👤 Moshage Han

Genes associated with body mass index (BMI), including FTO rs9939609,MC4R rs17782313, and BDNF rs6265, may influence BMI and regulate energy metabolism. While previous studies have explored health-related behavior changes, few have investigated both biochemical and behavior changes resulting from perceived genetic risk. This study investigated whether recognizing BMI-related genes affects health-related behaviors and alters blood metabolite levels. Normal and overweight adults aged 25-35 years (n = 100) were randomly assigned to an intervention group (n = 65) informed about BMI-related genetic information (FTO rs9939609, MC4R rs17782313, BDNF rs6265) and an uninformed group (n = 35, CON). The intervention group was further divided into Intervention-high risk (IHR, n = 36) and intervention-low risk (ILR, n = 29) subgroups. Dietary intake and physical activity (PA) were assessed using a 3-day dietary record and the IPAQ-short form. Blood metabolites were analyzed through multivariate analyses to identify significant differences among the groups, with measurements taken at baseline, 3 months, and 6 months. The IHR group exhibited increased dietary fat and fast foods intake, along with enhanced vigorous and moderate PA. Six metabolites were selected as biomarkers that were distinguishable among groups, and the relative serum cholesterol levels significantly decreased in the IHR group at 3 months. These results demonstrate that recognizing the BMI-associated genetic risk resulted in a short-term increase in PA but did not improve dietary intake. Increased PA was significantly associated with reduced cholesterol concentration, suggesting the clinical importance of physical activity in the genetically at-risk group. This study was reviewed and approved by the Seoul National University Institutional Review Board (IRB #1901/001-004) and registered on the Clinical Research Information Service (CRIS), KCT0004650 ( https://cris.nih.go.kr/cris/search/detailSearch.do /14091, 2020/01/28). Show less

Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies. Show less

There is a strong correlation between delayed diagnosis and high mortality rate in pulmonary arterial hypertension (PAH). Recent research indicates that circular RNAs (circRNAs) may serve as potential diagnostic biomarkers for PAH. This study aimed to identify important circRNAs associated with PAH to support early diagnosis and explore possible key disease mechanisms. GSE171827 and GSE113439 were obtained from the Gene Expression Omnibus (GEO) database to evaluate differentially expressed circular RNAs (DECs) and genes (DEGs). MicroRNAs (miRNAs) related to PAH were obtained from the Human microRNA Disease Database (HMDD). We validated changes in DEC expression levels using RT-qPCR in hypoxia- and normoxic-induced human pulmonary artery endothelial cells. Then, the potential relationship between DEC expression levels and mean pulmonary artery pressure (mPAP) in PAH patients was investigated. Finally, bioinformatics analyses were performed to construct a competing endogenous RNA (ceRNA) network and excavate the potential functions of DECs. Only hsa_circ₀₀₀₅₆₂₃ expression was significantly downregulated in PAH. Low hsa_circ₀₀₀₅₆₂₃ expression levels in the plasma of PAH patients were significantly associated with mPAP ( 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

How extravillous trophoblast (EVT) invasion is regulated during placental development remains an important question in reproductive biology. This study demonstrates that growth differentiation factor-11 (GDF-11) promotes EVT invasion by upregulating angiopoietin-like 4 (ANGPTL4) via ALK4/ALK5-SMAD3 signaling, revealing a novel mechanism in placental biology. Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Growth differentiation factor 11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to promote EVT cell invasion, yet the underlying molecular mechanisms remain largely unclear. In this study, RNA sequencing identified angiopoietin-like 4 (ANGPTL4), a multifunctional secreted protein, as a novel downstream target of GDF-11. In vitro experiments demonstrated that GDF-11 significantly upregulated ANGPTL4 expression in both HTR-8/SVneo cells and primary human EVT cells. Mechanistically, we found that the type I TGF-β receptors ALK4 and ALK5 were essential for mediating the stimulatory effect of GDF-11 on ANGPTL4 expression. Further analysis revealed that SMAD3, but not SMAD2, was the key transcription factor involved in this process. Using both loss- and gain-of-function approaches, we demonstrated that ANGPTL4 was required for GDF-11-induced EVT cell invasion. Importantly, serum levels of GDF-11 were markedly reduced in patients with preeclampsia (PE), a pregnancy disorder associated with shallow trophoblast invasion and poor placentation. Together, our findings uncover a previously unrecognized GDF-11-ANGPTL4 signaling axis that regulates EVT cell invasion and provides new insight into the pathophysiology of PE. Show less

This study investigates the effect of angiopoietin-like 4 (ANGPTL4) on allergic rhinitis (AR) and explores the underlying mechanisms. A mouse model of AR was generated through ovalbumin (OVA) challenge. The numbers of nasal rubbing and sneezing were counted and scored. Histological staining was conducted to analyze pathological alterations and inflammation in the mouse nasal mucosa. Inflammatory cytokines in serum and nasal lavage fluid (NALF) samples were analyzed using ELISA kits. Populations of regulatory T cells (Tregs) and Th17 cells in NALF or lymph nodes were analyzed using flow cytometry. Mice with AR were administered short hairpin (sh) RNAs targeting ANGPTL4. The effect of Notch pathway in AR severity was analyzed by gain- and loss-of-function assays. The consistent OVA challenge led to significant AR-like symptoms in mice, along with increased Notch signaling activation. Inhibiting this pathway using γ-secretase inhibitor (DAPT) markedly reduced the AR scores and alleviated inflammatory infiltration by improving Treg/Th17 cell balance. ANGPTL4 silencing significantly mitigated AR-related symptoms, Treg/Th17 cell imbalance, and inflammatory cascades in mice by inactivating the Notch signaling pathway. However, these alleviating effects of ANGPTL4 silencing on mice were negated by the administration of valproic acid, an agonist of the Notch signaling. This paper provides evidence that the ANGPTL4 knockdown shows significant therapeutic effects on AR by improving the Treg/Th17 cell balancing, effects achieved, at least in part, by blocking the Notch signaling pathway. Show less

The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less

This study investigates the differences in ligand-receptor interactions between the communication network of vascular endothelial cells (ECs) and photoreceptor cells (PRCs)in diabetic retinopathy (DR) the mechanism was verified by animal experiments. The GSE209872 data set, including retinal specimens from five Sprague-Dawley rats induced by streptozotocin, was obtained from Gene Expression Omnibus. CM and EC data were extracted individually for reclustering, functional enrichment and trajectory analyses. Cell communication analysis was conducted to investigate the altered signals and significant ligand-receptor interactions. Moreover, novel ligand-receptor interactions were validated using immunofluorescence staining using 2, 4 and 8 weeks DR model; DR was treated with AAV-shANGPTL4, and retinal function was detected by Haematoxylin and eosin staining (HE), TUNEL and ELISA. The expression of ligand-receptor in DR Retina was detected by qPCR and immunohistochemistry. Nine cell types were determined in DR. Cellular communication results revealed four signalling pathways, including PTN, MK, ANGPTL and CXCL, that were significantly changed in DR. Furthermore, 3 ligand-receptor pairs (Ptn-Ncl, Mkd-Ncl and Angptl4-Sdc4) were obviously upregulated between ECs and PRCs, the expression of which was verified via immunofluorescence in the DR model. After treatment with AAV-shANGPTL4, the retinal thickness and average density of RGCs were decreased (p < 0.05). TUNEL staining showed that knocking down ANGPTL4 reduced the apoptosis of DR (p < 0.05), and VEGF and IGF-1 expression were downregulated (p < 0.01). The expression of ligand-receptors also decreased in the DR Model (p < 0.01). The vascular ECs and PRCs demonstrate significant heterogeneities in DR. ANGPTL4 was a decreased ligand-receptor expression and improved retinal function as a potential therapeutic target against DR. Show less

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a key role in the cellular response to hypoxia, which plays a crucial role in the induction of abnormal angiogenesis and metastasis. Understanding the mechanism for the regulation of angiogenesis by HIF-1α-regulating miRNA will contribute to developing the strategy to prevent metastasis. We conducted a functional screening for HIF-1α-inhibiting miRNAs by evaluating the effects of miRNA mimics on HIF-1α expression and identified miR-5586-5p as an angiogenesis inhibitor through a mechanistic study. Angiogenic activity was assessed by tube formation assays using HUVEC cells exposed to conditioned media from miRNA-transfected breast cancer cells. In vivo activity of miR-5586-5p was examined through intratumoral injection of miRNA in orthotopic xenograft mice established by injecting MDA-MB-231 cells into the mammary fat pads of BALB/c nu/nu mice. The expression of the critical proangiogenic factors vascular endothelial growth factor A (VEGFA) and angiopoietin-like protein 4 (ANGPTL4) was inhibited by miR-5586-5p. Migration and tube formation of human umbilical vein endothelial cells were reduced in the conditioned medium prepared from miR-5586-5p-transfected cells. miR-5586-5p also suppressed the expression of heparin-binding EGF-like growth factor (HBEGF) and a disintegrin and metalloprotease 17 (ADAM17), which play a role in hypoxic signaling to induce the expression of VEGFA and ANGPTL4. HIF-1α, HBEGF, and ADAM17 were verified as the direct targets of miR-5586-5p responsible for the angiogenesis-suppressing function of miR-5586-5p. Expression levels of miR-5586-5p were lower in tumor tissues than in neighboring normal tissues of breast cancer patients. The expression of miR-5586-5p was inversely correlated to those of HIF-1α, HBEGF, ADAM17, VEGFA, and ANGPTL4. Angiogenesis and subsequent tumor growth were suppressed by intratumoral injection of miR-5586-5p in orthotopic MDA-MB-231 xenografts in mice. A potent tumor-suppressive function of miR-5586-5p applicable for the development of a novel cancer treatment strategy is herein described. Show less

Muscle atrophy, including glucocorticoid-induced muscle wasting from treatments such as dexamethasone (DEX), results in significant reductions in muscle mass, strength and function. This study investigates the potential of lonafarnib, a farnesyltransferase inhibitor, to counteract DEX-induced muscle atrophy by targeting key signalling pathways. We utilized in vitro models with C2C12 myotubes treated with DEX and in vivo models with Caenorhabditis elegans and DEX-treated Sprague-Dawley rats. Myotube morphology was assessed by measuring area, fusion index and diameter. Muscle function was evaluated by grip strength and compound muscle action potential (CMAP) in the gastrocnemius (GC) and tibialis anterior (TA) muscles. Molecular mechanisms were explored through RNA sequencing and Western blotting to assess changes in mitochondrial function and muscle signalling pathways. Lonafarnib (2 μM) significantly improved myotube area (1.49 ± 0.14 × 10 Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings. Show less

The quality of eggshells holds substantial economic significance and serves as a critical selection criterion in poultry breeding. Eggshell translucency significantly impairs their aesthetic quality, which is structurally attributed to the thinning of the eggshell membrane or reduced tensile strength. In this study, 836 dwarf white hens were selected, with 45 hens each assigned to the opaque group and the translucent group. Grading for eggshell translucency was conducted at 75, 80, and 85 weeks of age. Based on the results from these three gradings, 35 hens that consistently produced translucent eggs and 35 hens that consistently produced opaque eggs were reclassified into the translucent group and the opaque group, respectively. The thickness of the eggshell membrane, latitudinal and longitudinal tensile force and length, and other indicators related to eggshell membrane quality were measured. Correlation analysis was performed using RNA-seq genomics and DIA proteomics based on the relationships among these indicators. Transcriptome analysis revealed 179 significantly differentially expressed genes, indicating that the causes of translucent eggshells are associated with metabolism, signal transduction, the immune system, molecular binding, transport, and catabolism. Seven potential candidate genes, including Show less

Diabetic retinopathy (DR) is one of the major complications of diabetes, resulting in severe vision loss. Traction retinal detachment (TRD) is the main factor affecting the effect of proliferative diabetic retinopathy (PDR) surgery. Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) was adopted to analyze the proteomes of the vitreous in the TRD, vitreous hemorrhage (VH) and macular hole (MH) groups. By employing bioinformatics tools for GO and KEGG pathway annotation, as well as conducting protein-protein interaction(PPI) network analysis, we investigated the functional enrichment of proteins in the TRD vitreous and their associated pathways. Additionally, peptide center analysis was performed on the proteomic data to identify key differentially expressed proteins based on screening results. Bioinformatics analysis showed that DEPs is mainly enriched in the complement, the coagulation cascade systems and regulation of actin cytoskeleton. The protein interaction network analysis showed that the central proteins were mainly related to sphingolipid metabolism. APOA4, CHI3L1, LTBP2 were significantly up-regulated in TRD, which were related to the complement system, coagulation cascade and platelet activation, sphingolipid metabolism and other pathways. APOA4 and CHI3L1 protein in patients with TRD group raised significantly in the vitreous humor, shows the potential biomarkers for TRD. 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

Cholestasis in primary biliary cholangitis (PBC) induces delta bilirubin and lipoprotein-X (LpX), complicating biochemical interpretation. Comparative wet/dry chemistry analyses, total cholesterol (TC)/apolipoprotein B (Apo B) ratio calculation, and clinical-laboratory integration were utilized. Delta bilirubin (87.4 µmol/L) masked true bilirubin levels, while LpX falsely elevated LDL-cholesterol (LDL-C) (23.98 mmol/L) and induced pseudohyponatremia (Na⁺: 135 → 142 mmol/L). Integrated methodologies and clinician-laboratory collaboration are essential to mitigate diagnostic pitfalls in PBC. Show less

To investigate the relation of glycemic and lipid metabolism with brain structure and cognitive function in people with diabetes, so as to improve cognitive function in these individuals. Based on the UK Biobank, 26,394 patients, who were diagnosed with diabetes by doctors between 2006 and 2010, were included in the study. The demographic information, clinical data of glycemic and lipid metabolism and cognitive function (brain MRI and cognitive function scores) were collected. Multiple linear regression and non-restricted cubic spline analyses were used to investigate the relations of glycemic and lipid metabolism with brain structure and cognitive function. In this study, the mean age of people with diabetes (containing 39 % females) was 59.58 ± 7.21 years. Higher random blood glucose (β = -0.116, p < 0.001) and glycosylated hemoglobin (HbA1c) (β = -0.062, p = 0.051) were associated with a smaller brain volume. Higher HbA1c (β = 0.036, p < 0.001; β = 0.023, p = 0.021) was related with worse cognitive function. Further analysis showed that HbA1c < 6.5 % had a protective effect on cognitive function, and HbA1c = 6.5 %∼8.5 % and >8.5 % was unrelated and negatively related with cognitive function, respectively. Different types of lipids had varying effects on cognitive function. Higher total cholesterol (TC) (β = 0.125, p = 0.008), low density lipoprotein-cholesterol (LDL-C) (β = 0.086, p = 0.025), and ApoB (β = 0.092, p = 0.026) were associated with more significant brain structural abnormalities. Conversely, triglyceride (TG) = 0.75∼8.0 mmol/L was positively correlated with cognitive function (β = -0.036, p < 0.001; β = -0.044, p < 0.001; β = 0.058, p = 0.001), and higher ApoA (β = -0.032, p < 0.001; β = -0.033, p < 0.001; β = 0.047, p = 0.004) was associated with better cognitive function. The age-stratified analysis revealed that the impact of lipids on cognitive function was age-dependent. TC and LDL-C were related to brain structural abnormalities in the 55-60 age group, while TG had a stronger protective effect on cognitive function in older adults, particularly those aged 65-70 years. In people with diabetes, higher HbA1c (>8.5 %), as well as elevated TC, LDL-C, and ApoB, are associated with worse brain structure and cognitive function. Conversely, HbA1c < 6.5 % and elevated TG within the range of 0.75∼8.0 mmol/L have a protective effect on cognitive function, and the later exhibited more evident impact in older adults. To prevent or delay the onset of dementia in people with diabetes, it may be necessary to intensify glycemic control, targeting an HbA1c level of <6.5 %. Additionally, the age-specific lipid-lowering strategies shall be considered, with more flexible triglyceride-lowering goals for elderly patients. Show less

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are major contributors to the rise in metabolic disorders, particularly in developed countries. Despite the need for effective therapies, natural product-based interventions remain underexplored. This study investigated the therapeutic effects of Show less

Zhigancao Decoction (ZGCD) is derived from "Treatise on Febrile Diseases" and is traditionally prescribed for treating a variety of cardiovascular conditions. As of now, there are no data to support its use as a treatment for diabetic cardiomyopathy (DCM) and the mechanism behind the effect is unclear as well. In the present study, clinical evidence for the efficacy of ZGCD in patients with DCM was examined using a meta-analysis and its underlying anti-DCM molecular mechanisms were explored via network pharmacology. The current study utilized an extensive search strategy encompassing various domestic and foreign databases databases to retrieve pertinent articles published up to June 2024. In light of this, a thorough evaluation of the benefits and safety of Zhigancao decoction (ZGCD) was conducted in this study using RevMan and Stata. Subsequently, a number of active compounds and target genes for ZGCD were gathered from the TCMSP and BATMAN-TCM databases, while the main targets for DCM were obtained from databases such as GenCards, OMIM, TTD, and DrugBank. To select core genes, protein-protein interaction networks were generated using the STRING platform, and enrichment analyses were completed using the Metascape platform. Meta-analysis results were ultimately derived from 9 studies involving 661 patients in total. In comparison with WM therapy alone, the pooled results showed that ZGCD significantly enhanced overall effectiveness. Additionally, the utilization of ZGCD was leading to a reduction in LVEDV, LVESV and LVDD, also a greater increase in LVEF. Meanwhile, the utilization of ZGCD during intervention was more effective in reducing SBP, and DBP. In addition, the ZGCD showed potential in reducing the occurrence of adverse events. In the context of network pharmacology, five constituents of ZGCD-namely lysine, quercetin, gamma-aminobutyric acid, stigmasterol, and beta-sitosterol-are posited to exert anti-diabetic cardiomyopathy (anti-DCM) effects through interactions with the molecular targets ASS1, SERPINE1, CACNA2D1, AVP, APOB, ICAM1, EGFR, TNNC1, F2, F10, IGF1, TNNI2, CAV1, INSR, and INS. The primary mechanisms by which ZGCD may achieve its anti-DCM effects are likely mediated via the AGEs/RAGE signaling pathway, as well as through pathways related to lipid metabolism and atherosclerosis. In comparison to WM therapy alone, ZGCD demonstrates greater efficacy and safety in the management of DCM. ZGCD not only significantly reduces blood pressure, but also enhances cardiac function while producing fewer adverse effects. The therapeutic effects of ZGCD on DCM can likely be ascribed to its capacity to modulate the AGEs-RAGE signaling pathway, as well as its efficacy in enhancing lipid metabolism and mitigating atherosclerosis. identifier (INPLASY202430133). Show less

Contributing factors for the development of heart failure (HF) involve both apolipoprotein B (ApoB) and coronary microvascular dysfunction (CMD). Although ApoB has been linked to diverse cardiovascular risks, its association with CMD remains unclear. A total of 145 patients undergoing cardiac single-photon emission computed tomography (SPECT) scan was enrolled into this retrospective study. Based on ApoB serum level, all subjects were classified into three groups (Group 1-3). Myocardial flow reserve (MFR) was calculated using myocardial blood flow (MBF) tested in different contexts. ApoB serum level was positively correlated to rest MBF but inversely associated with stress MBF and MFR. Following adjustment for covariates, a significant relationship was observed between increased ApoB and decreased MFR. The predictive value of ApoB was test by Receiver Operating Characteristic Curve (ROC) analysis, showing an area under curve (AUC) of 0.87. The findings indicated that a higher level of ApoB correlated with the severity of CMD. Show less

Saturated fatty acid (SFA) and unsaturated fatty acid (UFA) have distinct impacts on health. Whether SFA and UFA are differentially transported in liver remains elusive. Here, we find the secretion of UFA but not SFA esters is retarded in a male mouse hepatic endoplasmic reticulum (ER) stress model. Among 13 members of protein disulfide isomerase (PDI) family, only PDIA1 (PDI) deficiency leads to hepatosteatosis and hypolipidemia. In PDI-deficient male mouse liver, there is a severe accumulation but secretory blockade of UFA esters, whereas the accumulation and secretion of SFA esters remain normal. PDI catalyzes the oxidative folding of microsomal triglyceride transfer protein (MTP). In addition, PDI deficiency in hepatocytes abolishes Apolipoprotein B-100 (ApoB-100) very low-density lipoprotein (VLDL) secretion while maintaining partial ApoB-48 VLDL secretion. In summary, we find that the secretion of UFA esters is PDI-MTP indispensable, while SFA esters could be transferred out of liver via ApoB-48 VLDL through a PDI-MTP-independent pathway. Show less

SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels. Leupeptin treatment induced lysosomal accumulation of SORT1, unaffected by si Show less

Diabetic nephropathy (DN) is the most intractable complication of diabetes. Despite decades of research, accurate diagnostic markers and effective therapeutic drugs are still elusive. Abnormal copper metabolism is also implicated in diabetes and its complications. This study aims to identify copper metabolism-related biomarkers and potential drugs for DN. DN datasets and copper metabolism-related genes (CMGs) were obtained from Gene Expression Omnibus (GEO) and GeneCards. Differentially expressed CMGs (DE-CMGs) were identified using the limma package and the Venn algorithm. Functional enrichment analysis and protein-protein interaction (PPI) network were performed to identify candidate hub genes. The single gene with an area under the receiver operating characteristic (ROC) curve > 0.7 was identified as a potential diagnostic biomarker of DN. Finally, these biomarkers were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in high-glucose-treated human proximal tubular (HK-2) cells. These validated hub genes were used to construct a combined prediction model, confirmed by additional GSE30528 and GSE30529 datasets. The correlation analysis between the expression level of the hub genes and the estimated glomerular filtration rate (eGFR) was carried out. Additionally, immune cell infiltration and potential target drugs were investigated for these biomarkers. Five hub genes associated with copper metabolism, namely CD36, CCL2, CASP3, LPL, and APOC3, were identified as biomarkers for the early diagnosis of DN. Utilizing multiple biomarkers enhanced diagnostic accuracy and specificity. CD36, CCL2, and CASP3 correlated negatively with eGFR levels, while LPL and APOC3 correlated positively. Additionally, these hub genes were significantly linked to various immune cell types, including macrophages M1 and M2, T cells, gamma delta resting dendritic cells, neutrophils, and NK cells. Furthermore, 15 agents targeting these biomarkers were retrieved from the DrugBank database. Our study identified key genes possibly related to copper metabolism in the pathological mechanism of DN that could serve as novel targets for the diagnosis and therapy of DN. Show less

Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. However, their interplay in GC prognosis remains unexplored. We analyzed RNA-seq and clinical data from The Cancer Genome Atlas Program and Gene Expression Omnibus databases. Using univariate Cox, LASSO, and multivariate Cox regression, we identified candidate genes and constructed a prognostic signature. Immune contexture, genomic alterations and drug sensitivity were compared between high- and low-risk group. The metabolic and aging related risk score, comprising 4 genes (GNAI1, GSTA1, APOC3, and LOX), was developed. Validation across multiple cohorts confirmed its robust prognostic performance. The model also effectively stratified patients into distinct risk subgroups with differential immune profiles and responses to immunotherapy. Notably, high-risk patients showed reduced sensitivity to common chemotherapeutic agents but may benefit from targeting the PI3K/mTOR pathway. Metabolic and aging related risk score serves as a promising tool for individualized risk assessment and therapeutic guidance in GC, warranting further clinical validation. Show less

Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) and triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit of statins for AS. It consequently remains uncertain whether lipid-lowering therapies have a role to prevent or treat AS. We used a drug-target MR approach to investigate the genetically predicted effect of lipid-lowering therapies on risk of AS. We collected summary statistics for LDL-c, TG, and AS from genome-wide association studies (GWAS) including 1 320 016, 1 253 277, and 412 181 European participants from the Global Lipids Genetics Consortium and FinnGen study, respectively. We identified genetic proxies for PCSK9 inhibitors, statins, bempedoic acid, and ezetimibe as single nucleotide polymorphisms in or within 200 kb of the target genes (PCSK9, HMGCR, ACLY, and NPC1L1, respectively), which were also significantly associated with LDL-c at P < 5 × 10-8. We used a similar approach to identify genetic proxies for the TG-lowering agents fenofibrates, APOC3 inhibitors, and ANGPTL3 inhibitors using the target genes PPARA, APOC3, and ANGPTL3, respectively. Inverse variance-weighted was the primary analysis method. Sensitivity analyses included weighted median, weighted mode, and MR-Egger, followed by the outlier-exclusion approaches MR-PRESSO and Cook's distance. We also performed multivariable analyses to evaluate whether the predicted effect of PCSK9 inhibition may be mediated by lipoprotein(a). We performed replication and negative control analyses using GWAS of AS and height including 653 867 and 408 112 participants, respectively. Genetically proxied PCSK9 inhibition was significantly associated with reduced AS risk (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.52-0.72, P < 0.0001) on main, replication, and all sensitivity analyses. Genetically proxied ezetimibe (OR 0.49, 95% CI 0.31-0.78, P = 0.003), bempedoic acid (OR 0.0054, 95% CI 0.0002-0.12, P = 0.0009), and statins (OR 0.61, 95% CI 0.46-0.81, P = 0.0006) were similarly associated with reduced AS risk, although the latter were not significant on replication analyses. Amongst the TG-lowering agents, genetically proxied APOC3 inhibition was associated with reduced AS risk (OR 0.78, 95% CI 0.70-0.88, P < 0.0001), but fenofibrate (OR 0.64, 95% CI 0.09-4.53, P = 0.65) and ANGPTL3 inhibitors (OR 1.05, 95% CI 0.77-1.43, P = 0.74) were not. Genetically proxied lipid-lowering therapies are significantly associated with reduced risk of AS. Early initiation and sustained administration of lipid-lowering therapies may prevent AS progression and warrants further research in the clinical trial setting. Show less

Metabolic reprogramming is a hallmark of cancer; however, the mechanisms driving metabolic heterogeneity across diverse cell types in the tumor microenvironment remain poorly understood. Most existing methods predict metabolic states at the pathway level but rarely map reaction-level alterations to their upstream regulators, thereby constraining both interpretability and translational relevance. We developed MetroSCREEN, a reference-guided computational framework that infers reaction-level metabolic flux propensity and nominates upstream regulators from bulk and single-cell transcriptomes. MetroSCREEN uses a fast enrichment-based procedure to quantify reaction-level metabolic activity. To characterize metabolic regulons, it integrates intrinsic gene-regulatory signals with extrinsic cell-cell interaction cues, then applies a robust multi-evidence ranking scheme to combine these information sources, and finally employs a constraint-based causal discovery module to infer regulatory directionality. MetroSCREEN accurately predicts reaction-level metabolic activities and their upstream regulators, as demonstrated using paired transcriptomic-metabolomic datasets from the cancer cell lines. We further validated predicted regulators with in-house single-cell CRISPR screens in PC9 cells targeting metabolic regulators. Applying MetroSCREEN to a pan-cancer single-cell atlas of more than 700,000 fibroblasts and myeloid cells across 36 cancer types, we identified ZNF281 and STAT1 as key regulators of collagen metabolism, which is elevated in extracellular-matrix-associated fibroblasts and macrophages at tumor margins. By contrast, APOE and KLF7 regulate sphingolipid metabolism and antigen presentation in macrophages. Leveraging extensive tumor profiles, MetroSCREEN also delineates metabolic subtypes and regulators associated with patient survival and response to immunotherapy. MetroSCREEN is a robust and scalable approach for characterizing metabolic heterogeneity and pinpointing metabolic regulators at single-cell resolution, unveiling novel antitumor targets for future metabolic interventions. The source codes of MetroSCREEN is available at the Github site https://github.com/wanglabtongji/MetroSCREEN . Show less

Cardiovascular dysfunction frequently accompanies aging and is often worsened by adverse lifestyle factors and genetic susceptibility. The apolipoprotein E (APOE) gene modulates susceptibility to cardiovascular disease, but how exercise and diet interact with APOE genotype remains insufficiently understood. We investigate the cardioprotective potential of exercise in humanized APOE-targeted replacement mice on control and high-fat diet, using photon-counting computed tomography (PCCT) and deep learning-based image segmentation. This study included 251 male and female mice in mid-to-late life of APOE2, APOE3, and APOE4 genotypes with variation in humanized NOS2 (HN) mediated innate immune response, exercise status (exercised vs. sedentary) and diet (control vs. high-fat). Mice underwent in vivo cine cardiac PCCT imaging following contrast enhancement with liposomal iodine nanoparticles. Stroke volume, ejection fraction, and myocardial mass were derived from automated segmentation of cardiac structures using a 3D U-Net model. We assessed main and interaction effects of genotype, sex, HN status, age, exercise and diet using generalized linear models, while Mann-Whitney U tests assessed effects of exercise within stratified subgroups. Exercise was a significant predictor of improvement in several cardiac functional metrics with a large effect size. The interaction between exercise and diet was a significant predictor of reduced body mass and myocardial mass. Stratified analyses found that exercise improves cardiac functional metrics in APOE4 mice on both diets, and APOE3 mice primarily on control diet, while benefitting HN mice more than non-HN mice. Voluntary exercise can partially rescue cardiac dysfunction induced by high-fat diet in adult APOE-targeted replacement mice, with benefits modulated by genotype, sex, and HN status. APOE4 and HN mice benefitted most from exercise. Contrast-enhanced PCCT combined with deep learning segmentation enables scalable, minimally invasive cardiac phenotyping and reveals interaction effects that are critical for designing precision lifestyle interventions in genetically at-risk populations. Show less

Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less

Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less