detection of depressive disorder. It has certain clinical requirements for simple, rapid and selective detection of apolipoprotein A4. Here, based on the DNA biped walker driven by DNAzyme, we designed a label-free surface-enhanced Raman scatting sensor for rapid detection of apolipoprotein A4. Compared with the typical DNA walker, the biped DNA walker has the advantages of large walking range and high magnification efficiency. The magnesium-dependent DNAzyme drives the DNA walker, which can cut the MBs sequentially. The resulting MBs fragments were then hybridized with AuNPs modified by repetitive adenine to make Au NPs proliferate on the substrate surface, resulting in a large number of cycles. Using 736 cm Show less

One of the pathological characteristics of obesity is fat accumulation of skeletal muscles (SKM) and the myocardium, involving mechanisms of insulin resistance and abnormal lipid metabolism. Apolipoprotein A-IV (ApoA-IV) is an essential gene in both glucose and lipid metabolisms. Using high-fat diet (HFD) induced obese In stable obese animal models, we find ApoA-IV-knockout mice show elevated TG content, enhanced expression of lipogenic enzymes and diminished phosphorylated AKT in SKM and the myocardium, but both stable hepatic expression of AAV- We find that ApoA-IV reduces fat accumulation by suppressing lipogenesis and improves glucose uptake in SKM and the myocardium by regulating the PI3K-AKT pathway. Show less

Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. Hi-C and RNA-seq were applied to study the 3D chromatin landscapes and gene expression of HCC and ANHT. Hi-C Pro was used to generate genome-wide raw interaction matrices, which were normalized via iterative correction (ICE). Moreover, the chromosomes were divided into different compartments according to the first principal component (E1). Furthermore, topologically associated domains (TADs) were visualized via WashU Epigenome Browser. Furthermore, differential expression analysis of ANHT and HCC was performed using the DESeq2 R package. Additionally, dysregulated genes associated with 3D genome architecture altered were confirmed using TCGA, qRT-PCR, immunohistochemistry (IHC), etc. RESULTS: First, the intrachromosomal interactions of chr1, chr2, chr5, and chr11 were significantly different, and the interchromosomal interactions of chr4-chr10, chr13-chr21, chr15-chr22, and chr16-chr19 are remarkably different between ANHT and HCC, which resulted in the up-regulation of TP53I3 and ZNF738 and the down-regulation of APOC3 and APOA5 in HCC. Second, 49 compartment regions on 18 chromosomes have significantly switched (A-B or B-A) during HCC tumorigenesis, contributing to up-regulation of RAP2A. Finally, a tumor-specific TAD boundary located on chr5: 6271000-6478000 and enhancer hijacking were identified in HCC tissues, potentially associated with the elevated expression of MED10, whose expression were associated with poor prognosis of HCC patients. This study demonstrates the crucial role of chromosomal structure variation in HCC oncogenesis and potential novel biomarkers of HCC, laying a foundation for cancer precision medicine development. Show less

Stable angina pectoris, resulting from coronary artery atherosclerosis, significantly affects quality of life and carries a high risk of cardiovascular events. Despite modern therapies, managing this condition remains challenging. Traditional Chinese medicine (TCM) views it as a syndrome of heart meridian obstruction by phlegm and blood stasis, necessitating improved circulation and phlegm resolution. This study aims to evaluate the efficacy of Jiangzhi Mai'an Granules, a TCM formulation, in treating stable angina pectoris and carotid atherosclerosis, with the goal of integrating TCM with Western medicine to enhance clinical outcomes and patients' quality of life. A total of 120 patients diagnosed with stable angina pectoris and carotid atherosclerotic plaques of the phlegm and blood stasis types were randomly divided into 2 groups. The control group (n = 60) received standard Western medical treatment, whereas the treated group (n = 60) received JZMA in addition to the standard regimen. The treatment duration in both the groups was 3 months. The outcomes measured included carotid intima-media thickness (CIMT), carotid plaque dimensions, TCM syndrome scores, and serum lipid profiles (total cholesterol [TC], triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein B [Apo B], and non-HDL-C) and lipoprotein phospholipase A2 (Lp-PLA2) levels before and after treatment. The treated group achieved a total efficacy rate of 93.3% (56/60), which surpassed the control group rate of 78.3% (47/60). The CIMT, carotid plaque thickness, and area in the treated group were significantly reduced posttreatment compared to baseline (P < .05) and were also lower than those in the control group (P < .05). Serum lipid levels, including TC, TG, LDL-C, ApoB and non-HDL-C were significantly decreased in both groups posttreatment (P < .05), and the treated group showed a further increase in HDL-C levels (P < .05). The treated group exhibited lower serum lipid levels than the control group posttreatment (P < .05). The TCM syndrome scores improved significantly in both groups after treatment (P < .05), with the treated group demonstrating a more pronounced reduction in scores than the control group (P < .05). The incidence of adverse events did not differ significantly between the 2 groups. JZMA combined with standard treatment effectively reduced CIMT, plaque size, and serum lipid levels, thereby enhancing clinical outcomes in patients with stable angina and carotid atherosclerosis. Show less

Observational studies have investigated the association between lipid-lowering drugs and breast cancer (BC) and endometrial cancer (EC), but some controversy remains. This paper aims to explore the causal relationship between genetic proxies for lipid-lowering drugs and breast and endometrial cancers using drug-target Mendelian randomization (MR). Analyses were mainly performed using inverse variance weighted (IVW), heterogeneity and horizontal pleiotropy tests, and sensitivity analysis to assess the robustness of the results and causal relationship. HMGCR, APOB, and NPC1L1 increased the risk of breast cancer, LPL increased the risk of endometrial cancer, and APOC3 decreased the risk of breast and endometrial cancer. No heterogeneity or horizontal pleiotropy was detected, and nor was there any evidence of an association between other lipid-lowering drugs and breast and endometrial cancer. Our study demonstrated genetically that HMGCR inhibition, APOB inhibition, and NPC1L1 inhibition decrease the risk of breast cancer, LPL agonist increases the risk of endometrial cancer, and APOC3 inhibition decreases the risk of breast cancer and endometrial cancer, and these findings provide genetic insights into the potential risks of lipid-lowering drug therapy. Show less

Adult tethered cord syndrome (ATCS) has a hidden onset and delayed clinical symptoms. The purpose of this study is to identify hub proteins in the cerebrospinal fluid of ATCS patients through bioinformatics analysis, and to find significant heterogeneity in these proteins between ATCS patients and non ATCS patients (control group). Firstly, differential genes were screened based on proteomic results. Compared with the control group, 18 differentially expressed proteins were upregulated and 18 differentially expressed proteins were downregulated in the cerebrospinal fluid of ATCS patients. Then, GO, KEGG, and GESA functional enrichment analysis showed that ATCS patients were active in biological processes such as coagulation, inflammatory response, and regulation of humoral immune response, suggesting the possibility of spinal cord injury. In addition, protein network interaction analysis indicates that APOB, APOC3, FGA, and FGG are defined as hub proteins. The correlation between ATCS patients and immune characteristics was analyzed using the CIBERSORT algorithm, which may have generated a unique immune microenvironment. Finally, Western blotting was used to experimentally validate APOB, APOC3, FGA, and FGG. The results showed that APOB, APOC3, FGA, and FGG were upregulated in the cerebrospinal fluid of ATCS patients and had an important impact on the repair and functional maintenance of spinal cord injury. They can be used as key proteins for early and accurate diagnosis and treatment of spinal cord thrombosis syndrome, and suggest that the spinal cord of ATCS patients may be damaged, which can serve as potential therapeutic targets. Show less

Small dense low-density lipoprotein cholesterol (sdLDL-C), as an emerging atherogenic factor of cardiovascular diseases, requires additional tests. We aimed to establish a sdLDL-C equation using standard lipid profile and evaluate its capacity of identifying the residual cardiovascular risk beyond LDL-C and apolipoprotein B (ApoB). This cross-sectional study included 25 435 participants from Health Management Cohort and 11 628 participants from China Health and Retirement Longitudinal Study (CHARLS) to construct and evaluate the sdLDL-C equation by least-squares regression model. The equation for sdLDL-C depended on low-density lipoprotein cholesterol (LDL-C) and an interaction term between LDL-C and the natural log of triglycerides (TG). The modified equation (sdLDL-C = 0.14*ln(TG)*LDL-C - 0.45*LDL-C + 10.88) was more accurate than the original equation in validation set (slope = 0.783 vs. 0.776, MAD = 5.228 vs. 5.396). Using the 80th percentile (50 mg/dL) as a risk-enhancer rule for sdLDL-C, accuracy of the modified equation was higher than the original equation in validation set (90.47% vs. 89.73%). The estimated sdLDL-C identified an additional proportion of high-risk individuals in BHMC (4.93%) and CHARLS (1.84%). The newly developed equation in our study provided an accurate tool for estimating sdLDL-C level among the Chinese population as a potential cardiovascular risk-enhancer. Show less

Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL. We hypothesized that in the liver, in addition to promoting cytosolic LD formation, FITM2 would also transfer TG from its site of synthesis in the ER membrane to nascent VLDL particles within the ER lumen. Experiments were conducted using a rat hepatic cell line (McArdle-RH7777, or McA cells), an established model of mammalian lipoprotein metabolism, and mice. FITM2 expression was reduced using siRNA in cells and by liver specific cre-recombinase mediated deletion of the Fitm2 gene in mice. Effects of FITM2 deficiency on VLDL assembly and secretion in vitro and in vivo were measured by multiple methods, including density gradient ultracentrifugation, chromatography, mass spectrometry, stimulated Raman scattering (SRS) microscopy, sub-cellular fractionation, immunoprecipitation, immunofluorescence, and electron microscopy. 1) FITM2-deficient hepatic cells in vitro and in vivo secrete TG-depleted VLDL particles, but the number of particles is unchanged compared to controls; 2) FITM2 deficiency in mice on a high fat diet (HFD) results in decreased plasma TG levels. The number of apoB100-containing lipoproteins remains similar, but shift from VLDL to low density lipoprotein (LDL) density; 3) Both in vitro and in vivo, when TG synthesis is stimulated and FITM2 is deficient, TG accumulates in the ER, and despite its availability this pool is unable to fully lipidate apoB100 particles; 4) FITM2 deficiency disrupts ER morphology and results in ER stress. The results suggest that FITM2 contributes to VLDL lipidation, especially when newly synthesized hepatic TG is in abundance. In addition to its fundamental importance in VLDL assembly, the results also suggest that under dysmetabolic conditions, FITM2 may be an important factor in the partitioning of TG between cytosolic LDs and VLDL particles. Show less

Rapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors and establish an accurate clinical prediction model for the rapid progression of NTLs post-PCI. PCSK9 inhibitors lower LDL-c levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI. We tried to test this hypothesis and explore the potential mechanisms. This retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. General characteristics, laboratory tests and inflammatory factors(IL-10, IL-6, IL-8, IL-1β, sIL-2R, and TNF-α) were collected. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI. There were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid, hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group. LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for the rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI). LDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters might predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors had a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque. ChiCTR2200058529; Date of registration: 2022-04-10. Show less

Dyslipidemia stands as an autonomous peril in the realm of atherosclerotic cardiovascular maladies. Prompt identification and timely intervention in the case of dyslipidemia hold promise for substantially curbing the onset and fatality rates associated with coronary heart disease. Traditional lipid surveillance metrics employed in clinical settings, such as low-density lipoprotein cholesterol, exhibit notable limitations. Conversely, lipid-derived parameters emerge as formidable contenders, demonstrating a capacity to amalgamate and quantify disparate risk factors and multifactorial etiologies inherent in a given disease. By encompassing a broader spectrum of information than singular indices, these parameters offer a more profound insight into disease progression by virtue of their grounding in the physiological intricacies of lipid metabolism. Drawing upon extant domestic and international guidelines and research, this discourse delineates and synthesizes four lipid-derived parameters with promising clinical applications: atherogenic index of plasma, non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, apolipoprotein B/A1 ratio, and lipoprotein combine index, and forwards a perspective grounded in current strides in clinical research. Show less

Diabetic cardiomyopathy (DCM) is a common diabetes complication with limited medications. Gegen Qinlian decoction (GQD) has been used in the treatment of diabetes and its related complications in China for several decades. In this study, network pharmacology was employed to predict the active ingredients, key targets, and pathways involved in the treatment of DCM by GQD and to validate it by animal experiments. The active ingredients of GQD were retrieved from TCMSP and published literature. DCM-related gene targets were searched in Drugbank, Genecards, Disgenet, and OMIM disease databases. Protein-protein interaction networks were constructed using the STRING database and Cytoscape. GO analysis and KEGG pathway enrichment analysis were performed using the Metascape platform. Moreover, a diabetic mouse model was established to evaluate the therapeutic effects of GQD by measuring serum biochemical markers and inflammation levels. Finally, the expression of predicted key target genes was determined using real-time quantitative PCR. A total of 129 active ingredients were screened from GQD. Moreover, 146 intersecting genes related to DCM were obtained, with key targets, including AKT1, TNF, IL6, and VEGFA. Lipid and atherosclerosis, AGE-RAGE, PI3K-AKT, and MAPK pathways were identified. Blood glucose control, decreased inflammatory factors, and serum CK-MB levels were restored after GQD intervention, and the same occurred with the expressions of PPAR-γ, AKT1, APOB, and GSK3B genes. Quercetin, kaempferol, wogonin, 7-methoxy-2-methyl isoflavone, and formononetin may exert major therapeutic effects by regulating key factors, such as AKT1, APOB, and GSK3B, in the inflammatory reaction, glycolipid oxidation, and glycogen synthesis related signaling pathways. Show less

Previous observational studies have reported a possible association between circulating lipids and lipid-lowering drugs and male infertility (MIF), as well as the mediating role of circulating vitamin D. Then, due to issues such as bias, reverse causality, and residual confounding, inferring causal relationships from these studies may be challenging. Therefore, this study aims to explore the effects of circulating lipids and lipid-lowering drugs on MIF through Mendelian randomization (MR) analysis and evaluate the mediating role of vitamin D. Genetic variations related to lipid traits and the lipid-lowering effect of lipid modification targets are extracted from the Global Alliance for Lipid Genetics Genome-Wide Association Study. The summary statistics for MIF are from the FinnGen 9th edition. Using quantitative expression feature loci data from relevant organizations to obtain genetic variations related to gene expression level, further to explore the relationship between these target gene expression levels and MIF risk. Two-step MR analysis is used to explore the mediating role of vitamin D. Multiple sensitivity analysis methods (co-localization analysis, Egger intercept test, Cochrane's Q test, pleiotropy residuals and outliers (MR-PRESSO), and the leave-one-out method) are used to demonstrate the reliability of our results. In our study, we observed that lipid modification of four lipid-lowering drug targets was associated with MIF risk, the LDLR activator (equivalent to a 1-SD decrease in LDL-C) (OR=1.94, 95% CI 1.14-3.28, FDR=0.040), LPL activator (equivalent to a 1-SD decrease in TG) (OR=1.86, 95% CI 1.25-2.76, FDR=0.022), and CETP inhibitor (equivalent to a 1-SD increase in HDL-C) (OR=1.28, 95% CI 1.07-1.53, FDR=0.035) were associated with a higher risk of MIF. The HMGCR inhibitor (equivalent to a 1-SD decrease in LDL-C) was associated with a lower risk of MIF (OR=0.38, 95% CI 0.17-0.83, FDR=0.39). Lipid-modifying effects of three targets were partially mediated by serum vitamin D levels. Mediation was 0.035 (LDLR activator), 0.012 (LPL activator), and 0.030 (CETP inhibitor), with mediation ratios of 5.34% (LDLR activator), 1.94% (LPL activator), and 12.2% (CETP inhibitor), respectively. In addition, there was no evidence that lipid properties and lipid modification effects of six other lipid-lowering drug targets were associated with MIF risk. Multiple sensitivity analysis methods revealed insignificant evidence of bias arising from pleiotropy or genetic confounding. This study did not support lipid traits (LDL-C, HDL-C, TG, Apo-A1, and Apo-B) as pathogenic risk factors for MIF. It emphasized that LPL, LDLR, CETP, and HMGCR were promising drug targets for improving male fertility. Show less

Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk. This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS. We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes and lipid-lowering drug therapy. In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP, and greater TRLP size (odds ratio [OR], 1.22-2.08) and total LDLP (OR, 1.22-1.75) and decreased LDL and HDL size compared to referent individuals. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (OR, 1.31-1.84). Total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B (ApoB) were also higher in all patient categories in age- and sex-adjusted analysis, with ApoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and ApoB elevations were observed in all patient categories after excluding individuals on lipid-lowering therapy. Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and ApoB concentrations, which conceivably contribute to high cardiometabolic risk. Show less

Ubiquitin-conjugating enzyme E2 N (UBE2N) is recognized in the progression of some cancers; however, little research has been conducted to describe its role in prostate cancer. The purpose of this paper is to explore the function and mechanism of UBE2N in prostate cancer cells. UBE2N expression was detected in Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data, prostate cancer tissue microarrays, and prostate cancer cell lines, respectively. UBE2N knockdown or overexpression was used to analyze its role in cell viability and glycolysis of prostate cancer cells and tumor growth. XAV939 or Axin1 overexpression was co-treated with UBE2N overexpression to detect the involvement of the Wnt/β-catenin signaling and Axin1 in the UBE2N function. UBE2N interacting with Axin1 was analyzed by co-immunoprecipitation assay. UBE2N was upregulated in prostate cancer and the UBE2N-high expression correlated with the poor prognosis of prostate cancer. UBE2N knockdown inhibited cell viability and glycolysis in prostate cancer cells and restricted tumor formation in tumor-bearing mice. Wnt/β-catenin inhibition and Axin1 overexpression reversed the promoting viability and glycolysis function of UBE2N. UBE2N promoted Axin1 ubiquitination and decreased Axin1 protein level. Show less

The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC. Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53 CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8 Activation of the CRKL/β-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC. Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/β-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC. Show less