Gliomas comprise a heterogeneous group of central nervous system tumors in which gene fusions (GFs) are significant oncogenic drivers and emerging diagnostic and therapeutic biomarkers. In cancer diag Show more
Gliomas comprise a heterogeneous group of central nervous system tumors in which gene fusions (GFs) are significant oncogenic drivers and emerging diagnostic and therapeutic biomarkers. In cancer diagnosis, GF detection largely relies on targeted short-read sequencing fusion panels, such as the Children's Hospital of Philadelphia (CHOP) Fusion Panel (FUSIP). While these panels are effective for detecting recurrent, well-characterized GFs, they are limited to predefined gene sets and cannot identify full-length transcripts. Here, we analyzed 49 high- and low-grade gliomas previously classified as fusion-negative by FUSIP using an untargeted whole-transcriptome RNA sequencing approach with Oxford Nanopore Technologies (ONT) long-read sequencing. This enabled transcriptome-wide fusion discovery of additional known and potentially novel oncogenic GFs beyond panel constraints. Long-read sequencing further allowed direct resolution of full-length fusion transcripts and their associated isoform structures. By integrating GF detection with isoform-level transcript analysis, we identified fusion-associated transcript isoforms with alternative splicing patterns that aligned near reported GF breakpoints, including Show less
Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. Howev Show more
Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. However, adaptive changes in respiratory metabolism and molecular mechanisms in lung tissues of small mammals under extreme water shortage conditions remain unclear. This study hypothesized that small desert mammals can adapt to extreme water shortage environments by regulating the plasticity of lung tissue gene expression and respiratory metabolism. Using 29 wild-caught Siberian jerboas ( Show less
Atherosclerosis (AS) is a major underlying cause of cardiovascular diseases, with hypercholesterolemia, inflammatory responses, and macrophage polarization being established key contributors. The role Show more
Atherosclerosis (AS) is a major underlying cause of cardiovascular diseases, with hypercholesterolemia, inflammatory responses, and macrophage polarization being established key contributors. The roles of NLRP3 inflammasome activation and macrophage polarization in AS pathogenesis have garnered significant research interest. This study investigated the therapeutic potential of Schisandrol B (Sol B) against AS using an in vivo model of ApoE Show less
Arterial thrombectomy (AT) is a cornerstone in the treatment of acute ischemic stroke (AIS) due to large vessel occlusion. However, the optimal therapeutic time window and the best management strategy Show more
Arterial thrombectomy (AT) is a cornerstone in the treatment of acute ischemic stroke (AIS) due to large vessel occlusion. However, the optimal therapeutic time window and the best management strategy for patients presenting beyond the conventional 4.5-hour timeframe remain areas of active investigation and debate. This retrospective cohort study aimed to analyze the effect of timing of AT on recovery in AIS. We retrospectively analyzed 117 AIS patients admitted between January 2021 and January 2023. Participants were categorized into 3 groups: early AT (onset-to-AT < 4.5 hours), late AT (onset-to-AT ≥ 4.5 hours), and late AT + intravenous thrombolysis (IT). Outcomes compared included clinical efficacy, National Institutes of Health Stroke Scale (NIHSS) scores, serum levels of neurotrophic factors, brain-derived neurotrophic factor, vascular endothelial growth factor, residual stenosis, vessel reocclusion, 3-month mortality, and 1-month complications. The total effective rate was higher in the early AT and late AT + IT groups than in the late AT group. Pretreatment NIHSS scores and serum neurological marker levels were comparable across all groups. After treatment, the early AT and late AT + IT groups showed significantly lower NIHSS scores, higher serum levels of neurological markers, and improved treatment efficiency compared to the late AT group. Prognosis-related markers also indicated better outcomes in these 2 groups. Additionally, complications such as mucocutaneous ecchymosis, gastrointestinal bleeding, and intracranial bleeding were significantly reduced in the early AT and late AT + IT groups. AT within 4.5 hours of stroke onset improves efficacy, reduces neurological injury, and decreases complications. For patients presenting beyond 4.5 hours, combining AT with IT achieves comparable therapeutic benefits. Show less
l-Pipecolic acid (l-PA) and its hydroxylated derivatives (hydroxypipecolic acids, HPAs) are non-proteinogenic amino acids that serve as valuable chiral building blocks for pharmaceuticals, antibiotics Show more
l-Pipecolic acid (l-PA) and its hydroxylated derivatives (hydroxypipecolic acids, HPAs) are non-proteinogenic amino acids that serve as valuable chiral building blocks for pharmaceuticals, antibiotics, and natural products. Conventional chemical synthesis of these compounds often suffers from operational complexity, poor environmental compatibility, and insufficient stereochemical control, driving a shift toward biosynthetic approaches. This review covers recent advances in enzyme engineering and synthetic biology aimed at enabling sustainable and efficient production of l-PA and HPAs. For l-PA biosynthesis, various metabolic engineering strategies to enhance its production in microbes are introduced, and enzyme cascades, single enzyme strategy, and immobilized enzyme strategy involved in l-PA production are discussed. Regarding HPAs biosynthesis, which involves the regioselective hydroxylation of l-PA, their structural features, catalytic mechanisms, and recent progress in the biosynthesis of diverse HPAs, the protein engineering of proline hydroxylase is emphasized. Finally, we present future perspectives to accelerate the biosynthetic production of l-PA and HPAs. Show less
Colorectal cancer (CRC) remains a major global health challenge, underscoring the need for reliable biomarkers to improve prognosis and therapeutic stratification. In this study, we comprehensively in Show more
Colorectal cancer (CRC) remains a major global health challenge, underscoring the need for reliable biomarkers to improve prognosis and therapeutic stratification. In this study, we comprehensively investigated the expression pattern, clinical significance, molecular functions, and immunological implications of LINGO1 in CRC. Integrative analyses of TCGA and GEO datasets, together with validation in 72 clinical CRC samples, demonstrated that LINGO1 is markedly overexpressed in tumors and strongly associated with advanced clinicopathological features and poor patient outcomes. Functional experiments revealed that both knockdown of LINGO1 in SW480 and LoVo cells and overexpression of LINGO1 in HCT116 cells significantly modulate malignant phenotypes, including proliferation, migration, invasion, and angiogenic capacity. Transcriptome-wide and pathway enrichment analyses further indicated that high LINGO1 expression is linked to epithelial-mesenchymal transition, angiogenesis, Wnt/β-catenin signaling, and other oncogenic pathways. Immunogenomic profiling, supported by multiplex immunofluorescence staining, showed that elevated LINGO1 is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T-cell infiltration and diminished GZMB expression, alongside upregulation of multiple immune checkpoint molecules. Collectively, our findings identify LINGO1 as a novel oncogenic driver and immune-modulatory biomarker in colorectal cancer, with potential value for prognosis and therapeutic targeting. Show less
Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the Show more
Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the treatment of HS is of critical importance. Using summary statistics from the eQTLGen Consortium, Decode database, and FinnGen cohort, we conducted transcriptome-wide and proteome-wide Mendelian randomization (MR) to discover potential pharmacological targets against HS, with subsequent validation via RNA sequencing. Upstream regulators and downstream mechanisms were further investigated to better understand the roles of the pathogenic gene. Drug prediction, molecular docking, and molecular dynamics (MD) simulation were employed to estimate the value of potential drugs for HS. A high level of fibroblast growth factor receptor 1 (FGFR1) significantly increased the risk of HS according to transcriptome-wide (P = 0.011) and proteome-wide MR (P = 0.002) analyses. RNA-seq further validated the high expression of FGFR1 in HS. Gene-gene interaction network and enrichment analysis identified FGFR1 as the core gene driving the progression of HS, highlighting multiple biosynthetic processes. Pharmacological evaluation of candidate drugs predicted stable binding between Ro-4396686 and FGFR1. Our findings suggest that FGFR1 can serve as promising target for optimizing HS treatments, potentially reducing the costs of drug development. Show less
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have revolutionized cancer therapy, yet primary and acquired resistance remain major clinical obstacles. Dysregulated angiogenesis fue Show more
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have revolutionized cancer therapy, yet primary and acquired resistance remain major clinical obstacles. Dysregulated angiogenesis fuels the development of an immunosuppressive tumor microenvironment, while crosstalk between immunity and angiogenesis further propels tumor immune evasion and treatment resistance. The present study aimed to establish a penpulimab-resistant model, delineate anti-PD-1 resistance traits via single-cell RNA sequencing, and unravel the precise mechanisms through which anlotinib-an anti-angiogenic agent-mitigates penpulimab resistance. These findings offer insights to guide clinical management of immune-pretreated patients. Single-cell sequencing analyses demonstrated that anlotinib reverses penpulimab resistance by reprogramming the tumor immune microenvironment, thereby boosting PD-1 blockade efficacy via modulation of immune infiltration and tumor signaling pathways. Identifying Apoe⁺ M2 macrophages, Srgn⁺ M1 macrophages, and Cxcl2⁺ T cells provides key cellular and molecular targets for developing clinically actionable immunotherapies. Taken together, this work validates the preclinical potential of anlotinib combined with immunotherapy for immunotherapy-resistant tumors. Show less
To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the w Show more
To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencing data from 280 CHH probands, we identified 15 potential splice-site variants in CHD7, ANOS1 and FGFR1 by using in silico software. The functional consequences of these variants were analyzed by the minigene assay or RT-PCR analyses of RNA taken from the peripheral lymphocytes. Detailed phenotyping was performed in the CHH patients harboring deleterious variants and their available family members. 11 out of 15 potential splice-site variants were demonstrated to cause mis-splicing, resulting in loss of function through deletion, insertion or frameshift of amino acids in the proteins. Most patients with deleterious splice-site variants in CHD7, ANOS1, FGFR1 presented with gene-specific non-reproductive phenotypes, confirming the pathogenic contribution of these variants to CHH. Our study indicated that splice-site variants in CHD7, ANOS1, FGFR1 underlie the genetic basis of ~3.9% of CHH patients, warranting the inclusion of potential splice-site variants for genetic diagnosis and counseling of CHH. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current ther Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD. Show less
Hongbin Zhang, Li Qiao, Fan Yang+5 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Elucidating effective components and mechanisms of traditional Chinese medicine (TCM) formulas remains a critical challenge for modernization. ErShiWei RouDouKou Pills (ESWRDK), a Tibetan formula with Show more
Elucidating effective components and mechanisms of traditional Chinese medicine (TCM) formulas remains a critical challenge for modernization. ErShiWei RouDouKou Pills (ESWRDK), a Tibetan formula with cardiovascular potential, lacks systematic exploration of its anti-atherosclerotic (AS) material basis and mechanisms. A novel six-stage cascade focused strategy integrating three-dimensional filtering mode, qualitative characterization, multi-component quantification, anti-AS efficacy, multi-lipidomics and bioactive compounds evaluation was proposed, advancing TCM research by holistic and multi-layered approach. UHPLC-MS combined with mass defect-ion intensity filtering (MD-ITF), DPIs, Nl and FBMN employed for profiling. Nine characteristic components were quantitated. A 12-week high-fat diet was fed to ApoE Firstly, the MD-ITF method and structural classification was established for complicated matrix. Secondly, 426 chemical components including 74 low-abundance were characterized. Thirdly, 9 characteristic components were quantified, and content distribution were profiled. Fourthly, ESWRDK reduced lipids, inflammation, and aortic plaques in AS mice. Fifthly, a total of 38, 23 and 48 differential biomarkers were identified predominantly linked to glycerophospholipids (GP) metabolism. WB confirmed ESWRDK downregulated hepatic PLA2, upregulated p-AMPK/AMPK and PPAR-α, and suppressed SREBP-1, orchestrating and mitigating lipid dysregulation. Finally, dehydrodiisoeugenol and agarotetrol bound PLA2, formed stable 1:1 static quenchingand inhibited PLA2 activity in vitro. A novel six-stage cascade-focused strategy was successfully established to elucidate ESWRDK's anti-AS mechanisms, offering feasible paradigm for advancing modernization of TCM. Show less
The neurovascular unit (NVU) represents a multicellular functional ensemble pivotal to the preservation of cerebral homeostasis, encompassing endothelial cells, pericytes, glial cells (astrocytes, mic Show more
The neurovascular unit (NVU) represents a multicellular functional ensemble pivotal to the preservation of cerebral homeostasis, encompassing endothelial cells, pericytes, glial cells (astrocytes, microglia, oligodendrocytes), and neurons. This complex orchestrates the regulation of blood-brain barrier (BBB) integrity, cerebral blood flow (CBF), and the metabolic microenvironment requisite for neuronal viability and functional competence. Accumulating lines of evidence have underscored that NVU dysfunction constitutes a critical early pathological event in neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VaD). The present review summarizes the structural composition and core physiological functionalities of the NVU, with particular emphasis on the emerging role of lipid metabolism dysregulation in mediating NVU impairment-an aberrant process encompassing lipid droplets, apolipoprotein E (APOE), ATPase phospholipid transporting 11B (ATP11B), triggering receptor expressed on myeloid cells 2 (TREM2), and ATP-binding cassette (ABC) transporters. We further delineate the mechanisms by which disrupted lipid homeostasis elicits neuroinflammation, amplifies oxidative stress, impairs amyloid-β (Aβ) clearance, and precipitates BBB breakdown, ultimately culminating in cognitive decline. Simultaneously, this review examines controversies within the field, such as the specific role of apolipoprotein E ε4 allele (APOE4) in disease and highlights the significant pathophysiological differences between preclinical animal models and human diseases. Therapeutic strategies targeting lipid metabolism or the blood-brain barrier still face considerable challenges in clinical translation. Meanwhile, emerging tools such as lipidomics contribute to systematically analyzing the associated dysregulated lipid networks, thereby aiding in the identification of novel therapeutic targets. Show less
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term tre Show more
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term treatments of the existing drugs suffered safety concerns. Show less
Physical activity (PA) is known to enhance brain health; however, prior research has predominantly concentrated on the total volume of PA, often overlooking the frequency of daily PA on an hourly basi Show more
Physical activity (PA) is known to enhance brain health; however, prior research has predominantly concentrated on the total volume of PA, often overlooking the frequency of daily PA on an hourly basis. This prospective cohort study examined 69,393 middle-aged and older adults, utilizing wrist-worn accelerometer data to assess PA. A novel PA frequency score was developed, which integrated light PA (LPA) and moderate-to-vigorous PA (MVPA) across 18 hourly segments (6:00 AM-12:00 AM). Participants were categorized into Inactive, Active, and Very Active groups. After adjusting for potential confounders, it was observed that individuals in the Active and Very Active groups exhibited a reduced risk of developing brain disorders such as dementia, anxiety, depression, migraine, Parkinson's disease, and stroke over a median follow-up period of 7.41 years. Magnetic Resonance Imaging (MRI) findings demonstrated that each unit increase in the PA frequency score correlated with a 51.55 mm Show less
Aging worsens Alzheimer's disease (AD) peripheral metabolism and central pathology, yet few interventions are effective when started late. Methionine restriction (MR) induces the hepatokine FGF21 and Show more
Aging worsens Alzheimer's disease (AD) peripheral metabolism and central pathology, yet few interventions are effective when started late. Methionine restriction (MR) induces the hepatokine FGF21 and may protect brain function, but its efficacy and mechanisms when started late are unclear. Fourteen-month-old male APP/PS1 mice received 17 weeks of MR (0.17% methionine); behavioral, histological, and molecular assays were performed and hippocampal FGFR1 was knocked down by adeno-associated virus. Late-life MR improved peripheral glucose/lipid profiles, reduced Aβ deposition, preserved synaptic markers, and suppressed neuroinflammation. MR-induced hepatic FGF21 and brain FGFR1-AMPKα signaling to inhibit NFκB; hippocampal FGFR1 knockdown abolished MR's neuroprotective effects while leaving peripheral metabolic changes intact. Even when initiated in late life, MR robustly reduces AD pathology via the hepatic FGF21-brain FGFR1 axis, independent of peripheral metabolic changes. These preclinical findings position MR and FGF21-FGFR1 axis as actionable late-life intervention targets with potential for clinical translation. Show less
Older adults' social participation is associated with frailty, but the transition patterns and their relationship with frailty remain unclear. This longitudinal study aims to explore the latent classe Show more
Older adults' social participation is associated with frailty, but the transition patterns and their relationship with frailty remain unclear. This longitudinal study aims to explore the latent classes and transition patterns of social participation in older adults with chronic non-communicable diseases and to assess their relationship with subsequent frailty. The data set from the China Health and Retirement Longitudinal Study (CHARLS) in 2018 (T1) and 2020 (T2) was analyzed, including 4793 older adults. Latent profile analyses (LPA) and latent transition analyses (LTA) were employed to identify latent classes and the transition probabilities of social participation at T1 and T2. The ANCOVA was employed to examine the frailty index at T2 was compared across transition patterns. The LPA results supported a 4-class model labeled as inactive group, voluntary group, social interaction group, and omni-engaged group. The probability of transition from the other groups to the inactive group was significant (33.3 %, 53.8 %, 54.4 %). Age, residence, marital status, and other demographic characteristics can significantly impact transition patterns. However, after controlling for baseline frailty and other covariates, transition patterns were not significantly associated with T2 frailty levels. The short-term (two-year) effect of qualitative shifts in social participation on frailty may be limited when pre-existing health status is accounted for. Future interventions should prioritize sustained engagement and investigate the longer-term effects of both qualitative and quantitative changes in social participation. Show less
Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adv Show more
Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance. PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes. GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement. Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine. The online version contains supplementary material available at 10.1186/s11658-026-00867-2. Show less
PICALM∶∶MLLT10 fusion gene-positive precursor B-cell acute lymphoblastic leukemia(pro-B-ALL)is clinically rare.This article reports the case of a 29-year-old female patient who presented a mediastinal Show more
PICALM∶∶MLLT10 fusion gene-positive precursor B-cell acute lymphoblastic leukemia(pro-B-ALL)is clinically rare.This article reports the case of a 29-year-old female patient who presented a mediastinal mass.Diagnostic investigations confirmed PICALM∶∶MLLT10 fusion gene-positive pro-B-ALL.The patient sequentially received radiotherapy and multiple lines of chemotherapy but developed short-term drug resistance and lineage change,progressing to mixed-phenotype acute leukemia.A review of relevant literature was conducted to analyze its pathogenesis and molecular characteristics,aiming to provide references for clinical diagnosis and treatment. Show less
Hypercholesterolemia and a high-fat diet promote 2 macrophage subtypes involved in atherosclerosis by inducing lipid droplet accumulation in foamy macrophages (FMs) and inflammatory activation in non- Show more
Hypercholesterolemia and a high-fat diet promote 2 macrophage subtypes involved in atherosclerosis by inducing lipid droplet accumulation in foamy macrophages (FMs) and inflammatory activation in non-foamy macrophages (NFMs). MicroRNAs are key regulators of macrophage function; for instance, The role of Unlike FMs, NFMs are primarily located in the plaque core and show higher Show less
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don Show more
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less
Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associ Show more
Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3 Overexpression of human ApoC3 in ApoC3 ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters. Show less
The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reac Show more
The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. Show less
The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progre Show more
The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progression of PD. This study aimed to investigate the specific molecular mechanism underlying the promotion of PD progression by METH through the regulation of microglial polarization and glycolysis. METH-induced C57BL/6 mice and BV2 cells were used to construct PD-like neurotoxicity animal and cell models for experimental investigation. Behavioral tests, immunohistochemistry and Nissl staining were used to assess the behavioral ability and neuronal damage of the animals. The levels of related proteins, inflammatory cytokines and glycolysis were detected using immunofluorescence, ELISA, Western blotting, and CCK-8 assays. METH treatment significantly promoted behavioral disorders in PD mice, reduced the number of TH-positive neurons, and aggravated neuronal damage in the substantia nigra (SN). In addition, METH decreased the M2 marker proteins Arg-1 and CD206 and increased the M1 marker proteins iNOS and CD86; the proinflammatory cytokines TNF-α, IL-β, and IL-6; and glucose uptake, glucose consumption and lactic acid production, thus promoting M1 polarization and glycolytic activity in BV2 cells. In terms of the underlying molecular mechanism, METH treatment significantly increased the level of LPA. METH promotes LPA expression via upregulation of LIPH expression, and activates the PI3K/AKT pathway. Knockdown of LIPH or treatment with BrP-LPA reduces the ability of METH to promote M1 microglial polarization and glycolytic activity. Furthermore, the addition of the PI3K/AKT signaling pathway activator 740 YP weakened the inhibitory effect of BrP-LPA on the above process. METH may promote M1 polarization and glycolytic activity in microglia by activating LIPH/LPA/PI3K/AKT signaling, thus promoting the progression of PD. Show less
The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether Show more
The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable. To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial. A prospective longitudinal cohort study. Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3). 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data. Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1-6 additional Aβ PET scans every 1.5-3 years. Those < 5 CL were classified as PET- and 5-20 CL as PET At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PET Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5-20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials. Show less
The quality of informal care for people with dementia (PwD) has gained increasing importance, as most PwD prefer home-based care over institutional placement. However, evidence-based intervention prog Show more
The quality of informal care for people with dementia (PwD) has gained increasing importance, as most PwD prefer home-based care over institutional placement. However, evidence-based intervention programs tailored to distinct care quality profiles remain limited. Additionally, the absence of clear thresholds to identify PwD receiving low-quality informal care poses a challenge for research and clinical practice. Thus, this study aimed to identify the profiles of quality of care (QoC) among informal caregivers of PwD, explore influencing factors of different profile, and determine the optimal cut-off score of the Exemplary Care Scale (ECS). A cross-sectional survey was conducted. A total of 213 dyads of PwD and their informal caregivers were recruited from memory clinic, rehabilitation clinic, and neurological clinic of a tertiary hospitals and communities in Wuhan, Hubei, China, between July 15, 2023, and July 14, 2024. Latent profile analysis (LPA) was employed to identify QoC profiles. Multinomial logistic regression was performed to explore influencing factors of profile membership. Receiver Operating Characteristic (ROC) analysis was conducted to determine the ECS cut-off score. Three distinct QoC profiles were identified: high (24.41%), moderate (44.60%), and low (30.99%). Among informal caregivers, lower monthly income, insufficient social support, and higher perceived overload were associated with low QoC profile, whereas, better quality of pre-illness relationship with PwD and greater activities of daily living (ADL) of PwD were associated with high QoC. ROC analysis yielded an optimal ECS cut‑off score of 15, with high sensitivity (0.993) and specificity (0.955). This study identified three distinct QoC profiles among caregivers of PwD, underscoring the heterogeneity of informal care quality. The identified predictors and the validated ECS cut‑off score of 15 provide an empirical basis for developing tailored screening tools and targeted interventions for high‑risk caregiver subgroups. Show less