CNS tumors are a significant cause of death in the adolescent and young adult (AYA; age 15-39 years) population; however, these patients often lack standardized treatments. In Canada, we have establis Show more
CNS tumors are a significant cause of death in the adolescent and young adult (AYA; age 15-39 years) population; however, these patients often lack standardized treatments. In Canada, we have established national multidisciplinary virtual AYA CNS tumor board rounds (national rounds) to improve and standardize care. From November 2021 to June 2024, 185 AYA patients with CNS tumors were presented from centers nationwide, including 138 patients with glioma. Before case presentation, 5.1% of patients with glioma were taking targeted agents or were enrolled in clinical trials. However, after national rounds, 72.6% of patients with pediatric-type glioma and 45.9% of patients with adult-type glioma were recommended clinical trials and/or targeted agents. Among the 44 patients with glioma who had received radiation therapy before national rounds, only 14 were recommended further radiation. Cumulatively, 68.9% of patients analyzed received a treatment recommendation that represented a change in clinical management compared with their previous treatments. Concurrently, we performed molecular review of 174 AYA CNS tumors during the study time frame. Using TruSight, we identified gene fusions involving Our results suggest that national rounds with centralized molecular review can direct AYA patients with CNS tumors toward targeted agents and clinical trials, while deferring radiation therapy. Taken together, our work details an ongoing effort to improve and standardize care of AYA patients with CNS tumors in Canada. Show less
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be exp Show more
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions. Show less
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in A Show more
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis. First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking. According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy. Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients. Show less
Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, bu Show more
Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders. Show less
End-stage renal disease (ESRD) is associated with high morbidity and mortality. Identifying patients with stage 4 chronic kidney disease (CKD) at risk of short-term progression to ESRD remains challen Show more
End-stage renal disease (ESRD) is associated with high morbidity and mortality. Identifying patients with stage 4 chronic kidney disease (CKD) at risk of short-term progression to ESRD remains challenging. Accurate prediction can improve advanced care planning and patient outcomes. This study aimed to develop and validate a machine learning (ML) model for predicting progression within 25 weeks (approximately six months) of ESRD in patients with stage 4 CKD. Electronic health records (EHRs) of patients with stage 4 CKD were analyzed. Nine ML models including Ridge regression (Ridge), random forest (RF), and eXtreme Gradient Boosting (XGBoost) were used to predict short-term progression to ESRD within 25 weeks. The models were trained and externally validated using the data of 346 and 105 patients. Of the 451 patients with stage 4 CKD, 219 developed ESRD. Among the evaluated models, XGBoost demonstrated the best overall performance. In the internal validation, it achieved an area under the curve (AUC) of 0.93, an accuracy of 0.90, and an F1 score of 0.89. In the external validation, XGBoost maintained the highest AUC (0.85), accuracy (0.79), and F1 score (0.79), along with the highest average precision (0.89) and a low log-loss (0.48), indicating strong discriminative ability and good generalizability. The top predictive features included high-density lipoprotein cholesterol, Alb, Cys C, ApoB, FGB, Bun, Neutrophil, and Total cholesterol. This study demonstrated the feasibility of ML for assessing ESRD prognosis based on easily accessible clinical features. XGBoost demonstrated superior performance in both internal and external validation, suggesting its potential for future patient screening. Show less
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strat Show more
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the ef Show more
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression. Show less
Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic criteria. To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patient Show more
Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic criteria. To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patients with FCS-based diagnostic methods. APPROACH enrolled 66 patients with FCS randomized to volanesorsen or placebo for 12 months. In 50 participants, genetic confirmation of FCS was based on the presence of pathogenic bi-allelic variants in LPL, APOC2, APOA5, GPIHBP1, or LMF1 genes. In 16 participants without a genetic diagnosis, FCS was diagnosed using clinical criteria and postheparin lipoprotein lipase activity ≤20% of normal. Plasma levels of apoC-III, triglycerides and related variables were measured at 3, 6, and 12 months. No significant differences were present in mean apoC-III reductions with volanesorsen at 3, 6, or 12 months in patients with FCS diagnosed either genetically or nongenetically. In contrast, the triglyceride reductions were statistically less robust in patients with genetic diagnosis at each timepoint, with mean (95% CI) percent reduction in triglycerides of -68.7% (-78.7, -58.6) vs -84.0% (-99.4, -68.6), P = .014 at Month 3; -58.2% (-78.1, -38.2) vs -84.5% (-122.4, -46.7), P = .009 at Month 6; and -35.6% (-57.7, -13.4) vs. -69.0% (-105.0, -33.1), P = .005 at Month 12. Patients with a genetic diagnosis had significantly lower response rates for achieved triglycerides <500 mg/dL, <750 mg/dL, <880 mg/dL and <1000 mg/dL than patients with a nongenetic diagnosis. All 5 episodes of acute pancreatitis occurred in patients with a genetic diagnosis. For a similar reduction in apoC-III in response to volanesorsen, triglyceride reduction is attenuated in patients with genetically vs nongenetically diagnosed FCS. 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
Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprote Show more
Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprotein lipase (LPL) activity. This expert opinion statement synthesizes current knowledge on the definition, pathophysiology, genetics, prevalence, diagnosis, and management of FCS. FCS typically manifests at a young age with persistent severe hypertriglyceridemia-defined as ≥10 mmol/L (≥885 mg/dL), or ≥1000 mg/dL (≥11.2 mmol/L) depending on region and whether Systeme International (SI) units are utilized-in the absence of secondary factors, resistance to conventional lipid-lowering therapies, and a high lifetime risk of acute pancreatitis. It is caused by biallelic pathogenic variants in the LPL gene encoding LPL, or 1 of 4 other related genes that encode proteins that interact with LPL. Affected individuals require a strict, lifelong very low-fat diet with <15% of energy from fat. Emerging therapies inhibiting apolipoprotein C-III show promise in reducing serum triglycerides and pancreatitis risk in patients with FCS. A multidisciplinary approach, encompassing dietary management, pharmacotherapy, and patient education, is pivotal in mitigating the significant morbidity associated with FCS. Show less
Metabolic associated fatty liver disease (MAFLD) is a globally recognized chronic metabolic disorder characterized by lipid metabolism abnormalities. Accumulating evidence indicates that exopolysaccha Show more
Metabolic associated fatty liver disease (MAFLD) is a globally recognized chronic metabolic disorder characterized by lipid metabolism abnormalities. Accumulating evidence indicates that exopolysaccharides (EPS) could modulate the gut microbiota structure and function to prevent and treat MAFLD. Herein, a novel EPS designated BVP1 was isolated from Bacillus velezensis CGMCC 24752. Structural analysis revealed that BVP1 is a neutral α-mannan consisting of a backbone of 1,2,6-linked α-D-Manp, with branches composed of T-linked α-D-Manp, 1,2-linked α-D-Manp, and 1,3-linked α-D-Manp. Animal experiments showed that BVP1 significantly alleviated hepatic steatosis, liver injury and inflammation, and enhanced antioxidant activity in MAFLD mice. Single-nucleus RNA sequencing analysis revealed that BVP1 could restore HFD-induced imbalances in liver sinusoidal endothelial cells, hepatic stellate cells, macrophages and Kupffer cells by upregulating the expression of the lipid degradation gene Cps1 and downregulating the expression of the lipid synthesis gene Acsl1 in these cell subpopulations. Interestingly, BVP1 reshaped the gut microbiota and fecal metabolite profile by enriching beneficial bacteria and associated metabolites including salicylic acid, spermidine, and 4-hydroxyphenyl acetate. Fecal microbiota transplantation experiments verified that the anti-MAFLD effects are mediated by the BVP1-modified gut microbiota. Our findings highlight the potential of BVP1 as a promising therapeutic agent for MAFLD treatment. Show less
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Al Show more
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less
Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism d Show more
Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified. This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD). We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches. Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy. Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy. Show less
Spontaneous Achilles tendon rupture (SATR) predominantly affects middle-aged and elderly individuals with chronic injuries. However, the exact cause and mechanism of SATR remain elusive, and potential Show more
Spontaneous Achilles tendon rupture (SATR) predominantly affects middle-aged and elderly individuals with chronic injuries. However, the exact cause and mechanism of SATR remain elusive, and potential therapeutic intervention or prevention is still insufficient. The present study aimed to uncover the key pathological molecules by using iTRAQ proteomics. The results identified 2432 candidate proteins in SATR patients using iTRAQ proteomic analysis. A total of 307 differentially expressed proteins (DEPs) were identified and linked to 211 KEGG signaling pathways including Coronavirus disease (COVID-19), focal adhesion, and ribosomes. GO enrichment analysis highlighted significant enrichment in processes such as biological adhesion, ossification, lipid (APOA4) processes, and extracellular matrix (ECM) organization (collagen). PPI network analysis identified hub genes such as serum albumin (ALB), fibronectin (FN1), and actin cytoplasmic 1. The WB analysis confirmed that FN1 and the receptor for activated C kinase (RACK1) were downregulated in the SATR tendon. Immunohistochemical staining revealed that collagen I and III were suppressed, while collagen II and APOA4 expression were higher in the SATR pathological tissue ( Show less
To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment. After the treatment with sevoflurane, CCK-8, Show more
To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment. After the treatment with sevoflurane, CCK-8, EdU and flow cytometry were employed to detect cell damage. The levels of N6-methyladenosine (m6A), METTL14 and DUSP6 were determined by qPCR and Western blot. The interaction between METTL14 and DUSP6 was analyzed using RIP-qPCR and Me-RIP methodologies. The cognitive function in mice were assessed by water maze test. After sevoflurane treatment, the cell viability, cell proliferation and METTL14 expression were markedly suppressed, while apoptosis was significantly enhanced. METTL14 overexpression elevated the levels of m6A and DUSP6, increased the binding level of METTL14 to DUSP6 mRNA, reducing damage to cells and cognitive dysfunction of mice. Knockdown of DUSP6 negated the beneficial effects observed with METTL14 overexpression. Sevoflurane induced POCD by regulating METTL14/DUSP6 through m6A methylation. Show less
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANG Show more
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less
Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herba Show more
Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herbal preparation consisting of Panax ginseng C.A.Mey (Hongshen) and Ophiopogon japonicus (Thunb.) Ker Gawl (Maidong), traditionally used for qi-replenishing, collapse-stabilizing, and lung-moistening therapy. Although clinically utilized in the management of SA-ALI, the specific mechanisms by which it acts against SA-ALI necessitate further investigation. The present study endeavors to comprehensively determine the therapeutic efficacy of SMI against SA-ALI through an integrated approach combining network pharmacology, metabolomics, metagenomic sequencing, and experimental validation. In this study, murine SA-ALI was established using lipopolysaccharide (LPS) and Poly(I:C). Results indicated that SMI administration significantly attenuated pulmonary inflammation, restored blood-gas barrier integrity, reduced serum pro-inflammatory cytokines and suppressed NF-κB pathway activation in SA-ALI mice. Network pharmacology elucidated the multi-targeted mechanism of SMI in modulating steroid hormone biosynthesis. Integrated metabolomics and target analysis revealed that ophiopogonin A/B and luteolin in SMI alleviates metabolic dysregulation by targeting key enzymes, including AKR1C3, HSD17B1/2, and SULT1E1. Metagenomic profiling demonstrated SMI-mediated gut microbiota remodeling, marked by suppression of pathogenic Chlamydiaceae (particularly Chlamydia abortus) and enrichment of commensal Lactobacillaceae. Correlation analysis showed that intestinal androstenedione and androsterone levels during SMI treatment recovery were negatively correlated with Chlamydia abortus abundance. In conclusion, SMI enhances the recovery from sepsis-associated SA-ALI by dual modulation of gut microbial ecology and host metabolic homeostasis, thereby establishing its potential as a multi-mechanistic therapeutic candidate for sepsis-related organ injury. Show less
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × L Show more
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) ( Show less
This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict na Show more
This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict natural compounds (NCs) with potential in Alzheimer's disease (AD) treatment. The NCs were identified based on activity related to seven AD-specific genes, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), and presenilin-1 (PSEN1). We implemented a computational pipeline using SELFormer and deep learning techniques, conducted optimal clustering and quantitative structure-activity relationship (QSAR) analyses, and performed a uniform manifold approximation and projection (UMAP) to categorize compounds based on bioactivity levels. Molecular docking analysis was carried out on selected compounds. To validate the computational predictions, we conducted in vitro studies using nerve growth factor (NGF)-differentiated PC12 cells. Finally, we mapped the relationships between food sources containing the identified compounds and their target proteins. Optimal clustering analysis revealed five distinct groups of NCs, while QSAR analysis highlighted variations in molecular properties across clusters. The UMAP projection identified 17 highly active NCs (pIC This integrated computational and experimental approach offers a promising framework for identifying potential NCs for AD treatment. The results contribute to exploring effective therapeutic strategies against AD. Show less
Cognitive decline is prevalent among older adults and may be associated with their daily activity behaviours. However, no studies have examined how cognitive decline affects older adults' activity beh Show more
Cognitive decline is prevalent among older adults and may be associated with their daily activity behaviours. However, no studies have examined how cognitive decline affects older adults' activity behaviours within a 24-h framework. This study investigates the relationship between cognitive function and 24-h activity behaviours in older adults, further exploring whether these associations differ by sex. This study analyses data from the eighth wave of the Survey of Health, Ageing and Retirement in Europe, conducting a cross-sectional analysis of 814 older adults. Cognitive function was assessed using the SHARE-Cog tool, encompassing 10-word immediate recall, 10-word delayed recall, verbal fluency, and self-reported memory. 24-h activity behaviours (moderate-to-vigorous physical activity [MVPA], light physical activity [LPA], sedentary behaviour [SB], and sleep) were objectively measured with thigh-worn accelerometers. Compositional multivariate linear regression models were constructed using compositional data as the response variable, with cognitive function measures as predictors. Higher MVPA was linked to better cognitive outcomes (verbal fluency, 10-word immediate recall, and 10-word delayed recall) while SB and longer sleep related to poorer performance, with these associations being stronger in women (model p ≤ 0.001). Among women, cognitive outcomes were significantly associated with all activity behaviours (p range = 0.010-0.045). Women who self-reported poor memory and scored 0 on the verbal fluency spent approximately 45% of their day in SB, whereas those reporting excellent memory and scoring 60 spent 40.06% (37.18%, 42.86%) and 36.41% (31.53%, 41.10%) of their day sedentary, respectively. In contrast, men's 24-h activity composition did not vary significantly with cognitive function (p range = 0.051-0.845). Older adults with better cognitive function tend to engage in more PA and reduce sedentary and sleep time. This relationship differed by sex, with females' activity behaviours being more sensitive to cognitive function changes. These findings suggest that interventions promoting healthy lifestyles in older adults should account for cognitive function, particularly in females. Show less
The causal relationships between the gut microbiota and prostate cancer, prostatitis, and benign prostatic hyperplasia remain uncertain. We intend to identify the causal connections between the gut mi Show more
The causal relationships between the gut microbiota and prostate cancer, prostatitis, and benign prostatic hyperplasia remain uncertain. We intend to identify the causal connections between the gut microbiota and prostatic diseases and investigate the potential mechanisms involved. A two-sample Mendelian randomization (MR) analysis was conducted to elucidate the impact of 196 gut microbiota on prostatic diseases risk. Reverse MR, linkage disequilibrium regression score (LDSC), and colocalization analyses were performed to strengthen causal evidence. Phenome-wide MR (Phe-MR) analysis was used to evaluate the potential side effects of targeting the detected gut microbiota. We designed a two-step MR study to assess the mediating effects of sex hormones, blood metabolites, and proteins. According to the MR analyses, 31 bacterial taxa were causally associated with prostatic diseases, of which 23 types were newly identified. In addition, Our study represents the first comprehensive exploration of the causal effects of the gut microbiota on prostatic diseases and reveals the mediating effects of sex hormones and blood metabolites on the "gut-prostate axis." Show less
Our previous investigations identified miR-30a-3p as a differentially expressed miRNA in ovine mammary tissue across sheep breeds with distinct lactation performance and different physiological stages Show more
Our previous investigations identified miR-30a-3p as a differentially expressed miRNA in ovine mammary tissue across sheep breeds with distinct lactation performance and different physiological stages. However, its regulatory mechanisms controlling mammary gland development and lactation remain unexplored. In this study, the effect of miR-30a-3p on the proliferation of ovine mammary epithelial cells (MECs) and the target genes of miR-30a-3p were investigated. The regulatory effects of miR-30a-3p on the expression of the target genes and the content of triglycerides in ovine MECs were also analyzed. The transfection of miR-30a-3p mimic was found to promote cell viability and the number of proliferated ovine MECs using CCK8 and Edu assays. On the contrary, the miR-30a-3p inhibitor showed the opposite results with the miR-30a-3p mimic. These results suggest that miR-30a-3p promotes the proliferation of ovine MECs. The dual luciferase assay revealed that Phosphatase and Tensin Homolog ( Show less
To investigate the risk factors associated with coronary heart disease (CHD) in patients with metabolic-associated fatty liver disease (MAFLD) and develop a nomogram prediction model. This study inclu Show more
To investigate the risk factors associated with coronary heart disease (CHD) in patients with metabolic-associated fatty liver disease (MAFLD) and develop a nomogram prediction model. This study included 394 patients with MAFLD who underwent coronary angiography at The Affiliated Hospital of Qingdao University between December 2019 and December 2024. The study cohort was divided in a 7:3 ratio into training and validation sets comprising 277 and 117 cases, respectively. The training group was further divided into the MAFLD-only ( Of the 394 MAFLD cases, 313 had CHD-related complications. Of the 277 patients in the training set, 220 had CHD, and of the 117 patients in the validation set, 93 had CHD. LASSO regression analysis revealed that the following variables were associated with the risk of CHD: sex, lipoprotein(a) (Lp[a]), low-density lipoprotein cholesterol, white blood cell count (WBC), glycated triglyceride-glucose index (TyG), and atherosclerosis index (AIP). Multivariate logistic regression analysis revealed that sex, Lp(a), WBC, TyG, and AIP were independent risk factors for CHD in MAFLD cases. A nomogram was constructed and an ROC curve was plotted, based on which the optimal cutoff value was determined as 0.698. The area under the curve of the nomogram in the training and validation cohorts was 0.860 (95% CI = 0.807-0.913) and 0.843 (95% CI = 0.757-0.929), respectively. Calibration curves for CHD risk probability showed good agreement between the nomogram's predicted probabilities and the observed event rates. DCA demonstrated the net clinical benefit of the constructed nomogram. Sex, Lp(a), WBC, TyG, and AIP emerged as independent risk factors for CHD in patients with MAFLD and the nomogram prediction model constructed using these factors could effectively predict CHD occurrence. Show less
The objective of this study was to assess the correlation between the ApoB/ApoA ratio and the recurrence of kidney stones in a Chinese adult population. We collected electronic records of patients wit Show more
The objective of this study was to assess the correlation between the ApoB/ApoA ratio and the recurrence of kidney stones in a Chinese adult population. We collected electronic records of patients with kidney stones who underwent surgical treatment at our hospital from March 2016 to March 2022. These patients were followed up and categorized into groups based on the recurrence of kidney stones. Parameters related to routine blood and biochemical tests, as well as the history of hypertension and diabetes mellitus, were gathered. Multiple imputation was applied for missing data. Subsequently, differences between the recurrence and non-recurrence groups were assessed using the chi-square test, independent samples t test, or Wilcoxon rank sum test. Logistic regression analysis, subgroup analysis, and propensity-matched analysis were conducted to evaluate the relationship between the ApoB/ApoA ratio and kidney stone recurrence. The study included a total of 923 participants aged > 18 years, among whom 296 experienced kidney stone recurrence during the follow-up period. An elevated ApoB/ApoA ratio was identified as a risk factor for kidney stone recurrence (adjusted OR = 2.48, 95% CI 1.04, 5.92). Propensity-matched analyses further supported the association, showing that elevated ApoB/ApoA ratios were linked to a higher risk of renal stone recurrence (OR = 3.37, 95% CI 1.24-9.17). The dose-response curve illustrated a positive linear correlation between the ApoB/ApoA ratio and the risk of kidney stone recurrence. Increased ApoB/ApoA ratios are positively correlated with the risk of kidney stone recurrence. This association remains significant, although a causal relationship cannot be definitively established. 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
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
Nolan Priedigkeit, Beth Harrison, Robert Shue+27 more · 2025 · Clinical cancer research : an official journal of the American Association for Cancer Research · added 2026-04-24
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to li Show more
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less
To clarify the anatomical characteristics of the lateral plantar ligament (LPL) of the transverse metatarsal arch (TMA) in the population of southwest Shandong Province, so as to complement the anatom Show more
To clarify the anatomical characteristics of the lateral plantar ligament (LPL) of the transverse metatarsal arch (TMA) in the population of southwest Shandong Province, so as to complement the anatomical structures of the midfoot and Lisfranc joint complexes. A total of 100 adult lower limbs were dissected and the types of LPL were divided according to their insertions, among them, 63 were (63%) and 37 were female (37%); 50 were on the left side (50%) and 50 were on the right side (50%). The fiber bundle length, origin width, insertion width, and thickness of the LPL were measured. (1) According to the insertions of the LPL, they were divided into: ① Type I, the LPL was inserted at the base of the second metatarsal (M2) in 47 cases; ② Type II, the LPL was inserted at the base of M2 and fused with tibialis posterior tendon (TPT) in 16 cases; ③ Type III, the LPL was absent in 16 cases; ④ Type IV, the LPL was inserted at TPT in 6 cases; ⑤ Type V, the LPL was inserted at the intermediate cuneiform (IC) in 1 case; ⑥ Type VI, bifid LPL with one bundle inserted at the base of M2, and the other bundle inserted at the medial cuneiform (MC) in 4 cases; ⑦ Type VII, two bundles of LPL inserted at the base of M2 in 8 cases; ⑧ Type VIII, the LPL consisted of 3 bundles; the distal, middle and proximal bundles was inserted at the base of M2, the TPT and the lateral side of navicular bone in 2 cases, respectively. (2) There was a statistical significance in the length of LPL between male (31.62 ± 3.83) mm and female (28.07 ± 3.46) mm (t=-3.050, P = 0.003). There was no statistical significance in the types of LPL between male and female (Z=-1.721, P > 0.05), and no statistical significance in the types between left and right sides (Z=-0.026, P > 0.05). According to our research, LPL originates from M5 and is divided into 8 types according to its insertion location, of which insertion at the base of M2 is the most common. In addition, we found that LPL has fibrous fusion with the long plantar ligament and the TPT, which may be involved in maintaining arch stability. The classification of LPL in this study is a supplement to the anatomical structure of the middle foot and Lisfranc joint complex, providing a new direction for the diagnosis and treatment of middle foot and arch injury in the future. Show less