👤 Yaru Guo

Computational modeling indicated that pathological high shear stress (HSS; 100 dyn/cm We used the Ibidi perfusion system to determine whether HSS applied to human PA endothelial cells (ECs) induces EndMT when compared with physiological laminar shear stress (15 dyn/cm EndMT, a feature of PAH not previously attributed to HSS, was observed. HSS did not alter the induction of transcription factors KLF (Krüppel-like factor) 2/4, but an ERG (ETS-family transcription factor) was reduced, as were histone H3 lysine 27 acetylation enhancer-promoter peaks containing ERG motifs. Consequently, there was reduced interaction between ERG and KLF2/4, a feature important in tethering KLF and the chromatin remodeling complex to DNA. In PA ECs under laminar shear stress, reducing ERG by siRNA caused EndMT associated with decreased BMPR2 (bone morphogenetic protein receptor 2), CDH5 (cadherin 5), and PECAM1 (platelet and EC adhesion molecule 1) and increased SNAI1/2 (Snail/Slug) and ACTA2 (smooth muscle α2 actin). In PA ECs under HSS, transfection of ERG prevented EndMT. HSS was then induced in mice by an aortocaval shunt, causing progressive PAH over 8 weeks. An adeno-associated viral vector (AAV2-ESGHGYF) was used to replenish ERG selectively in PA ECs. Elevated PA pressure, EndMT, and vascular remodeling (muscularization of peripheral arteries) in the aortocaval shunt mice were markedly reduced by ERG delivery. Pathological HSS reduced lung EC ERG, resulting in EndMT and PAH. Agents that upregulate ERG could reverse HSS-mediated PAH and occlusive vascular remodeling resulting from high flow or narrowed PAs. Show less

The SNP rs2414739 of Vacuolar protein sorting 13 homolog C(VPS13C) gene was identified to be linked with Parkinson's Disease (PD). Explore the clinical progression feature of PD patients with rs2414739 variant. Longitudinal data were obtained from the Parkinson's Progression Marker Initiative (PPMI) cohorts. Linear mixed models were used to test the effects of VPS13C with the progression of PD assessed by different scales. A total of 333 patients with PD were included and divided into rs2414739 carriers (n = 138) and noncarriers (n = 195). Patients with PD carrying VPS13C mutation had slower progression, assessed by total scores of MDS-UPDRS (II+III) (β = -1.834, p = 0.000, 95%CI: -2.767, -0.901) than noncarriers. The effect of VPS13C was significant both in the rate of change of UPDRS-II scores (β = -0.284, p = 0.028, 95%CI: -0.537, -0.031) and UPDRS-III scores (β = -0.894, p = 0.009, 95%CI: -1.558, -0.228). We further divided VPS13C carriers into heterozygous and homozygous carriers, and found that the rate of change of UPDRS(II+III) (β = -1.165, p = 0.039, 95%CI: -2.265,-0.062) scores and UPDRS-III scores (β = -9.521, p = 0.041, 95%CI: -18.524,-0.532) were significantly slow in heterozygous VPS13C carriers. There was only 20 homozygous VPS13C carriers, which was too small a sample to perform the analysis. VPS13C was associated with slow motor progression in PD patients. Show less

Renal ischemia-reperfusion injury (RIRI) stands as an unavoidable complication arising from kidney surgery, profoundly intertwined with its prognosis. The role of differentially expressed in FDCP 6 homolog (DEF6) in RIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which DEF6 regulated RIRI. RNA sequencing data and IP-MS were used to identify the expression and potential targets of DEF6 through bioinformatics analysis. To elucidate the impact of DEF6 on RIRI, both an in vivo model of RIRI in mice and an in vitro model of kidney cell hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of DEF6 on kidney damage mediated by RIRI. We confirmed that DEF6 was upregulated during RIRI and had a close correlation with RIRI-related inflammation and apoptosis. Moreover, inhibition of DEF6 could mitigate RIRI-induced kidney damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that DEF6 interacts with poly ADP-ribose polymerase 1 (PARP1) and suppresses the ubiquitination of PARP1. Inhibition of DEF6 resulted in reduced cleaveage of PARP1, leading to a marked suppression of PARP1-mediated apoptosis activation. The aggravation effect on inflammation and apoptosis achieved through DEF6 was nullified by the inhibition of NF-κB and Bax/Bcl2 signaling activation through PARP1 deletion. The findings from our study indicate that DEF6 suppressed the WWP2 mediated ubiquitination of PARP1 and modulates the activation of NF-κB and Bax/Bcl2 pathway, thus involved in RIRI-induced inflammation and apoptosis. These results suggest that DEF6 holds promise as a potential therapeutic target for mitigating RIRI. Show less

Sichuan donkeys are small-statured donkeys native to the plateau and mountainous regions of southwestern China. They are well-suited for transportation tasks in mountainous terrain and exhibit remarkable adaptability to the harsh environment, characterized by low temperatures and hypoxia. Adaptation to the local environment has shaped their unique genomic characteristics and is an important source of genetic variation. However, the genome-wide landscape of Sichuan donkeys remains undescribed. In this study, we obtained whole-genome sequencing data from 17 Sichuan donkeys and combined this data with published data of 99 donkeys from 9 other donkey breeds. We aimed to elucidate the population structure, genetic diversity, genetic differentiation, and selection pressure of Sichuan donkeys at the whole-genome level. Population structure and genetic diversity analysis showed that Sichuan donkeys were less influenced by the hybridization of foreign donkey breeds. They maintained a relatively pure lineage of Chinese native donkeys and exhibited higher genetic diversity. The study also found that Sichuan donkeys were genetically closest to Tibetan and Yunnan donkeys. Although their effective population size around 1000 years ago was smaller compared to Tibetan and Yunnan donkeys, it was still larger than that of other donkey breeds. Moreover, selective signature analysis (θπ, CLR, F This study clarified the genetic diversity, genetic differentiation, and effective population size of Sichuan donkeys by comparing them with other donkey breeds. Our findings contribute to deeper understanding of the high-altitude adaptability of Sichuan donkeys, and provide valuable information for the conservation and breeding of the breed. Show less

The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, the molecular underpinnings of lysosome-related genes (LRGs) in the context of PD remain partially elucidated. We collected RNA-seq data from the brain substantia nigra of 30 PD patients and 20 normal subjects from the GEO database. We obtained molecular classification clusters from the screened lysosomal expression patterns. The lysosome-related diagnostic model of Parkinson's disease was constructed by XGBoost and Random Forest. And we validated the expression patterns of signature LRGs in the diagnostic model by constructing a PD rat model. Finally, the linkage between PD and cancer through signature genes was explored. The expression patterns of the 33 LRGs screened can be divided into two groups of PD samples, enabling exploration of the variance in biological processes and immune elements. Cluster A had a higher disease severity. Subsequently, critical genes were sieved through the application of machine learning methodologies culminating in the identification of two intersecting feature genes (ACP2 and LRP2). A PD risk prediction model was constructed grounded on these signature genes. The model's validity was assessed through nomogram evaluation, which demonstrated robust confidence validity. Then we analyzed the correlation analysis, immune in-filtration, biological function, and rat expression validation of the two genes with common pathogenic genes in Parkinson's disease, indicating that these two genes play an important role in the pathogenesis of PD. We then selected ACP2, which had a significant immune infiltration correlation, as the entry gene for the pan-cancer analysis. The pan-cancer analysis revealed that ACP2 has profound associations with prognostic indicators, immune infiltration, and tumor-related regulatory processes across various neoplasms, suggesting its potential as a therapeutic target in a range of human diseases, including PD and cancers. Our study comprehensively analyzed the molecular grouping of LRGs expression patterns in Parkinson's disease, and the disease progression was more severe in cluster A. And the PD diagnosis model related to LRGs is constructed. Finally, ACP2 is a potential target for the relationship between Parkinson's disease and tumor. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner. GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis. Show less

Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. The MC4R POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity. Show less

Central to the process of axon elongation is the concept of compartmentalized signaling, which involves the A-kinase anchoring protein (AKAP)-dependent organization of signaling pathways within distinct subcellular domains. This spatial organization is also critical for translating electrical activity into biochemical events. Despite intensive research, the detailed mechanisms by which the spatial separation of signaling pathways governs axonal outgrowth and pathfinding remain unresolved. In this study, we demonstrate that mAKAPα (AKAP6), located in the perinuclear space of primary hippocampal neurons, scaffolds calcineurin, NFAT, and MEF2 transcription factors for activity-dependent axon elongation. By employing anchoring disruptors, we show that the mAKAPα/calcineurin/MEF2 signaling pathway, but not NFAT, drives the process of axonal outgrowth. Furthermore, mAKAPα-controlled axonal elongation is linked to the changes in the expression of genes involved in Ca Show less

Brain-derived neurotrophic factor (BDNF) is known for its potent prosurvival effect. Despite successfully replicating this effect in various clinical and pre-clinical models, the complete characterization of the molecular mechanisms underlying its neuroprotective action remains incomplete. Emerging research suggests a vital role for A-kinase anchoring proteins (AKAPs) as central nodal points orchestrating BDNF-dependent signaling. Among the over 50 identified AKAPs, AKAP6 has recently gained special attention due to its involvement in the neurotrophin-mediated survival of injured retinal ganglion cells (RGCs). However, the mechanisms by which AKAP6 responds to pro-survival BDNF signaling remain unknown. In this study, we shown that AKAP6 plays a crucial role in regulating BDNF-mediated NFAT transcriptional activity in neuronal survival by anchoring protein phosphatase calcineurin (CaN) and nuclear factor of activated T cells (NFATc4). Furthermore, we demonstrate that disrupting the anchoring of CaN diminishes the pro-survival effect of BDNF. Lastly, through experiments with NFATc4-/- mice, we provide evidence that NFATc4 acts downstream to BDNF's neuroprotection in vivo. These findings could offer valuable insights for developing neuroprotective strategies aimed at preserving injured neurons from degeneration and promoting their regeneration. Show less

Neovascular age-related macular degeneration (nvAMD) is the leading cause of severe vision loss in the elderly in the developed world. While the introduction of therapies targeting vascular endothelial growth factor (VEGF) has provided the first opportunity to significantly improve vision in patients with nvAMD, many patients respond inadequately to current anti-VEGF therapies. It was recently demonstrated that expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4), synergizes with VEGF to promote choroidal neovascularization (CNV) in mice and correlates with reduced response to anti-VEGF therapy in patients with nvAMD. Here, we report that expression of ANGPTL4 in patients with nvAMD increases following treatment with anti-VEGF therapy and that this increase is dependent on accumulation of hypoxia-inducible factor (HIF)-1α in response to inhibition of VEGF/KDR signaling in the retinal pigment epithelium (RPE). We therefore explored HIF-1 inhibition with 32-134D, a recently developed pharmacologic HIF-inhibitor, for the treatment of nvAMD. 32-134D prevented the expression of both VEGF and ANGPTL4 and was at least as effective as aflibercept in treating CNV in mice. Moreover, by preventing the increase in HIF-1α accumulation in the RPE in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective than either drug alone for the treatment of CNV. Collectively, these results help explain why many patients with nvAMD respond inadequately to anti-VEGF therapy and suggest that the HIF inhibitor 32-134D will be an effective drug-alone or in combination with current anti-VEGF therapies-for the treatment of patients with this blinding disease. Show less

This study aimed to determine the function of angiopoietin-related protein 4 (ANGPTL4) and bone morphogenetic protein 7 (BMP7) on hepatocellular carcinoma (HCC). Overexpressing plasmids were cotransfected into HepG2 cells to determine the interaction between ANGPTL4 and BMP7. The effect of ANGPTL4 on the stability of BMP7 is examined by detecting the expression and ubiquitination levels. Show less

It has been demonstrated that angiopoietin-like protein 4 (ANGPTL4) plays an important regulatory role in lipid metabolism and backfat deposition appears to vary in different pig breeds. However, the correlation between ANGPTL4 and backfat deposition have not been well characterized and the role of ANGPTL4 in regulating adipogenesis remains unclear. Therefore, this study aimed to investigate correlation between ANGPTL4 and backfat deposition and to explore the effects of ANGPTL4 on preadipocyte differentiation and the underlying mechanism. Our results showed that the backfat thickness and the ANGPTL4 gene expression of Laiwu pigs were significantly higher than those in DLY pigs and the ANGPTL4 gene expression was positively correlated with backfat thickness both in DLY pigs and Laiwu pigs. Moreover, an increase in ANGPTL4 expression and activation of autophagy were observed during the differentiation of stromal vascular fraction cells. In addition, knockdown of ANGPTL4 inhibited the differentiation of 3T3-L1 cells with decreased expression of LC3-II and ATG5 and increased expression of SQSTM1, suggesting the involvement of autophagy in ANGPTL4-mediated adipogenesis. In conclusion, these results suggested that ANGPTL4 is positively correlated with backfat deposition in pigs and knockdown of ANGPTL4 inhibits adipogenesis of preadipocyte via autophagy, providing new insights into the regulation of fat deposition and to improve the carcass quality and meat quality of porcine. Show less

Lung adenocarcinoma (LUAD) is a malignant tumor of the respiratory system that has a poor 5-year survival rate. Anoikis, a type of programmed cell death, contributes to tumor development and metastasis. The aim of this study was to develop an anoikis-based stratified model, and a multivariable-based nomogram for guiding clinical therapy for LUAD. Through differentially expressed analysis, univariate Cox, LASSO Cox regression, and random forest algorithm analysis, we established a 4 anoikis-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of LUAD patients in the TCGA and GEO databases, respectively. The low and high-risk score LUAD patients stratified by the model showed different tumor mutation burden, tumor microenvironment, gemcitabine sensitivity and immune checkpoint expressions. Through immunohistochemical analysis of clinical LUAD samples, we found that the 4 anoikis-related genes (PLK1, SLC2A1, ANGPTL4, CDKN3) were highly expressed in the tumor samples from clinical LUAD patients, and knockdown of these genes in LUAD cells by transfection with small interfering RNAs significantly inhibited LUAD cell proliferation and migration, and promoted anoikis. In conclusion, we developed an anoikis-based stratified model and a multivariable-based nomogram of LUAD, which could predict the survival of LUAD patients and guide clinical treatment. Show less

Hepatocellular carcinoma (HCC) is a malignant tumor that impacts individuals worldwide and is particularly prevalent in Asia. Angiopoietin-like protein 4 (ANGPTL4) plays an important role in regulating glucose and lipid metabolism in mouse liver. We sought to explore the effects of the ANGPTL4 gene on cell viability, migration, invasive capacity, and apoptosis of HCC cells. The expression of ANGPTL4 in HCC and paracancerous tissues was determined by immunohistochemistry and immunofluorescence assays. The ANGPTL4 knockdown cells were established by shRNA transfection. The effect of ANGPTL4 knockdown on HepG2 and Huh7 cells was determined by Cell Count Kit-8 (CCK-8), wound healing and transwell assays. Cell apoptosis was determined by flow cytometry. The ANGPTL4 expression was dramatically enhanced in HCC tissues than in paracancerous tissues ( High expression of ANGPTL4 is closely related to HCC. Knockdown of ANGPTL4 significantly inhibits the proliferation of HCC cells. This study provides a rationale for the ANGPTL4 gene, a molecular marker of HCC. Show less

Migraine is a common neurological disorder that affects more than one billion people worldwide. Recent genome-wide association studies have identified 123 genetic loci associated with migraine risk. However, the biological mechanisms underlying migraine and its relationships with other complex diseases remain unclear. We performed a phenome-wide association study (PheWAS) using UK Biobank data to investigate associations between migraine and 416 phenotypes. Mendelian randomization was employed using the IVW method. For loci associated with multiple diseases, pleiotropy was tested using MR-Egger. Single-cell RNA sequencing data was analyzed to profile the expression of 73 migraine susceptibility genes across brain cell types. qPCR was used to validate the expression of selected genes in microglia. PheWAS identified 15 disorders significantly associated with migraine, with one association detecting potential pleiotropy. Single-cell analysis revealed elevated expression of seven susceptibility genes (including ZEB2, RUNX1, SLC24A3, ANKDD1B, etc.) in brain glial cells. And qPCR confirmed the upregulation of these genes in LPS-treated microglia. This multimodal analysis provides novel insights into the link between migraine and other diseases. The single-cell profiling suggests the involvement of specific brain cells and molecular pathways. Validation of gene expression in microglia supports their potential role in migraine pathology. Overall, this study uncovers pleiotropic relationships and the biological underpinnings of migraine susceptibility. 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

Egg-laying performance is of great economic importance in poultry, but the underlying genetic mechanisms are still elusive. In this work, we conduct a multi-omics and multi-tissue integrative study in hens with distinct egg production, to detect the hub candidate genes and construct hub molecular networks contributing to egg-laying phenotypic differences. We identifiy three hub candidate genes as egg-laying facilitators: TFPI2, which promotes the GnRH secretion in hypothalamic neuron cells; CAMK2D, which promotes the FSHβ and LHβ secretion in pituitary cells; and OSTN, which promotes granulosa cell proliferation and the synthesis of sex steroid hormones. We reveal key endocrine factors involving egg production by inter-tissue crosstalk analysis, and demonstrate that both a hepatokine, APOA4, and an adipokine, ANGPTL2, could increase egg production by inter-tissue communication with hypothalamic-pituitary-ovarian axis. Together, These results reveal the molecular mechanisms of multi-tissue coordinative regulation of chicken egg-laying performance and provide key insights to avian reproductive regulation. Show less

A novel electrochemical immunosensor for detecting potential depression biomarker Apolipoprotein A4 (Apo-A4) was developed using a multi-signal amplification approach. Firstly, the sensor utilized a modified electrode material, NG-PEI-COF, combining bipyridine-functionalized covalent organic framework (COF) and polyethyleneimine-functionalized nitrogen-doped graphene (NG-PEI), providing high surface area and excellent electron transfer capability for the first-stage amplification in electrical signal conduction. Subsequently, gold nanoparticles (AuNPs) were further electrodeposited onto the electrode, providing good biocompatibility and abundant binding sites for immobilizing the target antigen, thus achieving the second-stage amplification in target recognition and binding. To address the lack of redox properties of the antigen, a tracer probe was formed by loading AuNPs, anti-Apo-A4, and toluidine blue (TB) successively onto COF, leading to the third-stage amplification in signal conversion. The constructed electrochemical immunosensor TB/Ab/AuNPs/COF-Apo-A4/AuNPs/NG-PEI-COF/GCE exhibited excellent detection performance against Apo-A4 with a linear range of 0.01 to 300 ng mL 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

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

Severe fever with thrombocytopenia syndrome (SFTS) is a rapidly progressive infectious disease triggered by a novel bunyavirus (SFTSV). Despite the critical role of host lipid metabolism in viral infections, research on dyslipidemia in SFTS remains limited. This retrospective study included 433 SFTS patients, who were stratified into survival group (n = 365) and death group (n = 68) and who were treated at the Shandong Public Health Clinical Center from September 2021 to December 2023. Additionally, 96 healthy controls with matching baseline characteristics were included from Shandong Provincial Hospital. Cross-sectional analysis based on admission data and longitudinal analysis over time were employed to survey the correlation between serum lipid profiles and mortality in SFTS patients. SFTS patients exhibited elevated triglyceride (TG) levels and reduced total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels compared to healthy individuals. Cross-sectional analysis demonstrated that lower LDL-C and apolipoprotein-B (ApoB) levels were related to elevated mortality risk in SFTS patients. Longitudinal analysis demonstrated that LDL-C and ApoB levels remained consistently lower in the death group, while TG levels gradually declined, and HDL-C levels gradually increased as the disease progressed. SFTS patients exhibit significant dyslipidemia compared to healthy individuals. Lower LDL-C and ApoB levels may independently influence mortality in SFTS patients. Elevated TG and reduced HDL-C levels may associate with disease progression. Show less

Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) polymorphisms at angiotensin-converting enzyme gene (ACE) and T/C polymorphisms in the angiotensin type 1 receptor gene (AGTR1) are related to diabetes and lipid levels, but the associations are controversial. Thus, the current research aimed to explore the effects of ACE I/D, AGTR1 rs5182 and diabetes mellitus on serum lipid profiles in 385 Chinese participants with an average age of 75.01 years. The ACE I/D variant was identified using the polymerase chain reaction (PCR) method, whereas the AGTR1 rs5182 polymorphism was identified using the PCR-based restriction fragment length polymorphism (PCR-RFLP) method and verified with DNA sequencing. Total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured using routine methods, and the lipid ratios were calculated. ACE I/D, but not AGTR1 rs5182, was a predictor of TG/HDL-C for the whole study population. Both ACE I/D and AGTR1 rs5182 were predictors of HDL-C and LDL-C levels in females but not in males. Moreover, in females, diabetes mellitus and ACE I/D were identified as predictors of TG and TG/HDL-C, whereas AGTR1 rs5182 and diabetes mellitus were predictors of TG/HDL-C. Moreover, diabetes mellitus and the combination of ACE I/D and AGTR1 rs5182 variations were predictors of TG and TG/HDL-C exclusively in females. The results demonstrated the potential for gender-dependent interactions of ACE I/D, AGTR1 rs5182, and diabetes on lipid profiles. These findings may serve as an additional explanation for the inconsistent changes of blood lipids in individuals with diabetes mellitus, thereby offering a novel perspective for the clinical management of blood lipid levels in diabetic patients. Show less

To evaluate the impact of differential emergency treatment measures on the prognosis of patients with ACS. 76 patients with ACS treated in the emergency department of our hospital from January 2017 to September 2021 were selected as the research objects. According to their main symptoms, general signs, and various examination results when arriving at the hospital, differential emergency treatment measures were implemented, so as to ensure the curative effect. After comprehensive emergency treatment, the venous blood test indicators of patients, including creatinine (CR), uric acid (UA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein A (LPA), Apolipoprotein AI (ApoAI), Apolipoprotein B (ApoB), Potassium ion (K+), glucose (GLU), Cardiac troponin I (cTn) returned to normal. In addition, the proportion of patients without cardiogenic shock, ventricular fibrillation, respiratory and cardiac arrest, cerebral infarction, cerebral hemorrhage, arrhythmia, heart rupture, and other adverse reactions are as high as 92% (70/76). For patients with ACS, it is necessary to take correct emergency rescue and treatment measures immediately, especially to actively implement the percutaneous coronary intervention (PCI) method, so as to give full play to the safety and effectiveness of emergency treatment and curb the possibility of patient death as much as possible. Show less

Aromatic caninurine formamase (AFMID) is an enzyme involved in the tryptophan pathway, metabolizing N-formylkynurenine to kynurenine. AFMID had been found significantly downregulated in clear cell renal cell carcinoma (ccRCC) in both tissue and urine samples. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction, and elevated fat deposition, it is unknown whether AFMID plays a role in tumorigenesis and the development of ccRCC. In the present study, AFMID overexpression had inhibitory effects for ccRCC cells, decreasing the rate of cell proliferation. Quantitative proteomics showed that AFMID overexpression altered cellular signaling pathways involved in cell growth and cellular metabolism pathways, including lipid metabolism and inositol phosphate metabolism. Further urine proteomic analysis indicated that cellular function dysfunction with AFMID overexpression could be reflected in the urine. The activity of predicted upregulators DDX58, TREX1, TGFB1, SMARCA4, and TNF in ccRCC cells and urine showed opposing change trends. Potential urinary biomarkers were tentatively discovered and further validated using an independent cohort. The protein panel of APOC3, UMOD, and CILP achieved an AUC value of 0.862 for the training cohort and 0.883 for the validation cohort. The present study is of significance in terms of highlighting various aspects of pathway changes associated with AFMID enzymes, discovering potential specific biomarkers for potential patient diagnosis, and therapeutic targeting. Show less

Our study aimed to investigate the role of lipids in melanoma risk and the effect of lipid-lowering drug targets on melanoma. Using Mendelian Randomization analysis, we examined the genetic agents of nine lipid-lowering drugs and their association with melanoma risk. We found that genetically proxied inhibition of HMGCR, ABCG5/ABCG8, and ANGPTL3 was associated with a reduced risk of melanoma. On the other hand, inhibition of LPL and Apo-B100 was significantly associated with an increased risk of melanoma. Sensitivity analyses did not reveal any statistical evidence of bias from pleiotropy or genetic confounding. We did not find a robust association between lipid traits NPC1L1, PCSK9, APOC3 inhibition, and melanoma risk. These findings were validated using two independent lipid datasets. Our analysis also revealed that HMGCR, ANGPTL3, and ABCG5/ABCG8 inhibitors reduced melanoma risk independent of their effects on lipids. This suggests that these targets may have potential for melanoma prevention or treatment. In conclusion, our study provides evidence for a causal role of lipids in melanoma risk and highlights specific lipid-lowering drug targets that may be effective in reducing the risk of melanoma. These findings contribute to the understanding of the underlying mechanisms of melanoma development and provide potential avenues for further research and therapeutic interventions. Show less