Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a li Show more
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' β-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and β-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78 % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8 % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress. Show less
Pharmaceutical and personal care products (PPCPs), as ubiquitous emerging contaminants, present undercharacterized neuropsychiatric hazards through environmental exposure. This investigation employs c Show more
Pharmaceutical and personal care products (PPCPs), as ubiquitous emerging contaminants, present undercharacterized neuropsychiatric hazards through environmental exposure. This investigation employs convergent multi-omics strategies - integrating toxicogenomic discovery, disease-associated genomic mapping, and transcriptomic profiling - to elucidate mechanistic linkages between PPCPs bioactivity and depressive pathogenesis. Through systematic analysis of Nanjing's aquatic chemical burden (prioritizing dimenhydrinate, ibuprofen, padimate-O, caffeine, and roxithromycin), we identified 3073 conserved molecular targets bridging PPCPs toxicity and depression etiology via Comparative Toxicogenomics Database and GeneCards interrogation. Functional ontology revealed dysregulated pathways encompassing lipidomic remodeling, IL-17-mediated neuroinflammation, and synaptic transmission deficits. Ensembled machine learning algorithms (Lasso regression, XGBoost, random forest) converged on seven high-fidelity candidate biomarkers (HSPA8, CBX1, CD59, CHAF1A, CUX1, ID2, RPL3) demonstrating stress-adaptive, chromatin regulatory, and immunomodulatory functions. Molecular docking predicted strong binding affinities between PPCPs and depression-related proteins, notably dimenhydrinate with CHAF1A (- 6.1 kcal/mol) and HSPA8 (- 6.1 kcal/mol), suggesting multi-target modulation. This work proposes a computational framework to map molecular interactions between specific PPCPs and depression-associated pathways. Candidate targets highlight testable hypotheses for future experimental validation. These findings suggest selected PPCPs with neuroactive properties may warrant further investigation as environmental modifiers of depression risk. Show less
The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Me Show more
The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Mendelian randomization (MR) is a technique employed to explore causal connections between two phenotypes. In our research, bidirectional two-sample MR analyses were utilized to evaluate the causal connections between vitiligo and multiple autoimmune diseases (systemic lupus erythematosus, Graves' disease, inflammatory bowel disease, alopecia areata [AA], type 1 diabetes mellitus [T1MD], and rheumatoid arthritis [RA]). Furthermore, we utilized summary-based Mendelian randomization (SMR) analysis to search for common susceptibility loci between two diseases that reciprocally elevate each other's risk. Finally, colocalization analyses were used to validate the robustness of the selected genes. There was an indication of potential causation between RA and vitiligo (IVW OR = 1.19; 95% CI = 1.05-1.13; p = 0.008). Furthermore, evident causal connections exist between vitiligo and AA (IVW OR = 1.14; 95% CI = 1.04-1.26; p = 0.008), T1MD (IVW OR = 1.14; 95% CI = 1.06-1.23; p < 0.001), and RA (IVW OR = 1.08; 95% CI = 1.03-1.13; p < 0.001). In SMR analyses and colocalization analyses, we identified three shared genes associated with both vitiligo and RA, including: FCRL3, FADS1, and FADS2. Our findings demonstrated that vitiligo and RA mutually act as risk factors for each other. Additionally, vitiligo had significant causal relationships with AA and type 1 diabetes. Show less
Previous studies have investigated the role of metabolic factors in risk of hematological malignancies with contradicting findings. Existing studies are generally limited by potential concern of rever Show more
Previous studies have investigated the role of metabolic factors in risk of hematological malignancies with contradicting findings. Existing studies are generally limited by potential concern of reverse causality and confounding by inflammation. Therefore, we aimed to investigate the associations of glucose, lipid, and apolipoprotein biomarkers with the risk of hematological malignancy. We performed a study of over 560,000 individuals of the Swedish AMORIS cohort, with measurements of biomarkers for carbohydrate, lipid, and apolipoprotein metabolism during 1985-1996 and follow-up until 2020. We conducted a prospective cohort study and used Cox models to investigate the association of nine different metabolic biomarkers (glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C, triglyceride (TG), apolipoprotein B (ApoB), apolipoprotein A-I (ApoA I), and ApoB/ApoA-I) with risk of hematological malignancy, after excluding the first five years of follow-up and adjustment for inflammatory biomarkers. We observed a decreased risk of hematological malignancy associated with one SD increase of TC (HR 0.93; 95% CI 0.91-0.96), LDL-C (HR 0.94; 95% CI 0.91-0.97), HDL-C (HR 0.92; 95% CI 0.86-0.99), and ApoA-I (HR 0.96; 95% CI 0.93-0.996). Our study highlights a decreased risk of hematological malignancy associated with a higher level of TC, LDL-C, HDL-C, and ApoA-I. Show less
Yunqi Xie, Haochen Wang, Yajie Zhang+5 more · 2025 · Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · Elsevier · added 2026-04-24
Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the bloo Show more
Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the blood-brain barrier and enter the brain to exert their effects. Moreover, some existing studies have pointed out that CS exposure is closely related to the accelerated pathology of Alzheimer's disease (AD). Transgenic mice with the five familial AD mutations (5xFAD), which are 1-month-old, were used for chronic CS exposure for 100 days. Subsequently, cognitive function and behavioral changes were evaluated through morris water maze and new object recognition tests. The acceleration of pathological changes due to CS exposure was assessed by HE, Tunel and Aβ immunohistochemical staining. Differential expression proteins and metabolites were screened through hippocampal proteomics and metabolomics analyses. Finally, the expression levels of key proteins were verified by Western blot. Compared with unexposed 5xFAD mice, the behavioral results of mice showed that FAD mice after CS exposure exhibited poorer cognitive abilities, with longer latencies in the Morris water maze, and decreased time spent and entries in the target quadrant. The results of pathological sections indicated that the total nuclei density in the DG and CA3 regions of the hippocampus of 5xFAD mice decreased significantly after chronic CS exposure, the number of TUNEL-positive cells increased, and the expression of Aβ42 increased. Multi - omics analysis revealed that CS exposure up - regulated the expression of 46 proteins and down - regulated the expression of 80 proteins in the hippocampus of 5xFAD mice, and caused changes in 92 metabolites. Analysis of the correlation between differential proteins and differential metabolites revealed six key cross-node proteins: Kng1, Hbb-b1, Fabp3, Apoa1, Ilk, and Apoa4. CS exposure may accelerate pathological changes and cognitive impairment in 5xFAD mice by affecting energy metabolism through the PPAR signaling pathway. Show less
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctori Show more
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE Show less
Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergen Show more
Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker α-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β. In injury-induced mouse disc degeneration model, fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45 Show less
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases Show more
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-th Show more
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less
Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mecha Show more
Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mechanisms in human Sertoli cells remain unclear. In this study, immortalized human Sertoli cells were exposed to BPS, and cell viability, proliferation, and transcriptomic changes were assessed, with bulk RNA sequencing integrated with single-cell transcriptomic profiles from non-obstructive azoospermia (NOA) testes to identify key regulatory factors. Potential BPS targets were predicted via pharmacophore mapping and confirmed through molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations, while functional validation was performed using NR1H3 knockdown and overexpression assays with luciferase reporter and Western blot analyses. BPS significantly inhibited cell viability and proliferation at concentrations ≥ 20 μM, inducing transcriptomic dysregulation involving cell cycle suppression, metabolic pathway alterations, and steroid biosynthesis disruption. Integration of computational and transcriptomic analyses identified NR1H3 as a direct BPS target, with docking and dynamics simulations demonstrating stable binding (-20.64 ± 2.26 kcal/mol), and experimental data showing that BPS reduced NR1H3 protein levels and transcriptional activity, while NR1H3 knockdown impaired cell survival and overexpression partially rescued BPS-induced cytotoxicity. These findings provide the first evidence that BPS impairs human Sertoli cell function by targeting NR1H3, revealing a critical role of NR1H3 in Sertoli cell survival and suggesting that BPS exposure may contribute to male infertility through NR1H3-mediated pathways. Show less
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of Show more
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn Show less
The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomi Show more
The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance. Show less
Fatty liver hemorrhage syndrome (FLHS) is the most common metabolic diseases in laying hens during the late-laying period, and it causes a significant economic burden on the poultry industry. The comp Show more
Fatty liver hemorrhage syndrome (FLHS) is the most common metabolic diseases in laying hens during the late-laying period, and it causes a significant economic burden on the poultry industry. The competing endogenous RNA plays crucial roles in the occurrence and development of fatty liver. Based on the previously constructed lncRNA-miRNA-mRNA networks, we selected the axis of ENSGALT00000079786-LPL-miR-143-5p for further study to elucidate its mechanistic role in development of fatty liver. In this study, we identified a novel highly conserved lncRNA (ENSGALT00000079786) in poultry, which we designated as lncRNA A2ml2 based on its chromosomal location. Fluorescent in situ hybridization (FISH) revealed that lncRNA A2ml2 was localized in both the nucleus and cytoplasm. Dual-luciferase reporter assay validated the targeted relationship between lncRNA A2ml2, miR-143-5p, and the LPL gene. To further analyze the lncRNA A2ml2 and miR-143-5p function, lncRNA A2ml2 overexpression vector was successfully constructed and transfected into Leghorn male hepatocellular (LMH) cells, which could remarkably inhibit cellular lipid deposition was detected by oil red staining (P < 0.01), the opposite occurred for miR-143-5p (P < 0.01). qPCR demonstrated an inverse correlation between miR-143-5p expression and lncRNA A2ml2 expression, and confirmed that miR-143-5p directly target lncRNA A2ml2. Similarly, we found an inverse correlation between expression of LPL and the expression of miR-143-5p. To further investigate the interactions among these three factors and their effects on cellular lipid metabolism, we assessed the expression levels of LPL by co-transfecting lncRNA A2ml2 with miR-143-5p mimic and miR-143-5p mimic binding site mutants. Co-transfection experiments showed that miR-143-5p diminished the promoting effect of lncRNA A2ml2 on LPL. Meanwhile, miR-143-5p has the capacity to mitigate the suppressive impact of lncRNA A2ml2 overexpression on lipid accumulation in LMH cells. The results revealed that lncRNA A2ml2 attenuated hepatic lipid accumulation through negatively regulating miR-143-5p and enhancing LPL expression in LMH cells. Our findings offer novel insights into ceRNA-mediated in FLHS and identify a novel lncRNA as a potential molecular biomarker. Show less
The lack of standardized objective approaches hinders the accurate diagnosis and treatment of depression. Herein, a novel electrochemical platform was created utilizing cost-effective and rapid 3D pri Show more
The lack of standardized objective approaches hinders the accurate diagnosis and treatment of depression. Herein, a novel electrochemical platform was created utilizing cost-effective and rapid 3D printing technology to overcome the constraints of conventional diagnostic methods. This method allows for highly sensitive detection of Apolipoprotein A4 (Apo-A4), an important biomarker for depression, using dual-signal outputs. The electrode material utilized in this setup consisted of a combination of carbon black/polylactic acid (CB/PLA) and ferrocene-chitosan-gold nanoparticles (Fc-CS-AuNPs). On the other hand, the signal label was composed of gold nanoparticles-thionine-secondary antibody (AuNPs-Thi-Ab Show less
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. Howeve Show more
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
Graphical Abstract Lipoprotein lipase (LPL) mediates peripheral tissue triglyceride (TG) uptake. Hepatic ANGPTL3 (A3) and ANGPTL8 (A8) form a complex and inhibit LPL activity in the white adipose tiss Show more
Graphical Abstract Lipoprotein lipase (LPL) mediates peripheral tissue triglyceride (TG) uptake. Hepatic ANGPTL3 (A3) and ANGPTL8 (A8) form a complex and inhibit LPL activity in the white adipose tissue (WAT) via systematic circulation. ANGPTL4 (A4) is expressed in WAT and inhibits LPL activity locally. Feeding increases hepatic A8 expression and increases its inhibition for WAT LPL activity together with A3, while feeding suppresses WAT A4 expression and releases its inhibition on LPL. At room temperature, the feeding-suppressed A4 overrides the feeding-increased A3/A8, resulting in increased LPL activity in WAT by food intake. Browning improves hepatic insulin sensitivity and increases postprandial A8 expression. The feeding-increased A3/A8 overrides the feeding-suppressed A4, resulting in suppressed LPL activity in WAT by food intake. This reprogrammed LPL regulation plays an important role in reprogramming TG metabolism during adipose tissue browning. Show less
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for Show more
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day. In this crossover design, 16 normal-weight, healthy men underwent three highly standardized in-lab nights of SR (4.25 h/night) and normal sleep (NS, 8.5 h/night) in randomized order, with 88 CVD blood protein biomarkers quantified using the Olink technology (and selected validation using ELISA) in the morning, evening, and immediately before and repeatedly after 30 min of high-intensity exercise. We found significant time-of-day-dependent changes in several CVD biomarkers. Whereas several proteins were exercise-induced across sleep conditions (such as the canonical exerkines IL- 6 and BDNF), exercise-induced proteomic dynamics differed in response to recurrent SR, compared with following NS. Moreover, SR compared with NS resulted in a biomarker profile previously associated with increased prospective risk of several CVDs across large-scale cohorts (such as higher circulating levels of IL-27 and LGALS9). Our findings highlight how dynamic physiology can modulate CVD biomarker levels. These results also underscore the need to consider sleep duration as a key determinant of cardiovascular health-an emphasis reflected in recent American Heart Association guidelines. Further studies in women, older individuals, and patients with prior CVD, and across different chronotypes and dietary schedules are warranted. Show less
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this Show more
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear-localized branched-chain α-ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage-inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin-mediated degradation of RAD51, thereby facilitating HRR-mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p-RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage-inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer. Show less
Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia an Show more
Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia and glucose intolerance, hallmark features of type 2 diabetes. While SEC16 homologue B (SEC16B), an endoplasmic reticulum export factor, has been linked to obesity, type 2 diabetes and lipid metabolism, its role in glucose regulation remains poorly defined. This study aims to investigate SEC16B's contribution to glucose homeostasis by systematically dissecting its conserved physiological mechanisms across species. To interrogate SEC16B's role, we combined Drosophila genetics (RNA interference-mediated dSec16 knockdown) with murine models (Sec16b deletion) under standard or high-fat diet conditions. Glucose and insulin tolerance tests assessed glucose homeostasis. Mechanistic insights into beta cell dysfunction were derived from immunostaining, glucose-stimulated insulin secretion assays and RNA-seq profiling of murine pancreatic islets. Both disruption of dSec16 in Drosophila and Sec16b deletion in mice triggered glucose intolerance under standard diet conditions, recapitulating conserved metabolic dysfunction. In addition, Sec16b loss impaired glycaemic control in mice fed a high-fat diet. Mechanistically, Sec16b deficiency impairs insulin secretion by downregulating cholinergic signalling and compromising intracellular Ca Our study reveals SEC16B, a genome-wide association study-identified obesity risk gene, as an evolutionarily conserved regulator of glucose homeostasis. By linking SEC16B to cholinergic-driven insulin secretion and calcium dynamics, we resolve a mechanistic gap in beta cell dysfunction and metabolic disease. This finding provides novel insights into the mechanisms underlying glucose homeostasis and may enhance our understanding of potential treatments for metabolic diseases. Show less
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immun Show more
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to Show more
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to enhance the quality of evidence concerning the effects of tamoxifen on these lipid parameters. Eligible RCTs published up to October 2024 were meticulously selected through a comprehensive search. A meta-analysis was then performed using a random-effects model, and results were presented as the weighted mean difference (WMD) with a 95% confidence interval (CI). Findings from the random-effects model revealed an increase in ApoA-I (WMD: 15.22 mg/dL, 95% CI: 6.43-24.01, P = 0.001), alongside decreases in ApoB (WMD: -9.33 mg/dL, 95% CI: -15.46 to -3.19, P = 0.003) and lipoprotein(a) (WMD: -3.35 mg/dL, 95% CI: -5.78 to -0.91, P = 0.007) levels following tamoxifen treatment in women. Subgroup analyses indicated a more significant reduction in lipoprotein(a) levels in RCTs with a duration of ≤24 weeks (WMD: -3.65 mg/dL) and in studies using tamoxifen doses of ≥20 mg/day (WMD: -4.53 mg/dL). This meta-analysis provides evidence that tamoxifen leads to a decrease in lipoprotein(a) levels, along with reductions in ApoB and increases in ApoA-I among women. Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus i Show more
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus in ducklings is limited. To dissect the molecular characteristics associated with pathobiology of ducklings to DHAV-3, we applied single-cell RNA-sequencing approach to profile the transcriptome of 1.4 million cells from 14 livers of DHAV-3 susceptible (S) and resistant (R) ducklings during viral infection and 4 uninfected healthy controls. We found that infected S ducks exhibited the activation of type I and II interferon pathways with elevated expression of interferon-stimulated genes (ISGs) compared to infected R ducks and healthy controls. DHAV-3 promoted proinflammatory phenotype and inhibited the cell apoptosis pathway of Kupffer cells of S ducks. Furthermore, we observed the elevated expression of host factor PLAC8 in S ducks and validated its ability to facilitate the infection of DHAV-3. We identified significant dysregulation of various genes in complement and coagulation cascades in hepatocytes2 exclusive to S ducks, together with over-secretion of ANGPTL4 from endothelial cells in S ducks which is confirmed to promote cellular migration, suggesting etiology of coagulopathic complications in ducks with severe DVH. Collectively, this study provides a rich resource for understanding the inflammatory immune signatures and cell communications underlying the pathogenesis of DHAV-3 infection, which may accelerate the development of better diagnostic methods and strategies for controlling this disease. Show less
This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to Show more
This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to their underlying genetic regulatory mechanisms, to elucidate the role of UFAs in acne pathogenesis. Clinical evidence synthesis: we systematically reviewed randomized controlled trials (RCTs) to evaluate the impact of UFA supplementation on acne treatment outcomes. Genetic analysis: two-sample Mendelian randomization (MR) analysis we used to investigate causal relationships between serum UFA metabolites and acne, identifying potential key regulatory enzymes. The synthesis of these RCT studies confirmed that UFA supplementation improved acne conditions. MR analysis revealed causal links between three serum UFA metabolites and acne, with dihomo-gamma-linolenic acid (DGLA) (OR = 8.457; 95% CI: 2.367-30.214; P-value = 0.001) as a risk factor and arachidonic acid (AA) (OR = 0.209; 95% CI: 0.071-0.618; P-value = 0.005) and eicosapentaenoic acid (EPA) (OR = 0.318; 95% CI: 0.102-0.991; P-value = 0.048) as protective factors. Functional annotation suggested enzymes such as Δ5 desaturase (FADS1) and Δ6 desaturase (FADS2) may play a role in acne regulation. This study offers evidence that supports a connection between UFAs and acne, examining this relationship from both clinical and genetic angles. These findings highlight the role of specific UFAs and their associated metabolic enzymes in the development of acne. Omega-3 UFAs seem to have a protective effect against acne, whereas certain types and ratios of omega-6 UFAs might contribute to acne formation. The varied impacts of UFAs on acne could be attributed to disease processes mediated by specific enzymes. However, the study's limitations include its genetic analysis being primarily based on European populations, which limits the applicability of the findings to other groups. Future research should aim to include a more diverse range of participants to improve the generalizability of the results. Show less
Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we i Show more
Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized fibroblast growth factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention. Show less
This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-p Show more
This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-protein (LP) diets. A total of 384 Hy-Line brown laying hens (32 weeks old) were divided into six groups: control (CON) diet with 16.5 % crude protein (CP), LP diet with 15 % CP, and LP diets supplemented with 3 %, 5 %, 7 %, and 9 % CM. Results showed that dietary CM supplementation of up to 5 % did not negatively affect the productive performance of laying hens fed LP diets. However, the groups receiving 7 % and 9 % CM exhibited a significant increase in the feed-to-egg ratio (P < 0.05). Additionally, dietary CM supplementation effectively enhanced egg yolk color in a dose-dependent manner (P < 0.05). Intestinal morphology analysis indicated that the 5 % CM group had a higher villus height-to-crypt depth ratio than the LP and 9 % CM groups (P < 0.05), with no significant differences among the other groups. Dietary supplementation with 3 %-7 % CM did not significantly affect serum and jejunal antioxidant capacity, and the 9 % CM group exhibited the highest levels of serum and jejunal malondialdehyde among the groups (P < 0.05). Dietary CM supplementation significantly increased anti-inflammatory cytokines (IL-4 and IL-10) and decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum and jejunal tissue of laying hens (P < 0.05). Moreover, CM supplementation significantly altered the cecal microbiota composition in laying hens, increasing the abundance of beneficial bacteria, such as Desulfovibrio and Megamonas. Furthermore, dietary CM supplementation significantly decreased serum triglyceride levels; downregulated liver mRNA levels of ACC, FAS, and SREBP-1C/2; and upregulated the mRNA levels of ACOX1, PPAR-α, Apob, and CPT in laying hens fed LP diets. In conclusion, CM supplementation should not exceed 5 % to avoid negative impacts on performance while supporting intestinal health and lipid metabolism. Show less
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusi Show more
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies. Show less