Metabolic abnormalities have become a prominent hallmark of malignant tumor and play a crucial role in the occurrence and development of lung adenocarcinoma (LUAD). however, the underlying mechanism i Show more
Metabolic abnormalities have become a prominent hallmark of malignant tumor and play a crucial role in the occurrence and development of lung adenocarcinoma (LUAD). however, the underlying mechanism involved this process is still far from being fully elucidated. In this study, we aimed to explore the essential factors regulating the glycolysis and proliferation process in LUAD. Bioinformation and immunohistochemistry were applied to screen and verify the expression pattern of the vital factors in LUAD. A series of biological function assays, including Cell Counting Kit 8 (CCK8), colony formation, 5-ethynyl-2'-deoxyuridineβ (EdU), seahorse assays and nude mouse transplantation tumor assays, were performed to demonstrate the impact of the family with sequence similarity 189 member A2 (FAM189A2) on the glycolysis and proliferation process in LUAD. Co-immunoprecipitation, immunofluorescence and dual-luciferase reporter gene and RT-qPCR were used to verify the FAM129A2 and the WW domains of E3 ubiquitin ligase (WWP2) interaction, as well as the influence of their combination on large tumour suppressor-1 (LATS1) ubiquitination level and Hippo signaling pathway activity. FAM189A2 was weakly expressed in the cytoplasm of LUAD, and associated with the poor prognosis of patients. FAM189A2 overexpression inhibited the glycolysis and proliferation processes of LUAD cells in vitro. Meanwhile, both the processes were enhanced following FAM189A2 knockdown. Mechanistically, FAM189A2 was identified to interact with WWP2 through its own PPxY motifs, hence weakened the WWP2-LATS1 affinity and inhibited the WWP2-mediated LATS1 ubiquitination, which ultimately resulted in a reduced yes-associated protein (YAP) nuclear translocation. In addition, Verteporfin (Hippo pathway inhibitor) or YAP knockdown could eliminate the biological effects of promoting proliferation and glycolysis in LUAD cells caused by FAM189A1 silence. FAM189A2 can be considered as a potential diagnostic and prognostic marker associated with LUAD, and suppresses the proliferation and glycolytic metabolism of LUAD cells via WWP2-LATS1-YAP signaling, which will provide a corresponding theoretical foundation for the development of small molecule inhibitors. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, yet efficient therapeutic approaches are lacking. The advent of glucagon-li Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, yet efficient therapeutic approaches are lacking. The advent of glucagon-like peptide-1 receptor (GLP-1R)-based multi-target agonists generated renewed optimism for MASLD. Building on preclinical and clinical data suggesting synergistic metabolic benefits, we hypothesized that combining glucose-dependent insulinotropic polypeptide receptor (GIPR) or glucagon receptor (GCGR) agonism with GLP-1R agonism would confer superior protective effects against MASLD and its complications. We identified genetic proxies of the effect of GLP-1R, GIPR, and GCGR by combining Mendelian randomization (MR), Bayesian colocalization, and linkage disequilibrium (LD) analyses. We then performed two-sample MR and colocalization analyses to estimate the causal effect of GLP-1R-based agonists on MASLD, its metabolic risk factors, and multi-organ complications. The MR analyses suggested genetically proxied GLP-1R-based agonists were causally associated with a reduced risk of MASLD (GIPR/GLP-1R agonist: OR: 0.17, 95%CI: 0.05-0.52, Pβ=β2.07βΓβ10 We identified the causal role of GLP-1R-based agonists in reducing the risk of MASLD and its complications, probably by improving systemic metabolic disorders and partly independent of their weight-loss effect. Show less
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its anti Show more
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against 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
This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glu Show more
This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). A prospective cohort of 150 diet-controlled GDM patients and 150 pregnant women with NGT, all delivering at our hospital, were selected based on predefined criteria. Data on demographics, physical parameters, and perinatal outcomes were compiled. Blood samples for fasting plasma glucose (FPG), homocysteine (Hcy), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and apolipoprotein A1 (apoA1) were collected before delivery. GDM patients exhibited higher levels of FPG, Hcy, and the apoB/apoA1 ratio, but lower HDL-C and apoA1 levels compared to the NGT group. Adverse outcomes such as macrosomia, premature rupture of membranes, and postpartum hemorrhage were more prevalent in the GDM group. In GDM patients, neonatal birth weight positively correlated with FPG and TG levels. Stratified Hcy analysis in GDM showed no significant differences in perinatal outcomes. However, the third quartile of the apoB/apoA1 ratio had a lower incidence of macrosomia compared to the first quartile, and the second quartile showed a higher incidence of birth asphyxia. GDM patients demonstrated increased levels of Hcy, FPG, and the apoB/apoA1 ratio, correlating with more adverse perinatal outcomes than healthy pregnant individuals. The relationships between Hcy, lipids, and these outcomes remain inconclusive, highlighting the need for further research. Show less
Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metaboli Show more
Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metabolic status in prediabetes, but their predictive value for cardiovascular mortality and stroke in this population remains unclear. We analyzed data from 74,678 White participants with prediabetes in the UK Biobank, defined by either HbA1c (5.7-6.4%) or fasting glucose (6.1-6.9Β mmol/L). Follow-up continued until October 10, 2023. Cox regression was used to examine associations between LE8, phenotypic age (PhenoAge), cardiovascular biological age (CBA), and outcomes of cardiovascular (CVD) mortality and stroke. Restricted cubic spline (RCS) models identified biological age risk thresholds. Mediation analysis assessed whether proteins such as CST3, EFEMP1, FES, IGFBP2, IGFBP6, LPA, PCSK9, and TIMP1 mediated these effects. Over a median follow-up of 13.4Β years, 2263 participants died from CVD causes. Each 1-year increase in CBA or PhenoAge was associated with aβ~β10% higher risk of CVD mortality (CBA aHRβ=β1.10; PhenoAge aHRβ=β1.09; both Pβ<β0.001), while each 1-point increase in LE8 score was linked to a 3% lower risk (HRβ=β0.97, Pβ<β0.001). The risk biological ages for these two indicators were also identified: PhenoAgeββ₯β58.52Β years and CBAββ₯β62.42Β years. Similar trends were observed for stroke. Mediation analysis revealed that CST3, TIMP1, IGFBP2, and IGFBP6 contributed to the biological pathways between aging/lifestyle and CVD outcomes. The combined LE8 and PhenoAge model showed the strongest predictive performance for CVD mortality (AUCβ=β0.716) and stroke (AUCβ=β0.638) over 15Β years. LE8 combined with phenotypic age provides prognostic value for CVD outcomes in prediabetes. These findings highlight the potential of lifestyle modification and delayed biological aging in reversing prediabetes and underscore comorbidity-related proteins as promising therapeutic targets. Show less
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains Show more
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing inΒ vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less
Sepsis remains a leading cause of mortality in critical care, with limited reliable biomarkers that reflect upstream pathophysiology and enable early risk stratification. Apolipoprotein E (ApoE), a li Show more
Sepsis remains a leading cause of mortality in critical care, with limited reliable biomarkers that reflect upstream pathophysiology and enable early risk stratification. Apolipoprotein E (ApoE), a lipid transporter with immune-regulatory functions, has shown inconsistent associations with sepsis outcomes. Its causal and clinically actionable role in sepsis risk requires clarification. We employed a multi-layered strategy integrating Mendelian randomization, colocalization, and phenome-wide association studies across five large proteogenomic cohorts (>500,000 individuals) to identify plasma proteins causally linked to sepsis. ApoE emerged as a top candidate and was validated in a clinical cohort of 291 ICU patients and in murine sepsis models. We assessed the relationship between ApoE levels and sepsis risk using logistic regression, restricted cubic spline models, and survival analyses, and explored underlying mechanisms via cytokine profiling, histopathology, and transcriptomics. ApoE was causally associated with sepsis risk in multiple independent datasets, supported by strong genetic colocalization (posterior probability for shared causal variant PP.H4Β >Β 0.80). In ICU patients, both low (adjusted OR 12.74, 95% CI 5.72-28.36) and high ApoE levels (adjusted OR 4.54, 95% CI 2.25-9.16) were independently associated with increased sepsis risk compared to medium levels, forming a significant U-shaped pattern (P_nonlinear < 0.001). This biphasic risk was mirrored in murine models, where both hypo- and hyper-expression of ApoE aggravated systemic inflammation, organ injury, and mortality. LDL cholesterol mediated onlyΒ ~Β 20% of the ApoE-sepsis association, indicating lipid-independent mechanisms. Plasma ApoE functions as a biphasic, dose-sensitive modulator of host response to sepsis. Both deficiency and excess disturb immune homeostasis and increase susceptibility, underscoring the need for precision-guided ApoE modulation in sepsis management. These findings provide a mechanistically grounded biomarker candidate and highlight new avenues for personalized therapy. Prospective trials are warranted to evaluate ApoE-targeted strategies in sepsis care. Show less
This study aims to explore the plastic changes in cell lineages during the progression of osteoarthritis (OA) and their relationship with dysregulation of signaling pathways and provide new molecular Show more
This study aims to explore the plastic changes in cell lineages during the progression of osteoarthritis (OA) and their relationship with dysregulation of signaling pathways and provide new molecular targets for precise treatment. Single-cell RNA sequencing (scRNA-seq) technology was utilized to perform high-resolution cell lineage analysis of OA patients. The mappings of distinct cell subpopulations were systematically constructed and revealed the changes in key cell types and their transformation trajectories throughout the progression of OA. Furthermore, KEGG and GO enrichment and pseudotime trajectory analysis were applied to elucidate the functional reprogramming of different cell types and the dynamic imbalance of their signaling networks in OA. Additionally, in vitro experiments were conducted to validate the biological functions of candidate genes in OA. Articular cartilage showed a transcriptional cellular heterogeneity in OA by scRNA-seq analysis; the annotated PreFC, FC, and PreHTC subsets accounted for the main part of OA samples. PreFC cells revealed transcription, signaling, and metabolic reprogramming in OA; pseudotime trajectory found that PreFC transformed to FC cells under the condition of hypoxia and metabolic reprogramming, while fibrosis and ECM degradation pathways showed intense upregulation in preHTC evolved from PreFC cells. HIF1A and ANGPTL4 were identified as key molecular regulators of OA progression, contributing to ECM degradation, inflammation, and apoptosis in chondrocytes, as confirmed through functional validation. The cellular trajectories of OA show significant plasticity changes which are influenced by the dysregulation of multiple signaling pathways. This research provides new insights into the pathological process of OA and offers potential targets for therapeutic strategies targeting these abnormal mechanisms. Show less
PoorΒ featherΒ growth not onlyΒ affectsΒ the appearance of the organism but also decreases the feedΒ efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet t Show more
PoorΒ featherΒ growth not onlyΒ affectsΒ the appearance of the organism but also decreases the feedΒ efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet the exact mechanism involved remains insufficiently understood. A total of 180 1-day-old broilers were selected and randomly divided into 3 treatments: control group (0.45% Met), Met-deficiency group (0.25% Met), and Met-rescue group (0.45% Met in the pre-trial period and 0.25% Met in the post-trial period). The experimental period lasted for 56 d, with a pre-trial period of 1-28 d and a post-trial period of 29-56 d. In addition, Met-deficiency and Met-rescue models were constructed in feather follicle epidermal stem cell by controlling the supply of Met in the culture medium. Dietary Met-deficiency significantly (Pβ<β0.05) reduced the ADG, ADFI and F/G, and inhibited feather follicle development. Met supplementation significantly (Pβ<β0.05) improved growth performance and the feather growth in broilers. Met-rescue may promote feather growth in broilers by activating the Wnt/Ξ²-catenin signaling pathway (GSK-3Ξ², CK1, Axin1, Ξ²-catenin, Active Ξ²-catenin, TCF4, and Cyclin D1). Compared with Met-deficiency group, Met-rescue significantly (Pβ<β0.05) increased the activity of feather follicle epidermal stem cell and mitochondrial membrane potential, activated Wnt/Ξ²-catenin signaling pathway, and decreased the content of reactive oxygen species (Pβ<β0.05). CO-IP confirmed that mitochondrial protein PGAM5 interacted with Axin1, the scaffold protein of the disruption complex of the Wnt/Ξ²-catenin signaling pathway, and directly mediated Met regulation of Wnt/Ξ²-catenin signaling pathway and feather follicle development. PGAM5 binding to Axin1 mediates the regulation of Wnt/Ξ²-catenin signaling pathway, and promotes feather follicle development and feather growth of broiler chickens through Met supplementation. These results provide theoretical support for the improvement of economic value and production efficiency of broiler chickens. Show less
Stroke, including cerebral ischemia and cerebral hemorrhage, is one of the leading causes of mortality worldwide. The narrow therapeutic window limits the efficacy and applicability of current treatme Show more
Stroke, including cerebral ischemia and cerebral hemorrhage, is one of the leading causes of mortality worldwide. The narrow therapeutic window limits the efficacy and applicability of current treatments such as thrombolysis and endovascular thrombectomy. This urgent need for effective therapies has shifted the focus towards mitigating the secondary inflammation and tissue damage that follow intracerebral hemorrhage. Spatial transcriptomic analysis of mouse brains post-ischemia has revealed that the ApoE-TREM2 signaling pathway is central to the complex interactions between microglia and various surrounding cells, coordinating the formation of neuroglial scars, suggesting that TREM2 is a key participant in post-stroke pathology and a potential therapeutic target. This review aims to provide an insightful synthesis of TREM2, including its structure, signaling pathways, and the role of its soluble form, sTREM2, in the nervous system. We systematically summarize the signaling pathways and mechanisms by which TREM2 modulates microglial function, including promoting phagocytosis, exerting anti-inflammatory properties, modulating lipid metabolism, and enhancing cell survival. We also highlight the TREM2's interactions with other cell types post-stroke, such as macrophages and B cells. Furthermore, we discuss advancements in TREM2-targeted drug development, emphasizing the potential of TREM2 agonists and antibodies to modulate microglial function and inflammation, which sets the stage for future research and drug development. 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, etΒ 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
Tryptophan (Trp) is an essential amino acid acting as a key nutrition factor regulating animal growth and development. But how Trp modulates food intake in pigs is still not well known. Here, we inves Show more
Tryptophan (Trp) is an essential amino acid acting as a key nutrition factor regulating animal growth and development. But how Trp modulates food intake in pigs is still not well known. Here, we investigated the effect of dietary supplementation of Trp with different levels on food intake of growing pigs. The data showed that dietary Trp supplementation with the standardised ileal digestibility (SID) Trp to lysine (Lys) ratio at both 0Β·18 and 0Β·20 significantly increased the food intake by activating the expression of orexigenic gene agouti-related peptide (AgRP) and inhibiting the expression of anorexigenic gene pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and melanocortin receptor 4 (MC4R) in the hypothalamus. Meanwhile, the level of anorexigenic hormones appetite-regulating peptide YY (PYY) in the duodenum and serum and leptin receptor in the duodenum were also significantly decreased. Importantly, both the kynurenine and serotonin metabolic pathways were activated upon dietary Trp supplementation to downregulate MC4R expression in the hypothalamus. Further mechanistic studies revealed that the reduced MC4R expression activated the hypothalamic AMP-activated protein kinase (AMPK) pathway, which in turn inhibited the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) activity to stimulate food intake. Together, our study unravels the orexigenic effect of dietary Trp supplementation in pigs and expands its potential application in developing nutrition intervention strategy in pig production. Show less
The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker Show more
The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker strategy in the prediction of incident diabetes. In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006-2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein-1 (VAP-1), fibrinogen-like protein 1 (FGL1), angiopoietin-like protein 6 (ANGPTL6), and angiopoietin-like protein 4 (ANGPTL4). Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow-up. Blood VAP-1 was significantly associated with incident diabetes in the overall population (HRβ=β0.724, Pβ<β0.05), participants under 65βyears old (HRβ=β0.685, Pβ<β0.05), those with a BMI of β₯24βkg/m Gender- and BMI-specific biomarker strategy can improve the prediction of incident diabetes. A subgroup-specific biomarker strategy is a novel approach in the prediction of incident diabetes. Show less
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave ada Show more
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave adaptation by comparing brain transcriptomes of sympatric cave-dwelling ( Show less
High-grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum-resistance is a serious challenge in its treatment. Long non-coding RNAs (lncRNAs) play critical Show more
High-grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum-resistance is a serious challenge in its treatment. Long non-coding RNAs (lncRNAs) play critical regulatory roles in the occurrence and development of cancers. Here, using RNA sequencing of tumor small extracellular vesicles (sEVs) from HGSOC patients, the lncRNA CATED is identified as significantly upregulated in both tumors and tumor-derived sEVs in platinum-resistant HGSOC, and low CATED levels correlate with good prognosis. Functionally, CATED enhances cisplatin resistance by promoting cell proliferation and inhibiting apoptosis in vitro and in vivo. These effects could be transferred via CATED-overexpressing sEVs from donor cells and HGSOC tumor sEVs. Mechanistically, CATED binds to and upregulates DHX36 via PIAS1-mediated SUMOylation at the K105 site, and elevated DHX36 levels increase downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating the MAPK pathway to promote platinum-resistance in HGSOC. Antisense oligonucleotide mediated knockdown of CATED reverse platinum-resistance in sEV-transmitted mouse models via the DHX36-RAP1A-MAPK pathway. This study newly identifies a sEV-transmitted lncRNA CATED in driving HGSOC platinum-resistance and elucidates the mechanism it regulates the interacting protein through SUMOylation. These findings also provide a novel strategy for improving chemotherapy in HGSOC by targeting CATED. Show less
The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationsh Show more
The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationship between them. The serum levels of ApoA5 and Mfge8 in obese and healthy people were compared, and the obesity mouse model induced by the high-fat diet (HFD) was established. In addition, primary cardiomyocytes were purified and identified from the hearts of suckling mice. The 0.8 mmol/L sodium palmitate treatment was used to establish the lipid deposition cardiomyocyte model Show less
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) ag Show more
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), accelerated ammonium metabolism of HLCs, which was derived from adipose derived mesenchymal stem cells (ADSCs). Human ADSCs were seed in flat bottom plate, then our differentiation protocol was used for 21 days. OCA treatment had been performed in Step3 for 10days. Then, 1) hepatic maturation, 2) urea cycle genes, 3) urea production, and 4) ammonium metabolism was compared depend on the presence or absence of OCA. HLCs had been successfully produced for 21 days. HLCs with OCA showed significantly higher mRNA expressions of AAT than those without OCA. HLCs with OCA showed significantly higher mRNA expressions of urea cycle genes such as SLC25A13, CPS1, and OTC. Urea production was also tended to be upregulated by OCA addition. HLCs with OCA showed significantly higher clearance of NH4Cl at 6hr and 24 hr after addition of NH4Cl. FXR agonist, OCA, accelerates ammonium metabolism of ADSCs derived HLCs. HLCs could be one of treatment options of hepatic encephalopathy of patients with liver failure or urea cycle disorder in the future. J. Med. Invest. 72 : 54-59, February, 2025. Show less
Oocyte maturation-coupled mRNA post-transcriptional regulation is essential for the establishment of developmental potential. Previously, oocyte mRNA translation efficiencies focused on the trans-regu Show more
Oocyte maturation-coupled mRNA post-transcriptional regulation is essential for the establishment of developmental potential. Previously, oocyte mRNA translation efficiencies focused on the trans-regulation of key RNA-binding protein (RBPs), rarely related to RNA structure. RNA G-quadruplexes (rG4s) are four-stranded RNA secondary structures involved in many different aspects of RNA metabolism. In this study, we have developed a low-input technique for rG4 detection (G4-LACE-seq) in mouse oocytes and found that rG4s were widely distributed in maternal transcripts, with enrichment in untranslated regions, and they underwent transcriptome-wide removal during meiotic maturation. The rG4-selective small-molecule ligand BYBX stabilized rG4s in the oocyte transcriptome and impaired spindle assembly and meiotic cell cycle progression. The proteomic spectrum results revealed that rG4 accumulation weakened the binding of a large number of RBPs to mRNAs, especially those associated with translational initiation. Ribosomal immunoprecipitation and translational reporter assays further proved that rG4s in the untranslated regions negatively affected the translational efficiency of key maternal mRNAs. Overexpression DEAH/RHA family helicase-36 partially reverses BYBX-induced oocyte developmental defects, suggesting its importance in rG4 regulation. Collectively, this study describes the distribution, dynamic changes, and regulation of rG4s in the mouse maternal transcriptome. Before meiosis resumption, a large number of rG4s in oocytes are necessary to maintain the translatome at a low level, and DHX36-mediated rG4 removal promotes a translational switch and is required for successful maternal-to-zygotic transition. Show less
This study aims to identify and characterize daily activity accumulation patterns (bouts of physical activity and sedentary behavior) among adolescents and then to explore the associations between the Show more
This study aims to identify and characterize daily activity accumulation patterns (bouts of physical activity and sedentary behavior) among adolescents and then to explore the associations between these groups and depressive symptoms. A total of 521 adolescents aged 13-18β―years from Wuhan and Changsha, China, were included. Bouts of physical activity (PA) and sedentary behavior (SED) were measured using accelerometers. The Center for Epidemiologic Studies Depression Scale was used to assess participants' depressive symptoms. Latent profile analysis was employed to identify distinct groups based on their activity patterns. Three distinct groups were identified: "Prolonged sitters" ( The synergistic effect of strategies to reduce total SED duration by limiting SED bouts to 30β―min or less and increasing light physical activity (LPA) may also be effective in alleviating depressive symptoms in adolescents. Show less
Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Show more
Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Although growing evidence highlights the involvement of plasma proteins in atherogenesis, their causal contributions to disease pathogenesis are poorly understood. To address this gap, we conducted a proteome-wide Mendelian randomization (MR) analysis using cis-pQTLs (cis-protein quantitative trait loci) from the deCODE and UKB-PPP cohorts (~90,000 individuals) as instrumental variables. We integrated colocalization analysis, summary-data-based MR (SMR), and HEIDI tests to systematically prioritize causal plasma proteins. Key findings were replicated in the CARDIOGRAMplusC4D (coronary artery disease, CAD) and FinnGen (CVD) cohorts. Functional validation was performed through phenome-wide association studies (PheWAS), single-cell transcriptomics, histological staining, and ELISA assays to characterize protein expression patterns in specific cell types and tissues. Among 2,711 plasma proteins analyzed, 28 showed strong genetic associations with atherosclerosis. Of these, five proteins (ADK, ANGPTL4, CD4, MGAT1, SYT11) met strict validation criteria through colocalization (posterior probability of colocalization, PP.H4β>β0.8) and SMR. Subsequent replication using MR and PheWAS further confirmed the causal roles of ADK, CALB2, and COMT in CAD and other CVD outcomes. Notably, CALB2 was specifically enriched in mast cells within atherosclerotic plaques and adipose tissue, and plasma levels were significantly elevated in patients with severe carotid artery stenosis (CAS). This study identifies 28 novel therapeutic targets for atherosclerosis using a rigorous multi-omics approach. Our findings establish CALB2 as a promising biomarker and therapeutic target, particularly in severe CAS, by linking genetic evidence to cell-type-specific expression and clinical phenotypes. These insights pave the way for precision medicine approaches in the prevention and treatment of CVD. The online version contains supplementary material available at 10.1186/s12967-025-07269-6. Show less
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR su Show more
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR surrogate markers: the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio and the TyG index (the product of fasting plasma glucose and triglycerides). We identified genome-wide significance loci within four gene clusters: GCKR, MLXIPL, APOA5, and APOC1, uncovering 197 genes associated with IR. Transcriptome-wide association analysis revealed significant associations between these clusters and TyG, primarily in adipose tissue. Gene ontology analysis highlighted pathways related to Alzheimer's disease, glucose homeostasis, insulin resistance, and lipoprotein dynamics. The study identified sex-specific genes associated with TyG. Polygenic risk score analysis linked both IR markers to gout and hyperlipidemia. Our findings elucidate the complex relationships between IR surrogate markers, genetic predisposition, and disease phenotypes in the Taiwanese population, contributing valuable insights to the field of metabolic research. Show less
The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and ei Show more
The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and eighty patients with chest pain were recruited in the case-control study. A2M-AS1 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was utilized for evaluating the diagnostic value. Pearson's correlation analysis was used to analyze the correlation between A2M-AS1 and conventional AMI biomarkers. AMI-associated risk indicators were identified using logistic regression analysis. A significant reduction of serum A2M-AS1 was measured in AMI patients relative to chest pain patients. A2M-AS1 had an area under the curve (AUC) of 0.927 to distinguish AMI patients from those with chest pain. Pearson's correlation analysis showed that A2M-AS1 was adversely correlated with white blood cell (WBC) (r=-0.6682, Pβ<β0.001), low density lipoprotein cholesterol (LDL-C) (r=-0.5795, Pβ<β0.001), creatine kinase MB (CK-MB) (r=-0.6022, Pβ<β0.001) and cTnl (r=-0.5473; Pβ<β0.001), while positively correlated with high density lipoprotein cholesterol (HDL-C) (rβ=β0.6445, Pβ<β0.001). Relative to non-Major Adverse Cardiovascular Events (non-MACE) group, serum A2M-AS1 was obviously declined in the MACE group of AMI patients with high capacity to distinguish the MACE group from the non-MACE patients (AUCβ=β0.802). Additionally, A2M-AS1 (Pβ=β0.013; ORβ=β0.268; 95%CIβ=β0.095-0.760) was a risk indicator for predicting MACE with AMI patients, as well as age (Pβ=β0.014; ORβ=β3.478; 95%CIβ=β1.285-9.414). A reduction in A2M-AS1 expression was observed in AMI patients, suggesting its potential as an underlying indicator for AMI diagnosis. Show less
Dan Zeng, Yunsheng Zhang, Hu Xia+4 more Β· 2025 Β· Comparative biochemistry and physiology. Part D, Genomics & proteomics Β· Elsevier Β· added 2026-04-24
To investigate the key regulatory genes and pathways related to growth traits in the Dongtingking crucian carp (Carassius auratus indigentiaus), the transcriptomes of brain, intestine, and muscle tiss Show more
To investigate the key regulatory genes and pathways related to growth traits in the Dongtingking crucian carp (Carassius auratus indigentiaus), the transcriptomes of brain, intestine, and muscle tissues were sequenced at early juvenile stage using RNA-Seq from two groups with extreme growth rates (fast-growing and slow-growing). A total of 65, 184, and 130 differentially expressed genes (DEGs) were detected in the brain, intestine, and muscle, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted that the PPAR signaling pathway, Insulin/PI3K/Akt/mTOR/FoxO/AMPK pathway, and Protein digestion and absorption pathways are crucial for growth in this species. Based on the transcriptome data, 32 key DEGs were identified, mainly participating in processes such as cell proliferation and differentiation, growth, development, and metabolism. Prominent examples are cyclic AMP-responsive element-binding protein 5 (creb5b), forkhead box protein O1-A (foxo1a), transcription factor AP-1-like (jun), lipoprotein lipase-like (lpl), angiopoietin-like 4 (angptl4), and egl nine homolog 3-like (egln3). This study enhances the understanding of the genetic factors and regulatory mechanisms responsible for variations in growth rates and provides a valuable basis for further studies on the regulatory mechanisms of growth in C. auratus indigentiaus. Show less
Lung adenocarcinoma (LUAD), the predominant histological subtype of non-small cell lung cancer, demonstrates critical regulatory involvement of RNA-binding proteins (RBPs) and circular RNAs (circRNAs) Show more
Lung adenocarcinoma (LUAD), the predominant histological subtype of non-small cell lung cancer, demonstrates critical regulatory involvement of RNA-binding proteins (RBPs) and circular RNAs (circRNAs) in tumorigenic processes. Emerging evidence highlights the circRNA-autophagy regulatory axis as a crucial modulator of cancer progression. This study systematically investigates the functional interplay within the RBP-circRNA-autophagy network in LUAD pathogenesis. Employing RNA pull down, mass spectrometry and RNA immunoprecipitation facilitated the exploration of the circRAPGEF5 binding protein. M6A methylation RNA immunoprecipitation-PCR was utilized for m6A analysis. Immunofluorescence (IF) and fluorescence in situ hybridization (FISH) assays were conducted to ascertain the subcellular localization of target genes. Employing mRFP-GFP-LC3 fluorescent lentivirus labelling facilitated the monitoring of autophagy flow levels. Xenografts in mice were instrumental in affirming the role of circRAPGEF5. Through comprehensive molecular profiling, we identified elevated circRAPGEF5 expression in LUAD cells, which significantly suppressed autophagic flux while promoting malignant phenotypes including enhanced proliferation, migration, and invasion. Mechanistic investigations revealed that circRAPGEF5 directly interacts with the KH3-4 functional domain of Insulin-like Growth Factor 2 mRNA-Binding Protein 2 (IGF2BP2), an m6A reader protein. This interaction facilitated IGF2BP2-mediated stabilization of NUP160 mRNA, a nuclear pore complex component. Genetic ablation of NUP160 through RNA interference effectively restored autophagic activity, thereby attenuating the aggressive biological behaviors of LUAD cells. In vivo validation using xenograft models demonstrated that the circRAPGEF5/IGF2BP2/NUP160 signaling axis promotes tumor growth and metastatic dissemination through autophagy suppression. Our findings reveal a novel epigenetic regulatory mechanism wherein m6A-modified circRAPGEF5 orchestrates autophagy inhibition via IGF2BP2-dependent stabilization of NUP160 transcripts, ultimately driving LUAD progression and metastasis. These results establish the circRAPGEF5/IGF2BP2/NUP160 axis as a potential therapeutic target for LUAD intervention. Show less
Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicat Show more
Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor Ξ² Show less
Atherosclerosis (AS) is a prevalent chronic arterial disease characterized by excessive cholesterol accumulation in the arterial intima. While substantial progress has been made in elucidating its ris Show more
Atherosclerosis (AS) is a prevalent chronic arterial disease characterized by excessive cholesterol accumulation in the arterial intima. While substantial progress has been made in elucidating its risk factors and pathogenesis, the upstream signaling molecules that drive the initiation and progression of AS remain poorly understood. Analysis of monocyte samples from the GSE23746 database revealed that Histone Deacetylase 6 (HDAC6) expression was significantly downregulated in patients with carotid atherosclerosis compared to healthy controls. In vitro experiments further demonstrated that HDAC6 deficiency markedly promotes foam cell formation in macrophages, a process dependent on its deacetylase activity. Mechanistically, HDAC6 interacts with signal transducer and activator of transcription 3 (STAT3) and regulates its acetylation at K685, a critical modification that facilitates macrophage foam cell formation. Specifically, the loss of HDAC6-mediated deacetylation leads to increased STAT3-K685 acetylation, which in turn upregulates the expression of CD36 and SRA, thereby enhancing cholesterol uptake in macrophages. Our findings establish HDAC6 as a protective regulator in atherosclerosis, which maintains lipid metabolic homeostasis by modulating the STAT3-CD36/SR-A axis. We also observed that systemic HDAC6 knockout exacerbated atherosclerotic progression in high-fat diet-fed ApoE Show less
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti Show more
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-ΞΊB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less
Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisyste Show more
Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisystem comorbidity network of CAS and clarify underlying genetic mechanisms. In 467β484 participants from the UK Biobank, observational and polygenic phenome-wide association studies evaluated associations between CAS and 1571 phenotypes, integrating disease-trajectory analyses to visualise temporal patterns. Associations replicated across observational and polygenic analyses were tested using two-sample Mendelian randomisation (MR) based on 22 CAS-related variants from FinnGen. Polygenic risk score (PRS) analyses excluding specific genes assessed their contributions, particularly LPA and plasma lipoprotein(a) (Lp(a)) levels. CAS was associated with higher risks of 42 cardiovascular and non-cardiovascular conditions, most prominently metabolic, endocrine, haematological and respiratory disorders. Temporal analyses showed that circulatory and metabolic diseases typically precede other comorbidities in CAS trajectories. MR findings were consistent with causal effects of CAS on multiple cardiovascular diseases, iron-deficiency anaemia, mental disorders and pleural effusion. When LPA variants were removed from the CAS PRS or plasma Lp(a) concentration was adjusted for, most associations lost significance, indicating a shared LPA/Lp(a)-mediated genetic pathway. CAS is embedded within a broad multisystem comorbidity network, driven largely by genetic variation at LPA and elevated Lp(a). These findings highlight pleiotropic mechanisms linking valvular calcification with systemic disease and support LPA-targeted therapies as a promising avenue for reducing the multisystem burden of CAS. Show less
Dynamic responsive structural colored materials have drawn increased consideration in a wide range of applications, such as colorimetric sensors and high-safety tags. However, the sophisticated intera Show more
Dynamic responsive structural colored materials have drawn increased consideration in a wide range of applications, such as colorimetric sensors and high-safety tags. However, the sophisticated interactions among the individual responsive parts restrict the advanced design of multimodal responsive photonic materials. Inspired by stimuli-responsive color change in chameleon skin, a simple and effective photo-crosslinking strategy is proposed to construct hydroxypropyl cellulose (HPC) based hydrogels with multiple responsive structured colors. By controlling UV exposure time, the structural color of HPC hydrogels can be effectively controlled in a full-color spectrum. At the same time, HPC hydrogels showcase temperature and mechanical dual-responsive structural colors. In particular, the microstructure of HPC hydrogels undergoes a transition from the chiral nematic phase to the nematic phase under the action of external stretching, leading to a significant reflection of circularly polarized light (CPL) to linearly polarized light (LPL). Given the diverse responsiveness exhibited by HPC hydrogels and their unique structural transition properties under external forces, we have explored their potential applications as dynamic anti-counterfeiting labels and optical skins. This work reveals the great possibility of using structural colored cellulose hydrogels in multi-sensing and optical displays, opening up a new path for the exploration of next-generation flexible photonic devices. Show less