B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined r Show more
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27-IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction-mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Show less
Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. Howe Show more
Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. However, their interplay in GC prognosis remains unexplored. We analyzed RNA-seq and clinical data from The Cancer Genome Atlas Program and Gene Expression Omnibus databases. Using univariate Cox, LASSO, and multivariate Cox regression, we identified candidate genes and constructed a prognostic signature. Immune contexture, genomic alterations and drug sensitivity were compared between high- and low-risk group. The metabolic and aging related risk score, comprising 4 genes (GNAI1, GSTA1, APOC3, and LOX), was developed. Validation across multiple cohorts confirmed its robust prognostic performance. The model also effectively stratified patients into distinct risk subgroups with differential immune profiles and responses to immunotherapy. Notably, high-risk patients showed reduced sensitivity to common chemotherapeutic agents but may benefit from targeting the PI3K/mTOR pathway. Metabolic and aging related risk score serves as a promising tool for individualized risk assessment and therapeutic guidance in GC, warranting further clinical validation. Show less
Goose foie gras production requires force-feeding with high-energy feed, disrupting hepatic lipid homeostasis and causing excessive lipid accumulation. To investigate the formation mechanism, we colle Show more
Goose foie gras production requires force-feeding with high-energy feed, disrupting hepatic lipid homeostasis and causing excessive lipid accumulation. To investigate the formation mechanism, we collected liver samples from Landes geese at pre-force-feeding (D0), mid-force-feeding (D16), and terminal-force-feeding (D25) stages. Overfeeding shifted liver color from reddish-brown to yellow, significantly increasing size and weight. Histological analysis revealed pronounced lipid droplet accumulation in hepatocytes. Biochemical analysis indicated force-feeding groups (D16, D25) exhibited continuous and significant decreases in liver moisture, crude ash, and crude protein content compared to D0, while crude fat increased substantially. Integrated transcriptomic and lipidomic analyses identified 497 differentially expressed genes (DEGs) and 368 differential lipid molecules (DLMs) between D16 and D0, and 303 DEGs and 172 DLMs between D25 and D16. KEGG enrichment highlighted four pathways associated with fatty liver formation: glycerolipid metabolism, adipocytokine signaling pathway, ErbB signaling pathway, and MAPK signaling pathway. Within these, key genes ( Show less
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while Show more
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while also assisting in the production and organization of new viral components. However, NSPs are not incorporated into viral particles, and their subsequent fate within host cells remains poorly understood. Additionally, their role in viral pathogenesis requires further investigation. This study aimed to discover the ultimate fate of NSP6 in host cells and to elucidate its role in viral pathogenesis. We investigated the effects of NSP6 on cell death and explored the underlying mechanism; moreover, we examined the degradation mechanism of NSP6 in human cells, along with analysing its correlation with coronavirus disease 2019 (COVID-19) severity in patient peripheral blood mononuclear cells (PBMCs). NSP6 was demonstrated to induce cell death. Specifically, NSP6 interacted with EI24 autophagy-associated transmembrane protein (EI24) to increase intracellular Ca This study reveals that KLHL22-mediated ubiquitination controls NSP6 stability and that NSP6 induces autophagic cell death via calcium overload, highlighting its cytotoxic role and suggesting therapeutic strategies that target calcium signaling or promote NSP6 degradation as potential interventions against COVID-19. Show less
Studying the molecular properties of drugs and their interactions with human targets aids in better understanding the clinical performance of drugs and guides drug development. In computer-aided drug Show more
Studying the molecular properties of drugs and their interactions with human targets aids in better understanding the clinical performance of drugs and guides drug development. In computer-aided drug discovery, it is crucial to utilize effective molecular feature representations for predicting molecular properties and designing ligands with high binding affinity to targets. However, designing an effective multi-task and self-supervised strategy remains a significant challenge for the pretraining framework. In this study, a multi-task self-supervised deep learning framework is proposed, MTSSMol, which utilizes ≈10 million unlabeled drug-like molecules for pretraining to identify potential inhibitors of fibroblast growth factor receptor 1 (FGFR1). During the pretraining of MTSSMol, molecular representations are learned through a graph neural networks (GNNs) encoder. A multi-task self-supervised pretraining strategy is proposed to fully capture the structural and chemical knowledge of molecules. Extensive computational tests on 27 datasets demonstrate that MTSSMol exhibits exceptional performance in predicting molecular properties across different domains. Moreover, MTSSMol's capability is validated to identify potential inhibitors of FGFR1 through molecular docking using RoseTTAFold All-Atom (RFAA) and molecular dynamics simulations. Overall, MTSSMol provides an effective algorithmic framework for enhancing molecular representation learning and identifying potential drug candidates, offering a valuable tool to accelerate drug discovery processes. All of the codes are freely available online at https:// github.com/zhaoqi106/MTSSMol. Show less
With the development of optical anti-counterfeiting and the increasing demand for high-level information encryption, multimodal luminescence (MML) materials attract much attention. However, the discov Show more
With the development of optical anti-counterfeiting and the increasing demand for high-level information encryption, multimodal luminescence (MML) materials attract much attention. However, the discovery of these multifunctional materials is very accidental, and the versatile host suitable for developing such materials remains unclear. Here, a grossite-type fast ionic conductor CaGa Show less
The competency of specialist nurse clinical educators is crucial for the effectiveness of specialist nurse training programmes. However, variability in teaching competency and training needs among edu Show more
The competency of specialist nurse clinical educators is crucial for the effectiveness of specialist nurse training programmes. However, variability in teaching competency and training needs among educators remains insufficiently studied, especially in the context of rapidly evolving healthcare education in China. This study aimed to identify distinct core competency profiles among clinical educators for specialist nurses, examine associated socio-demographic factors, and explore differences in training needs across profiles. A cross-sectional online survey was conducted with 3,945 specialist nurse clinical educators from 30 Chinese regions. The Chinese version of the Nurse Educator Core Competency Scale (NECCS) and a self-developed training needs questionnaire were used. Latent Profile Analysis (LPA) identified competency subgroups, while multinomial logistic regression and Kruskal-Wallis tests examined associated variables and training needs. Latent Profile Analysis identified three competency profiles: foundational (8.6%), intermediate (43.0%), and advanced (48.4%), with mean scores of 43.89, 68.24, and 91.68, respectively. Educators without prior training were significantly more likely to belong to the foundational (OR = 3.195, p < 0.001) and intermediate (OR = 1.676, p < 0.001) groups compared to those with training experience. Advanced-competency educators showed the highest demand for curriculum design training, with 75% rating it as highly necessary. In contrast, educators in the intermediate group identified clinical teaching methods and techniques as their top training need (58.7%). Those in the foundational group prioritised common pedagogical methods and instructional technologies (54.7%). Clinical educator competencies vary by background characteristics and training exposure. Tailored, competency-based training is needed to address these gaps and enhance the quality of specialist nursing education. Show less
Interleukin-27 (IL-27) is a cytokine that is reported to be highly expressed in the peripheral blood of patients with pulmonary tuberculosis (PTB). IL-27-mediated signaling pathways, which exhibit ant Show more
Interleukin-27 (IL-27) is a cytokine that is reported to be highly expressed in the peripheral blood of patients with pulmonary tuberculosis (PTB). IL-27-mediated signaling pathways, which exhibit anti- Mycobacterium tuberculosis (Mtb) properties, have also been demonstrated in macrophages infected with Mtb. However, the exact mechanism remains unclear. This study aimed to clarify the potential molecular mechanisms through which IL-27 enhances macrophage resistance to Mtb infection. Both normal and PTB patients provided bronchoalveolar lavage fluid (BALF). Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and stimulated with 50 ng/mL macrophage-colony stimulating factor (M-CSF) to obtain monocyte-derived macrophages (MDMs). Using 100 ng/mL phorbol 12-myristate 13-acetate (PMA), THP-1 cells were induced to differentiate into THP-1-derived macrophage-like cells (TDMs). Both MDMs and TDMs were subsequently infected with the Mtb strain H37Rv and treated with 50 ng/mL IL-27 prior to infection. The damage and inflammation of macrophages were examined using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and Western blotting. Patients with PTB had elevated levels of IL-27 in their BALF. Preconditioning with IL-27 was shown to reduce H37Rv-induced MDMs and TDMs apoptosis while also decreasing the levels of Cleaved Caspase-3, Bax and the proinflammatory cytokines TNF-α, IL-1β, and IL-6, promoting the expression of Bcl-2 and the anti-inflammatory factors IL-10 and IL-4. Silencing of the IL-27 receptor IL-27Ra increased macrophage damage and inflammation triggered by H37Rv. Mechanistically, IL-27 activates autophagy by inhibiting TLR4/NF-κB signaling and activating the PI3K/AKT signaling pathway, thereby inhibiting H37Rv-induced macrophage apoptosis and the inflammatory response. Our study suggests that IL-27 alleviates H37Rv-induced macrophage injury and the inflammatory response by activating autophagy and that IL-27 may be a new target for the treatment of PTB. Show less
Stroke is a life‑threatening cerebrovascular disorder categorized into two major subtypes: Ischemic and hemorrhagic. Characterized by high morbidity and mortality rates, its clinical management remain Show more
Stroke is a life‑threatening cerebrovascular disorder categorized into two major subtypes: Ischemic and hemorrhagic. Characterized by high morbidity and mortality rates, its clinical management remains challenging due to limited therapeutic options. Interleukin (IL)‑27, a pleiotropic cytokine with demonstrated neuroprotective potential, has emerged as a promising candidate for stroke intervention. IL‑27 exerts immunomodulatory effects within the central nervous system, including suppression of proinflammatory T‑cell proliferation and induction of regulatory T‑cell differentiation. These mechanisms collectively attenuate neuroinflammation, mitigate neuronal apoptosis and prevent neurodegenerative processes. The efficacy of IL‑27 in reducing cerebral damage in both ischemic and hemorrhagic stroke models has been validated, although clinical translation remains to be achieved. The present review summarizes: i) The epidemiology of stroke; ii) the immunoregulatory functions of IL‑27 and its neuroprotective mechanisms across stroke subtypes; iii) innovative brain‑targeted delivery approaches; iv) IL‑27 clinical applicability with supporting evidence; and v) possible risks and solutions in clinical applications. By collating the current knowledge, the present study provides a translational framework for advancing IL‑27‑based therapies in stroke management. Show less
The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concom Show more
The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concomitant LPL/PCN. Retrospectively analyzed clinical and laboratory data of 14 cases. Three patients initially presented with immunoglobulin (Ig) M paraprotein, 1 with IgG paraprotein, and 10 had simultaneous diagnoses of PCN and LPL. In 13 cases, flow cytometry detected both LPL and PCN in marrow biopsies. Furthermore, immunohistochemistry highlighted the 2 neoplastic populations, demonstrating an increased proportion of plasma cells and their expression of cyclin D1, CD56, and/or a non-IgM isotype restriction. All cases exhibited discordant heavy-chain isotypes between LPL and PCN. Thirteen of the 14 cases (92.9%) had concordant light-chain restrictions between the 2 neoplasms, and the remaining case (7.1%) showed discordant light-chain restrictions. Of the 12 patients with follow-up, 5 were treated with myeloma regimens, 2 with LPL regimens, 3 with combined therapy, and 2 with observation alone. Follow-up ranged from 2 to 146 months (median, 12.5 months). One patient died of PCN progression, one died of comorbidity, and 10 patients were alive with or without disease. Survival analysis showed no significant difference from the control. The discordant heavy-chain isotype restrictions between PCN and LPL suggest biclonal B-cell neoplasms, which is supported by PCN's phenotypic distinction, such as the expression of cyclin D1 and/or CD56. However, our series exhibited a tendency toward concordant light-chain restrictions between the 2 neoplasms, raising the possibility that PCN may evolve from LPL through class switching. 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 in 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
Time-restricted feeding (TRF) is a dietary intervention that has been shown to have numerous health benefits. However, it is important to further investigate the potential effectiveness of TRF in addr Show more
Time-restricted feeding (TRF) is a dietary intervention that has been shown to have numerous health benefits. However, it is important to further investigate the potential effectiveness of TRF in addressing sarcopenic obesity (SO), which is characterized by a combination of age-related obesity and sarcopenia. In this study, 14-month-old C57BL/6J male mice were fed either regular chow diet or high-fat diet (HFD), and had either ad libitum or restricted access to food for 8 hours daily (Intervention for 7 months). For the human trial (ChiCTR2100052876), obese individuals (n=21) with a Body Mass Index ≥28 were recruited and instructed to adopt an 8-hour eating window and a 16-hour fasting period. Here, we found that the TRF intervention significantly reduced global fat mass (P < .001) and volume (P < .05), and increase lean mass compared to mice fed with HFD. Furthermore, TRF improved overall metabolic mobility (8h TRF+HFD vs. AL+HFD). This intervention also enhanced liver FGF21 protein levels (P < .01) and the expression of FGFR1 and FGF21 target genes in adipose and muscle tissues, thus improving mitochondrial quality control in these tissues. Notably, TRF interventions led to a significant decrease in serum FGF21 levels (P < .05). In the human trial, TRF intervention resulted in a significant reduction in weight (P < .001) and body fat levels (P < .001) among obese individuals, as well as a decrease in serum GLU (P < .001), insulin (P < .001), and TC levels (P < .05). Overall, the findings indicate that TRF intervention improves SO by regulating liver FGF21 expression, thereby enhancing FGF21 sensitivity in adipose and muscle tissues. Show less
Xiaolei Song, Chenchen Wang, Qin Ding+8 more · 2025 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important path Show more
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD. Show less
Conjugated linoleic acid (CLA) isomers have been reported to reduce body weight and promote glycolipid metabolism in animals. In a preliminary study, we revealed that trans-10, cis-12-CLA (10,12-CLA) Show more
Conjugated linoleic acid (CLA) isomers have been reported to reduce body weight and promote glycolipid metabolism in animals. In a preliminary study, we revealed that trans-10, cis-12-CLA (10,12-CLA) plays an important role in modulating lipid metabolism in chickens. However, the underlying mechanism remains unclear. In this study, we constructed an isolated in vitro model with primary chicken hepatocytes to investigate the effect of 10,12-CLA on lipid metabolism. 10,12-CLA inhibited lipid accumulation by decreasing the mRNA expression of sterol regulatory element-binding protein-1c (SREBP-1c), SREBP2, 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), fatty acid synthase (FAS), adipose triacylglyceride lipase (ACC), and lipoprotein lipase (LPL) and increasing the mRNA expression of peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1 (CPT1) and adipose triacylglyceride lipase (ATGL). Furthermore, 10,12-CLA treatment activated the protein expression of extracellular signal-regulated kinase 1/2 (ERK1/2) and AMP-activated protein kinase (AMPK), whereas treatment with the ERK1/2 inhibitor U0126 reversed the inhibitory effects of 10,12-CLA on lipid accumulation by blocking the ERK1/2-AMPK pathway, leading to increased lipid accumulation and triglyceride content in primary chicken hepatocytes. These findings suggest that in chicken hepatocytes, 10,12-CLA alleviates hepatocyte lipid deposition by activating the ERK1/2-AMPK pathway, promoting fatty acid oxidation and reducing lipid synthesis, revealing the potential mechanism through which 10,12-CLA regulates hepatic lipid metabolism in chickens. Show less
Jinyu Bai, Xueli Qiu, Huajian Shan+10 more · 2025 · Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · Oxford University Press · added 2026-04-24
The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptor Show more
The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptors and act as universal adaptor proteins to mediate the activation of key downstream signaling pathways. However, it remains unclear whether and how Gαi1/3 proteins mediate Wnt/β-catenin signal transduction. In this study, we utilized single-cell sequencing analysis and employed viral transfection and gene editing techniques to alter the expression of Gαi1/3 in mouse embryonic osteoblast precursor cells. We examined the relationship between Gαi1/3 expression and the Wnt/β-catenin signaling pathway. Immunoprecipitation and confocal experiments were conducted to further explore the mechanisms by which Gαi1/3 exerts its functions. Osteogenic-related protein levels were detected by Western blotting, and the effects of Gαi1/3 proteins on osteogenic function were examined through alkaline phosphatase and Alizarin red staining. Additionally, micro-CT was used to compare bone mass in mice with different levels of Gαi1/3 expression, showing the relationship between Gαi1/3 and bone formation. Our findings indicate that Gαi1/3 proteins are significantly inversely correlated with age. Gαi1/3, rather than Gαi2, mediates the Wnt/β-catenin signaling pathway and promotes osteogenesis. Mechanistically, Gαi1/3 interacts with Axin1 and recruits it to the cell membrane, leading to inactivation of the β-catenin degradation complex. This results in β-catenin accumulation and nuclear translocation, where it activates the transcription of osteogenic genes. In vivo experiments further confirm that knockdown of Gαi1/3 significantly inhibits bone formation in mice. Our study identified Gαi1/3 as key regulatory proteins in Wnt/β-catenin signaling-mediated osteogenesis, and further elucidated its molecular mechanism in bone formation, which may provide a new therapeutic target for osteoporosis. Show less
Recent researches highlight the interdependence of lipoprotein(a) [Lp(a)] and Lp(a)-associated cardiovascular risk with the background inflammatory burden. This study aimed to investigate whether syst Show more
Recent researches highlight the interdependence of lipoprotein(a) [Lp(a)] and Lp(a)-associated cardiovascular risk with the background inflammatory burden. This study aimed to investigate whether systemic inflammation modulates Lp(a)-associated coronary stenosis in chronic coronary syndromes (CCS). A total of 1513 participants undergoing angiography at a tertiary cardiology center in China were included in our retrospective, cross-sectional study. Participants were categorized into normal, mild, and severe groups based on the Gensini Scores, which quantitatively assess stenosis severity. Multinomial logistic models were calculated according to accompanying systemic inflammation concentration. Participants with elevated Lp(a) levels had a high coronary stenosis risk: fully adjusted model odds ratios (ORs) [95% confidence intervals (CIs)] for the mild vs. normal and severe vs. normal groups were 1.47 (1.11-1.96) and 1.68 (1.21-2.33). Notably, the strongest Lp(a)-coronary stenosis associations after multi-variable adjustment persisted only in low inflammation concentration [systemic inflammation response index (SIRI) < 0.64)] [mild vs. normal, OR 2.03, 95% CI 1.17-3.54, Elevated Lp(a) correlates with coronary stenosis only in low inflammation concentration. Considering systemic inflammation in personalized Lp(a)-lowering therapies is more conducive for CCS managements. Show less
Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases Show more
Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less
The angiopoietin-like protein 4 (ANGPTL4), also known as fasting-induced adipose factor, is a secreted glycoprotein that belongs to the ANGPTL protein family. Due to its expression in various cell typ Show more
The angiopoietin-like protein 4 (ANGPTL4), also known as fasting-induced adipose factor, is a secreted glycoprotein that belongs to the ANGPTL protein family. Due to its expression in various cell types and tissues and its interactions with other proteins, ANGPTL4 plays diverse roles within its family, exhibiting a wider range of molecular functions. For instance, ANGPTL4 is intricately involved in modulating central energy metabolism and enhancing exercise endurance, while also acting as a pivotal mediator in the interaction between gut microbiota and host lipid metabolism. Moreover, the expression of ANGPTL4 is directly controlled by aging-related signaling pathways. Its excessive activation accelerates the aging process by triggering mechanisms like heightened oxidative stress, epithelial-mesenchymal transition (EMT) and fibrosis, abnormal lipid accumulation, and cellular arrest, thereby advancing the development of age-related diseases. Given the pivotal roles of ANGPTL4 and its associated molecules in organ fibrosis and cancer advancement, targeting ANGPTL4 emerges as a promising therapeutic approach. However, the intricate and sometimes conflicting functions of the two cleavage fragments of ANGPTL4, namely N-terminal fragment (nANGPTL4) and C-terminal fragment (cANGPTL4), in different chronic diseases-exerting inhibitory or stimulatory effects depending on the disease stage-have posed challenges to the progress of ANGPTL4 antibody therapy. This review provides an overview of the biological mechanisms of ANGPTL4, its dual impact on fibrosis and tumorigenesis, and highlights its recent advancements as a potential biomarker in age-related diseases and inflammation-related conditions. ANGPTL4 is a high-potential but complex target, requiring mechanism-driven strategies for safe clinical translation. Show less
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focu Show more
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less
The per-particle pathogenicity of very-low-density lipoprotein (VLDL) and lipoprotein(a) [Lp(a)] with risk of valvular heart diseases (VHD) other than aortic stenosis compared with low-density lipopro Show more
The per-particle pathogenicity of very-low-density lipoprotein (VLDL) and lipoprotein(a) [Lp(a)] with risk of valvular heart diseases (VHD) other than aortic stenosis compared with low-density lipoprotein (LDL) remains unclear. Single-nucleotide polymorphism specific clusters associated with LDL cholesterol (LDL-C), VLDL cholesterol (VLDL-C) and Lp(a) were identified. The relationships of genetically predicted variation in apolipoprotein B (apoB) in these lipoproteins with risk of VHD and its major types (aortic stenosis, aortic regurgitation, and mitral regurgitation) were evaluated to determine the comparative pathogenicity by Mendelian randomization (MR) analyses. The VHD odds ratio (OR) per 1 g/L higher apoB was 1.09 [95 % confidence interval (CI) 1.04-1.15] in LDL vs. 1.45 (95 % CI 1.25-1.69) in VLDL vs. 2.71 (95 % CI 1.92-3.82) in Lp(a) based on the cluster-based MR analyses. The polygenic scores for each lipoprotein weighted by apoB similarly showed a greater OR of VHD per 1 g/L apoB in VLDL [1.20 (95 % CI 1.06-1.37)] and in Lp(a) [2.54, (95 % CI 1.95-3.32)] compared with that in LDL [1.05 (95 % CI 1.01-1.08)]. Multivariable MR analyses further revealed the strong effects of VLDL-C and Lp(a) on VHD risk independent of LDL-C. In addition, significant associations between Lp(a) and all three major types of VHD were observed, while LDL and VLDL had no impact on aortic and mitral regurgitation. VLDL and Lp(a) appear to have significantly greater per-particle pathogenicity in VHD compared to LDL. The distinct impacts of lipoproteins on different VHD subtypes suggest the inadequacy of just focusing on LDL-lowering treatment for valve disorders. Show less
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabol Show more
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development. Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells. Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib. The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors. Show less
Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achiev Show more
Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achieve satisfactory outcomes. Therefore, it is imperative that we approach the progress of AMD from novel perspectives in order to explore new therapeutic strategies. We obtained transcriptomic data from the macular and the peripheral retina from patients with AMD and a control group from the Gene Expression Omnibus (GEO) database. Through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified differentially expressed genes (DEGs) that were significantly enriched in functions associated with ferroptosis. Subsequent application of machine learning techniques enabled the identification of key hub genes, whose diagnostic potential was further validated. Additionally, the expression of these hub genes was corroborated in both animal and cellular models. Finally, we performed a functional enrichment analysis of these hub genes. In the macula of patients with AMD, 452 DEGs were identified, while in the peripheral retina, 222 DEGs were discovered. Within the macula, 19 genes were associated with ferroptosis, compared to 3 in the peripheral retina. Consequently, the macular was selected as the primary focus of the study. Subsequent screening of these 19 genes using LASSO regression, Support Vector Machine (SVM), and Random Forest algorithms identified four hub genes: FADS1, TFAP2A, AKR1C3, and TTPA. Consequently, we utilized cigarette smoke extract (CSE) to either stimulate retinal pigment epithelial (RPE) cells in vitro or administer it via intravitreal injection, thereby establishing in vitro and in vivo models of AMD. Results from RT-PCR and Western blot analyses revealed an upregulation of FADS1, AKR1C3, and TTPA, while TFAP2A exhibited decreased expression. Finally, we investigated the infiltration of immune cells within the macular and performed a functional enrichment analysis of the hub genes. We identified four key ferroptosis-related genes (FRGs)-FADS1, AKR1C3, TFAP2A, and TTPA-that possess diagnostic relevance for AMD and correlate with immune cell infiltration. Moreover, significant changes in both mRNA and protein expression levels of these genes have been observed in in vitro experiments and mice models. Show less
Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Diseas Show more
Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP×TL interaction term. AD risk was associated with shorter TL (β = -0.18, We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis. Show less
The causal relationship between the familial hypercholesterolemia (FH) and intestinal vascular diseases was unnoticed. This study aims to investigate the cause-and-effect relationship of FH with risk Show more
The causal relationship between the familial hypercholesterolemia (FH) and intestinal vascular diseases was unnoticed. This study aims to investigate the cause-and-effect relationship of FH with risk of intestinal vascular diseases in human. A Mendelian randomization (MR) analysis was performed by extracting summary-level datasets for FH or FH concurrently with ischemic heart disease (IHD) and intestinal vascular diseases from the FinnGen study including 329,115, 316,290 and 350,505 individuals. The inverse-variance weighted (IVW) method and the weighted median method were applied to analyze the causal relationships between FH or FH concurrently with IHD and the risk of intestinal vascular diseases. Cochran's Q statistic method and MR-Egger regression were used to assess heterogeneity and pleiotropy. The IVW method demonstrated that FH was significantly associated with higher odds of intestinal vascular diseases [OR (95%CI): 1.22 (1.03, 1.45)] ( In conclusion, FH was causally positive-associated with the increased risk of intestinal vascular diseases, revealing a potential unfortunate outcome for FH. Therefore, patients with FH should pay closely attention to the risk of intestinal vascular diseases. Our study may provide evidence for new diagnostic and therapeutic strategies in clinical practices. 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
This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each part Show more
This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each participant underwent PET/CT scanning using [ A total of 101 participants were included (mean age 63.267 ± 9.344 [range 39-86 years]). In benign lung lesions, [ [ Show less
Oxidative deterioration of fish oil in aquafeeds poses a significant challenge to fish health and aquaculture sustainability, making it crucial to mitigate this issue through healthy and green nutriti Show more
Oxidative deterioration of fish oil in aquafeeds poses a significant challenge to fish health and aquaculture sustainability, making it crucial to mitigate this issue through healthy and green nutritional strategies. This study examined the potential of stevia chlorogenic acid (SCGA), a bioactive byproduct of stevia processing, to alleviate intestinal injury, gut microbiota dysbiosis, and lipid metabolism disorders induced by oxidized fish oil in turbot. Four diets with equal nitrogen and lipid contents were formulated: a control diet (PC) containing 5 % fresh fish oil, an oxidized fish oil diet (OFO) comprising 5 % oxidized fish oil, and two additional OFO diets supplemented with 200 mg/kg (OFO200) or 400 mg/kg (OFO400) of SCGA. Each dietary treatment was randomly assigned to three replicates, each containing 40 fish weighing approximately 16.99 ± 0.01 g, and administered over a 10-week period. Fish fed the OFO diet exhibited significantly compromised growth performance, as indicated by decreased WGR and SGR, along with reduced serum immune indices (IgM, C3, and C4) and lipid parameters (TC, HDL, LDL), and elevated serum D-LA levels (P < 0.05). Moreover, dietary OFO markedly suppressed antioxidant enzyme activities (serum SOD; intestinal SOD, GSH-Px, and CAT) and elevated MDA concentrations (P < 0.05). Additionally, OFO reduced intestinal expression of tight junction-associated genes (Claudin-4, Claudin-7, Occludin) while increasing expression levels of MLCK, Keap1, inflammatory mediators (IL-6, IL-1β, TNF-α2, NF-κB, IFN-γ), and Caspase7 (P < 0.05). Notably, the TLR signaling pathway-related genes were upregulated, accompanied by pronounced shifts in gut microbiota composition (P < 0.05). In hepatic tissue, lipogenesis-associated genes (FAS, ACC) were significantly increased, while key genes involved in lipid transport and β-oxidation (CD36, LPL, ACOX1, PPARγ) exhibited reduced expression (P < 0.05). Dietary supplementation with 200 and 400 mg/kg SCGA effectively mitigated these detrimental impacts. SCGA restored growth performance, serum immune parameters, and antioxidant enzyme activities to levels comparable to the PC group. It also normalized gene expression related to intestinal barrier function, inflammation, apoptosis, and hepatic lipid metabolism. Furthermore, SCGA supplementation modulated gut microbiota structure by increasing beneficial genera and decreasing potential pathogens. In conclusion, SCGA effectively improves growth performance, alleviates OFO-induced intestinal injury and microbial dysbiosis, and regulates lipid metabolism in turbot. These findings provide theoretical insights and technical support for the application of SCGA in aquaculture. Show less
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies Show more
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4 Show less