Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- T Show more
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- TNBC mechanisms of UA by network pharmacology and experimental validation. TNBC cell lines MDA-MB-231 and BT-549 cells were treated with UA. A CCK-8 assay was performed to detect cell growth, while flow cytometry assessed cell cycle arrest and apoptosis. The underlying mechanism and potential targets of UA for TNBC treatment were investigated by network pharmacology, including PharmMapper database, GO, KEGG enrichment, and PPI analysis. The protein expressions and phosphorylation levels of FGFR1, AKT, and ERK were measured by western blot. Pull-down assay, cellular thermal shift assay (CETSA), and molecular docking were used to analyze the interaction between UA and FGFR1. Xenograft models were established to examine the effect of UA on TNBC tumor growth. UA effectively reduced cell viability, induced apoptosis, and arrested cell cycle in TNBC cells. Moreover, UA significantly regulated the expression of Bcl-2 and Bax to induce apoptosis. The results of network pharmacology and western blot suggested that UA reduced FGFR1/AKT/ERK pathway. Furthermore, pull-down, CETSA, and molecular docking results revealed that UA directly bound to FGFR1. In the xenograft model, UA inhibited the growth by suppressing FGFR1. In this study, we employed network pharmacology and experimental approaches to elucidate the mechanism of UA on TNBC. The results demonstrated that UA targeted FGFR1 to inhibit TNBC via mediating FGFR1/AKT/ERK pathway. Our findings demonstrate that UA inhibits the FGFR1/AKT/ERK pathway by directly targeting FGFR1, thereby suppressing TNBC progression and supporting its potential as a therapeutic agent for TNBC treatment. Show less
Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi- Show more
Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi-component activity. The effectiveness of these botanical extracts is thought to involve complex interactions among diverse constituents; however, the molecular basis of such interactions remains insufficiently understood. In this study, we explored the anti-inflammatory properties of the ethanol extract of Polygonum multiflorum (PME) through a combination of chemical profiling and computational analysis. PME was found to reduce the production of nitric oxide, inducible nitric oxide synthase, and interleukin-6 in LPS-stimulated RAW 264.7 macrophages. Using HS-SPME-GC-MS in conjunction with network pharmacology, we identified 32 volatile constituents, among which five core compounds were predicted to be associated with three inflammation-related targets: ESR1, FASN, and NR1H3. Dual-ligand molecular docking and molecular dynamics simulations suggested that the sequence of ligand binding may influence the stability and interaction patterns of protein-ligand complexes, offering insights into possible mechanisms of synergy and antagonism mediated by key residues such as ARG394 in ESR1. Overall, these findings contribute to a better understanding of how binding order and structural context may shape constituent-target interactions, providing a basis for the further development of multi-component natural product strategies against inflammation. This study underscores the relevance of incorporating multi-ligand dynamics into natural product research and presents an integrated experimental-computational framework to investigate the cooperative or competitive behaviors of functional food constituents, thereby supporting the rational design of optimized multi-target formulations. Show less
Oxidative stress is crucial in the development of cutaneous melanoma, but its role in melanoma is controversial. We aimed to identify melanoma-associated targets and understand the underlying mechanis Show more
Oxidative stress is crucial in the development of cutaneous melanoma, but its role in melanoma is controversial. We aimed to identify melanoma-associated targets and understand the underlying mechanism. Differential expressed genes (DEGs) were discovered between control and melanoma samples, and a protein-protein interaction (PPI) network was constructed to find key genes. The prediction accuracy of LMOD1 was assessed by receiver operating characteristic (ROC) curves, and pan-cancer analysis was also performed for LMOD1 expression and immune characteristics. The downstream pathway of LMOD1 was found via KEGG analysis. The effects of LMOD1 on oxidative stress, apoptosis, CD4 + T cells and the downstream pathway were evaluated in melanoma cells and mice. We identified ACTG2, CNN1, LMOD1, MYH11, MYL9, MYLK, TAGLN, TPM1 and TPM2 as melanoma-related DEGs, which could separate control and melanoma samples. The area under curve (AUC) of LMOD1 was > 0.89, indicating high prediction accuracy. LMOD1 expression was decreased in melanoma, and LMOD1 notably correlated with B cells, CD4 T cells, neutrophils, macrophages and dendritic cells (DCs). Overexpression of LMOD1 promoted apoptosis, enhanced migration and invasion, and activated oxidative stress in melanoma cells. LMOD1 promoted apoptosis via activating oxidative stress. The RIG-I-like receptor signaling (RLR) was a downstream pathway of LMOD1. Overexpression of LMOD1 activated oxidative stress, increased apoptosis and CD4 + T cells, and elevated RIG-I and MDA5, while Cyclo (Phe-Pro) (cFP) reversed the results. LMOD1 triggers oxidative stress-mediated apoptosis in melanoma via activating the RLR pathway, which provides promising targets and regulatory pathway for melanoma. Show less
The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new ch Show more
The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new chicken 7TM receptor (Ch-7TM) was discovered in mononuclear phagocytes (MNPs) derived from chicken peripheral blood mononuclear cells (PBMCs). To explore the functions of Ch-7TM, RNA interference (RNAi) was used to silence the Ch-7TM messenger RNA (mRNA) of MNPs, using small interfering RNA (siRNA) designed with BLOCK-iT™ RNAi Designer. Herein we demonstrated that silencing of the Ch-7TM mRNA induced apoptosis of MNPs, suggesting that Ch-7TM contributed to the survival of MNPs. Moreover, chicken sera could inhibit the Ch-7TM-silencing-induced apoptosis in MNPs. The survival factor presented in fraction 16 (F16) of chicken sera was highly protective against the Ch-7TM-silencing-induced apoptosis in MNPs. The proteins from F16 were identified as vitamin D-binding protein (DBP) and apolipoprotein A-IV (ApoA-IV), which might be potential candidates for survival factors. The protective effect of vitamin D and ApoA-IV indicated that Ch-7TM might involve the intracellular oxidation-reduction balance, although more evidence is needed to confirm this function. The siRNA screening serves as an excellent model for studying the functions of chicken MNPs receptors. Show less
Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD. To Identify new potential targets fo Show more
Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD. To Identify new potential targets for CKD through metabolites and their regulatory genes. A total of 233 metabolites from the genome-wide association studies (GWAS) Catalog were utilized for Mendelian randomization (MR) with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to very low-density lipoprotein (VLDL) were selected for MR with CKD and metabolites. The total effect of the fatty acid desaturase 1 gene (FADS1) on CKD and metabolite-mediated effects were calculated. Bulk RNA-seq were used to validate FADS1 expression in the kidney tissues of patients with CKD. The cholesteryl esters to total lipids ratio in medium VLDL (odds ratio [OR] = 0.84; P.adj = .039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84; P.adj = .003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18; P.adj = .009) and the triglycerides to total lipids ratio in very small VLDL (OR = 1.1; P.adj < .001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.1; P.adj = .001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96%, respectively, were obtained. The differential expression of FADS1 was observed in the kidney tissues of patients with CKD. FADS1 is a risk factor for CKD and a novel therapeutic target. Four metabolites mediate the detrimental effect of FADS1 in CKD. Show less
1,3-dilinoleoyl-2-palmitoylglycerol (LPL) is an important structural lipid in breast milk fat, which plays an important role in the health of infants, and therefore the development of an efficient met Show more
1,3-dilinoleoyl-2-palmitoylglycerol (LPL) is an important structural lipid in breast milk fat, which plays an important role in the health of infants, and therefore the development of an efficient method for the preparation of such compounds is necessary. In the present study, LPL was efficiently catalytically synthesized by immobilized lipase ANL-MARE as a biocatalyst using tripalmitate and linoleic acid in a solvent-free system, and its digestive properties were investigated. The optimal process conditions for the enzymatic acidolysis of LPL were optimized by response surface test: the molar ratio of PPP:LA was 1:10, the enzyme addition was 13.60%, the reaction temperature was 50℃, and the reaction time was 5 h. At this time, the relative content of LPL in the product was 67.78%, of which the relative content of sn-2 palmitic acid (sn-2 PA) accounted for 71.50%. In vitro gastrointestinal digestion of LPL resulted in the release of 59.69% of its fatty acids. The digested product contained higher levels of free unsaturated fatty acids and palmitic acid monoacylglycerols. In conclusion, the immobilized enzyme ANL-MARE has great potential to catalyze the preparation of LPL, which provides a new strategy and theoretical basis for the efficient preparation of human milk fat substitutes. Show less
Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) Show more
Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration. Show less
Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-ac Show more
Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK-mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK-mediated phosphorylation of AKT decreases ubiquitin-mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient-derived organoids (PDOs), enhances doxorubicin-induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention. Show less
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevale Show more
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute Show more
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes-downregulation of PUFA synthesis and upregulation of histone lactylation-in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI. Show less
By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sou Show more
By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sought to use whole tissue culture to define the role of VLDL secretion by small yellow follicles (SYFs) along their development under normal and heat stress (HS) conditions. Under thermoneutral conditions (39 °C), chicken SYFs increased MTTP activity, apoB expression and VLDL secretion, while underwent cell apoptosis along the time course. Despite relieved ER stress and protein ubiquitinylation, inhibition of VLDL secretion by Lomitapide and Mipomersen greatly increased triglyceride accumulation, impaired estradiol production and cell proliferation, and accelerated cell apoptosis in accordance with upregulated caspase 3/7 activity, JNK activation, protein carbonylation, and MDA accumulation. Exposure to HS at 44 °C boosted cell apoptosis in a duration-dependent manner. Acute HS for 3 h enhanced VLDL secretion, impaired estradiol production and cell proliferation, and promoted IL-1b production, oxidative damages, and cell apoptosis, whereas except MDA content and cell proliferation, the detrimental effects were halted after 13 h recovery. Lomitapide and Mipomersen augmented lipid accumulation, oxidative stress, inflammatory response, and exacerbated transient impairment of estradiol secretion and cell proliferation in SYFs under 3 h HS and after recovery, but failed to rescue cell viability despite relieved ER and proteostatic stress. In conclusion, routine secretion of VLDL by SYFs serves as an intrinsic mechanism to sustain cell viability and functions to support the whole program required for follicle development, while under HS, this mechanism provisionally rescues steroidogenesis and cell proliferation. Show less
Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death fro Show more
Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather were HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation. Show less
To investigate the direct and indirect relationships between statin use, low-density lipoprotein cholesterol (LDL-C) levels, and intracerebral hemorrhage (ICH), providing new insights into this comple Show more
To investigate the direct and indirect relationships between statin use, low-density lipoprotein cholesterol (LDL-C) levels, and intracerebral hemorrhage (ICH), providing new insights into this complex scientific question. In this cohort study, UK Biobank data from 2006 to 2010 were used to construct Structural Equation Models of statin use, LDL-C, and ICH, including 414,253 participants with LDL-C data. Published Genome-Wide Association Studies data were used for drug-target Mendelian Randomization analysis. The study included 414,253 participants, comprising 225,454 women (54.4%) with a mean age of 56.07 (8.11) years. During a median follow-up of 14.01 years, 2973 patients experienced ICH. Structural Equation Modelling showed the indirect effect (path a∗b) of statin on ICH was 0.003 (P < 0.001), the direct effect (path c') was -0.001 (P = 0.568), the total effect (path c) was 0.002 (P = 0.391), and the mediation proportion of LDL-C (a∗b/c) was 150.0%. Mendelian Randomization showed a negative association between LDL-C levels and ICH (β: -0.663, SE: 0.229, P = 0.004), with no causal relationship between statin use and ICH (β: -1.454, SE: 3.133, P = 0.643). Drug-targeted Mendelian Randomization revealed LDL-C levels, predicted by variants in or near HMGCR, PCSK9, CETP, ABCG8/5, and LAP, were negatively associated with ICH risk. This study confirmed that statins increase the risk of ICH primarily through their LDL-C-lowering effects, rather than the direct effects of the statins themselves. LDL-C is negatively associated with ICH, an association not confined to the effects of the HMGCR loci. This advance provides evidence for the controversy between statin use, LDL-C levels, and ICH risk. Show less
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchang Show more
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchange of cholesterol (C) from HDL to ApoB-containing lipoproteins. CETP inhibition increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C) while modestly decreasing TG. Considering that CETP inhibitors block removal of TG from TG-rich lipoproteins (TRL), it is interesting that CETP inhibition decreases TG concentrations. TG levels are largely regulated by lipoprotein lipase (LPL), the enzyme primarily responsible for hydrolyzing TG. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating LPL inhibitor, while the TG-lowering apolipoprotein A5 (ApoA5) acts by suppressing ANGPTL3/8-mediated LPL inhibition. To better understand CETP biology, we studied the effects of CETP overexpression and CETP inhibition on the levels of ANGPTL3/8 and ApoA5 in circulation using dedicated immunoassays. CETP-overexpressing transgenic mice had increased TG and normal ANGPTL3/8 levels but manifested dramatically reduced ApoA5 concentrations. Administration of the CETP inhibitor evacetrapib had no effect on ANGPTL3/8 levels in CETP-overexpressing mice or in humans. However, evacetrapib administration increased ApoA5 concentrations in both species. In human subjects, evacetrapib treatment increased circulating ApoA5 levels in the late-stage ACCELERATE and ACCENTUATE studies by 160.1% and 204.7%, respectively. Our results uncover a previously unrecognized link between CETP and ApoA5 by showing that CETP overexpression reduces ApoA5 levels while CETP inhibition increases ApoA5 concentrations. Show less
Growing evidence suggests that lipid metabolism may play a crucial role in mood disorder pathophysiology, and the correlation between blood lipids and mood disorder remains further clarified. This pro Show more
Growing evidence suggests that lipid metabolism may play a crucial role in mood disorder pathophysiology, and the correlation between blood lipids and mood disorder remains further clarified. This prospective, population-based cohort study utilized data from the UK Biobank. The study included 268,098 and 292,121 participants who had never been diagnosed with depression or bipolar disorder and who had complete data at both the baseline and follow-up points. A principal component analysis (PCA) was conducted on seven blood lipids, and the first three principal components (PCs) were derived. Cox regression analysis was employed to examine the correlation between the risk of mood disorders and the PCs. Multiplicative interaction and sensitivity analyses were also conducted. The relationship between blood lipids and neurological biomarkers was explored using Spearman's analysis. PC1, primarily reflecting levels of Apolipoprotein B (ApoB), cholesterol, and low-density lipoprotein cholesterol (LDL-C), showed a protective effect against depression, with HRs of 0.98 (95 % CI: 0.96,1.00) in the fully adjusted Cox regression model. In contrast, PC2, characterized by opposite loadings for triglycerides and high-density lipoprotein cholesterol (HDLC), was positively associated with the risk of depression and bipolar disorder.(HR = 1.03,95 % CI: 1.01,1.06; HR = 1.11, 95 % CI: 1.01,1.23). Increased PC2 level was related to a significant increase in bipolar disorder risk among participants with high genetic risk (genetic risk score > 90 %, HR = 1.22, 95 % CI: 1.02,1.46). Complicated correlations between blood lipids and serum neuroproteins were detected. These findings suggest complex associations between blood lipid profiles and the risk of depression and bipolar disorder. Show less
We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete toleroge Show more
We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete tolerogenic adjuvant that acts systemically to form an active vaccine in situ with endogenous pathogenic autoantigens. This active vaccine suppresses autoimmunity by expanding antigen-specific Treg cells in affected tissues. In a mouse model of atherosclerosis, 8206 successfully targeted all three analyzed pathogenic autoantigens (ApoB, HSP60, and HMGB1) and inhibited disease progression. These findings suggest that 8206 can potentially serve as a universal treatment vaccine for autoimmune diseases by eliminating the need for exogenous immunogens, with implications for broad applications in immunotherapy. Show less
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediat Show more
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10⁹/L vs. 403.53*10⁹/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. Show less
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu Show more
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu and Angus is a prevalent method for achieving a better marbling level. However, the molecular mechanisms governing IMF regulation in these crossbreeds remain poorly understood. To elucidate the mechanism of IMF deposition in these crossbred cattle, we conducted a comparative transcriptomic analysis of Show less
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder Show more
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. Show less
Different serum lipid and lipid-lowering agents are reported to be related to the occurrence of intracerebral aneurysm (IA). However, the causal relationship between them requires further investigatio Show more
Different serum lipid and lipid-lowering agents are reported to be related to the occurrence of intracerebral aneurysm (IA). However, the causal relationship between them requires further investigation. Mendelian randomization (MR) analysis was performed on IA and its subtypes by using instrumental variants associated with six serum lipids, 249 lipid metabolic traits, and 10 lipid-lowering agents that were extracted from the largest genome-wide association study. Phenome-wide MR analyses were conducted to identify potential phenotypes associated with significant lipid-lowering agents. After multiple comparison adjustments ( This study not only supports that serum lipids (TG and HDL-C) are associated with IA but also confirms the positive effect and absence of safety concerns of intervening Show less
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the Show more
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the central nervous system, play a crucial role in modulating the pathological processes associated with AD. Jiajian Shuyu Pills (JJSYP) are frequently employed in the treatment of AD, purportedly by enhancing the physiological functions of human tissues and organs to modulate the immune response. Nevertheless, the underlying mechanisms by which JJSYP exert their therapeutic effects in the context of AD remain inadequately elucidated. This study aimed to assess the effects of JJSYP on cognitive enhancement and the alleviation of neuroinflammation in the treatment of AD, as well as to explore the underlying mechanisms using mouse models. The components of JJSYP in serum were analyzed using HPLC-Q/TOF-MS. APP/PS1 transgenic mice served as AD models in this investigation. Cognitive function in the AD mice was assessed through the Mirror Water Maze Test and the Novel Object Recognition Test. The quantification of apoptotic hippocampal cells was conducted using Nissl staining and TUNEL staining. Immunofluorescence (IF) and Western blot (WB) analyses were employed to examine microglial activation and the expression of relevant proteins. Transcriptomic sequencing analysis and network pharmacology were administrated to explore the potential mechanisms of JJSYP in AD treatment. Inflammatory cytokine levels in the brain were measured using RT-PCR. A total of 74 absorbed prototype components from JJSYP were identified. JJSYP effectively improved cognitive function and neuroapoptosis in AD model mice by modulating the activation of microglia. The JJSYP intervention alleviated neuroinflammation by suppressing microglial activation and reducing the accumulation of amyloid β-protein. Through transcriptome sequencing and WB verification, 34 differentially expressed genes (DEGs) were identified, including ACKR3, NR1H3 and Adra1a. Following treatment with a high dose of JJSYP, both ACKR3 and NR1H3 showed a significant decrease compared to the model group. Conversely, ADRA1A expression was reduced in model group compared to the control group, but increased following high dose JJSYP treatment. Research involving RNA sequencing and network pharmacology indicated that JJSYP altered the activation of CXCL12/ACKR3 signaling pathways in the hippocampus. JJSYP exhibits potential anti-Alzheimer's Disease effects and warrants further investigation and development as a prosper treatment for AD. Show less
Angiopoietin-like protein 8 (ANGPTL8) forms complexes with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity, and decreased LPL activity is an established cardiovascular risk factor. S Show more
Angiopoietin-like protein 8 (ANGPTL8) forms complexes with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity, and decreased LPL activity is an established cardiovascular risk factor. Serum levels of ANGPTL4/8 and C-terminal domain-containing ANGPTL4 (CD-ANGPTL4) are positively associated with cardiovascular death, however, the underlying mechanisms remain incompletely understood. The present study investigated relationships of ANGPTL3, ANGPTL3/8, CD-ANGPTL4, and ANGPTL4/8 with coronary artery calcification (CAC) progression (using Agatston scores) and incident coronary events. ANGPTL3, ANGPTL3/8, CD-ANGPTL4, and ANGPTL4/8, were measured using dedicated immunoassays in participants of the Heinz Nixdorf Recall (HNR) study, an unselected, population-based cohort of subjects free from cardiovascular disease at baseline. CAC measurements were performed at baseline and after 5 years in 2887 participants, and there was follow-up for coronary events (median duration 18.8 years). Median Agatston scores increased over 5 years from 6.70 (t Associations of ANGPTL3 and ANGPTL3/8 with coronary atherosclerosis progression and incident coronary events were inconsistent, while CD-ANGPTL4 and ANGPTL4/8 were associated with both coronary atherosclerosis progression and incident coronary events. Associations of ANGPTL4/8 and CD-ANGPTL4 with cardiovascular events may reflect progression of coronary atherosclerosis conferred by diabetes, inflammation, or the potential intrinsic effects of CD-ANGPTL4 and ANGPTL4/8. Show less
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate cli Show more
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate clinical characteristics and therapeutic targets concerning FOXO1 fusion status. 65 pediatric RMS patients were enrolled. Clinical data were analyzed using Kaplan-Meier estimates and Cox regression. Surgically resected tumor tissues were subject to single-cell RNA sequencing (scRNA-seq). Patient-derived xenograft (PDX) was establish and dissociated to cells for high-throughput drug screening. Among the 65 patinets (36 patients with embryonal RMSs (ERMSs), 15 patients with alveolar RMSs (ARMSs) and 14 patients with other types of RMSs), 73.3% of ARMSs were defined as fusion positive (FP) while 6 ERMS (ERMS)s were also FP. Cox regression analysis identified FOXO1 fusion as a risk factor alone and combined with pathologic subtype, sex and age or metastasis status. scRNA-seq revealed distinct transcription factor networks between FP and FN RMS, showing up-regulated activity of OLIG2, NHLH1, SNAI1, TFF3 and other TFs related to neural development and differentiation. MAPK, PI3K-Akt, and mTOR pathways were enriched in FP-RMS tumor cells. High-throughput drug screening of PDX-derived cells identified sensitive drugs targeting FP-RMS specific signatures. AMG-337 was selected and validated for its anti-tumor effect. FOXO1 fusion status influences RMS clinical outcomes, including rare FP-ERMS cases. scRNA-seq combined with drug screening identified MET as a promising therapeutic target in FP-RMS. Show less
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical Show more
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hep Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application. Show less
Adipose tissue metabolism plays a crucial role in sheep meat quality and the optimization of adipose tissue utilization. To reveal the molecular mechanisms of adipose tissue metabolism during growth i Show more
Adipose tissue metabolism plays a crucial role in sheep meat quality and the optimization of adipose tissue utilization. To reveal the molecular mechanisms of adipose tissue metabolism during growth in naturally grazing sheep, we investigated the mRNA and miRNA profiles in subcutaneous adipose tissue (SAT) from naturally grazing Sunit sheep at 6, 18, and 30 months of age (Mth-6, Mth-18, and Mth-30). We identified 927 differentially expressed (DE) genes and 134 DE miRNAs in the SAT of sheep at different growth stages. Specifically, the expressions of Show less