Journal of advanced research最新文献

Introduction: Magnesium (Mg) alloys, with favorable mechanical properties, biodegradability, and biocompatibility, are promising materials for cerebrovascular stents. However, rapid degradation, delayed endothelialization, and ischemia-reperfusion-induced microvascular injury limit their clinical application.

Objectives: This study aims to develop a composite coating that integrates corrosion inhibition and drug delivery functions to achieve degradation regulation, rapid endothelialization, and vascular protection of Mg-based cerebrovascular stents.

Methods: The optimal corrosion inhibitor was screened from nineteen amino acid-derived Schiff bases using quantum chemical calculations and corrosion inhibition experiments. The selected Schiff base was immobilized on the Mg alloy surface via silane modification to construct a corrosion-resistant coating (Silane-loaded tryptophan Schiff base coating, defined as PMSB-X), whose performance was evaluated by electrochemical measurements and immersion tests. Subsequently, a carbon quantum dot-mediated nanodrug layer (NP-X) integrating sulfonated hyaluronic acid (S-HA) and Shenmai injection (SMI) was structured via ultrasonic atomization. The biological performance of the coating was systematically assessed through in vitro cell studies and in vivo animal experiments.

Results: Tryptophan-derived Schiff base (SB-Trp) exhibited the highest corrosion inhibition efficiency (81.5%). The PMSB-5 coating constructed based on SB-Trp reduced the corrosion current density of Mg alloy to 9.96 × 10^-9 A·cm^-2, indicating significantly enhanced corrosion-inhibition capability and effective regulation of degradation kinetics. The NP-10 coating exhibited multiple biological functions, including reducing the hemolysis rate, inducing macrophage M2 polarization, inhibiting the proliferation of smooth muscle cells (SMCs) while promoting their contractile phenotype, and promoting the growth of human umbilical vein endothelial cells (HUVECs). Furthermore, the coating activated human cerebral microvascular endothelial cells (HCMECs), indicating pro-angiogenic potential. Animal experiments confirmed that the NP-10 coating simultaneously achieved degradation regulation and suppression of tissue hyperplasia and inflammation.

Conclusion: This bifunctional coating enables delayed Mg degradation, promotes endothelialization, and provides neurovascular protection, provides an important strategy for promoting the functional design of neurovascular treatment devices.

Introduction: Accelerated brain aging, reflected by greater brain-age-gap (BAG), has been linked to increased susceptibility to neurodegenerative and psychiatric disorders, yet its genetic underpinnings, modifiable factors, and broader health consequences remain undetermined.

Objectives: To precisely estimate brain age and systematically investigate the genetic architecture, lifestyle and environmental determinants, and systemic disease risks associated with accelerated brain aging.

Methods: Using routinely collected magnetic resonance imaging data, we applied a DenseNet model to estimate brain age and calculated BAG as a biomarker of aging pace. We analyzed 500 K whole genome sequencing data from UK Biobank to elucidate the genomic architecture of BAG, capturing both common and rare variants, and used AlphaFold3 to assess protein structural alterations induced by missense mutations. We implemented multiple linear regression to examine associations of BAG with demographics, lifestyle, environment, and telomere length. We conducted a Phenome-wide association study (PheWAS) to investigate multisystem disease risk linked to BAG.

Results: Among a total of 42,385 participants (mean [SD] age, 65 [7.7] years; 52.8% female), the brain age model estimated BAG with a mean absolute error of 2.49 years. Whole genome sequencing identified two novel BAG-related noncoding variants, rare missense variants in KIAA0513 with a suggestive association, and significant enhancer DNase Hypersensitivity sites (DHS) of PAX6. Structural modeling revealed protein alterations from missense mutations, suggesting potential mechanisms of accelerated brain aging. In addition, unhealthy lifestyles, adverse environmental exposures, and shorter telomere length were linked to BAG. PheWAS analysis showed that 69 disease were significantly associated with BAG (HRs: 1.03-1.39 per BAG year), with mental and neurological disorders ranking highest, followe by cardiovascular and metabolic diseases.

Conclusion: This study integrates neuroimaging, genomics, questionnaire, and medical records to provide a comprehensive framework for understanding the multifactorial mechanisms of brain aging and guiding precision prevention strategies.

Introduction: Spinocerebellar ataxia type 3 (SCA3) is caused by ATXN3 CAG expansions, yet repeat length explains only 50-70% of age at onset (AO) variability, suggesting the influence of additional genetic modifiers. We investigated whether transcription factor 4 (TCF4), harboring an intronic CAG repeat and highly expressed in SCA3-vulnerable regions, modifies AO.

Objectives: To explore the modifying effect of TCF4 intronic CAG repeats on SCA3 AO and investigate the underlying molecular mechanisms.

Methods: We conducted a cross-sectional study of 1,439 genetically confirmed Chinese SCA3 individuals (1,212 symptomatic, 227 asymptomatic). TCF4 CAG repeats were categorized as Short (7-13), Medium (14-39), and Long (≥40). Statistical frameworks included hierarchical regression, survival analyses, and extensive sensitivity testing. Functional validation was performed in HEK293T cells stably expressing normal (20Q) or pathogenic (84Q) ataxin-3, transfected with CDS-only or intron-retaining TCF4 constructs harboring 11, 24, or 100 intronic CTG repeats.

Results: TCF4 showed no direct effect on AO but significantly modulated the ATXN3-AO relationship. Regression analyses revealed length-dependent amplification of the ATXN3 effect across TCF4 groups (-2.04 to -3.18 years/repeat). Modification was most pronounced in early-onset patients (AO ≤ 25; Δadjusted R² = 0.048, p < 0.001). Survival analyses and extensive sensitivity tests consistently confirmed these findings. Mechanistically, TCF4 and ataxin-3 exhibited direct physical interaction. Notably, we identified a bidirectional pathogenic synergy: expanded ataxin-3 synergistically exacerbated TCF4 CTG length-dependent splicing defects, protein reduction, and RNA foci formation, while TCF4 expansion reciprocally promoted mutant ataxin-3 aggregation.

Conclusion: TCF4 intronic CAG repeat length-dependently modifies SCA3 age at onset through bidirectional molecular synergy with expanded ataxin-3. These findings reveal a novel intronic genetic modifier and establish the pathogenic interaction between non-coding and coding repeat expansion loci as a disease-modifying mechanism in repeat expansion disorders.

Introduction: Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive.

Objectives: To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism.

Methods: To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues.

Results: THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice.

Conclusion: Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications.

Background: Drought is a major constraint in arid and semi-arid regions, leading to a reduction in soil organic carbon (SOC) by suppressing microbial activities and limiting organic matter inputs. The decrease in soil health frequently threatens agricultural productivity and ecosystem sustainability. Arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) can offer a sustainable strategy to enhance SOC in drylands.

Aim of review: While the sole effects of AMF or PGPR are often studied, their interactive effects on global SOC sequestration under drought conditions remain systematically unexplored. This review aims to address this critical knowledge gap by conducting, for the first time, a comprehensive meta-analysis of global studies from 1998 to 2025. The objective is to quantitatively evaluate the interaction effect of AMF and PGPR co-inoculation on SOC dynamics and its underlying mechanisms in adaptation to drought environments.

Key scientific concepts of review: Based on 989 observations, the meta-analysis reveals that both single and co-inoculation of AMF and PGPR significantly improve SOC levels. This increase is driven by enhancing key SOC fractions, including microbial biomass carbon, easily oxidizable carbon, dissolved, light fraction, and particulate organic carbon accumulation. The AMF-PGPR co-inoculation strategy is particularly effective across diverse conditions, significantly enhancing SOC in coarse (46%) and medium-textured (54%) soils across acidic (48%) and alkaline (48%) pH in various cropping systems by improving root and shoot traits. Different genera of AMF (Glomus, Rhizophagus) and PGPR (Bacillus, Pseudomonas) synergetically enhance SOC through glomalin production (48-51%), hyphal architecture (122%), phytochrome production (52%), and microbial enzymatic activities. AMF and PGPR co-inoculation enhances SOC accumulation by improving enzymatic activities (39-90%) and plant traits (44-251%). This meta-analysis concludes that AMF-PGPR co-incoulation is a sustainable strategy for increasing global soil carbon sequestration, thereby improving soil health and crop productivity in dryland ecosystems.

Introduction: Lithium manganate (LMO) is a new type of pollutant that is extensively applied in the manufacture of lithium-ion batteries. Accumulating evidence indicates that both manganese (Mn) and lithium (Li) can cross the blood-brain barrier and accumulate within the hippocampus. However, the neurotoxic effects of LMO on hippocampal core functions and the involved molecular mechanisms are still unclear.

Objectives: This study observed whether LMO exposure impairs hippocampus-dependent learning and memory in mice and investigated related mechanisms and intervention strategies.

Methods: A whole-body inhalation exposure system was employed to simulate occupationally relevant in vivo exposure to LMO, with mice exposed to concentrations of 0, 1.35, 13.5, and 135 mg/m³ for 28 and 45 days, corresponding approximately to 3 and 5 human years. In parallel, in vitro co-exposure models were established using HT-22 cells and primary hippocampal neurons treated with Mn and Li. Neurobehavioral, neuropathological, live-cell imaging-based assays were used to assess learning and memory impairment, neuronal damage, and retrograde axonal transport dysfunction. RNA-sequencing and molecular biology approaches were conducted to explore and validate mechanisms. Mid1 silencing/knockdown and valproic acid (VPA) treatment were used to assess whether modulation of Mid1-related changes attenuates LMO-induced neurotoxicity.

Results: The results demonstrated that LMO exposure impaired learning and memory in mice. Mechanistically, LMO or Mn and Li co-exposure up-regulates the E3 ubiquitin ligase Mid1 which promotes the degradation of dynein light chain family members Dynlrb2 and Dynlt4 through the ubiquitin-proteasome pathway. This disruption impairs retrograde axonal transport in hippocampal neurons, resulting in neuronal injury and ultimately compromising learning and memory function in mice. Suppression of Mid1 ,or VPA treatment significantly improved the observed neuronal damage and the expression levels of factors related to axonal retrograde transport.

Conclusion: This study indicates that LMO inhalation exposure is associated with learning and memory deficits and hippocampal neuronal injury, accompanied by Mid1-related ubiquitin-proteasome alterations and disrupted retrograde axonal transport.

Introduction: Osteoporosis, a "silent killer" among the elderly, is marked by progressive bone loss and microstructural deterioration. Oligopeptides derived from black bean, particularly tetrapeptides, have shown notable osteogenic potential, yet their therapeutic roles in regulating bone metabolism and preventing osteoporosis remain unclear.

Objectives: This study explored the osteoanabolic effects of black bean-derived tetrapeptides and elucidated their underlying mechanisms.

Methods: In vitro assays were conducted using MC3T3-E1 pre-osteoblasts derived from mouse calvaria to assess osteogenic differentiation upon tetrapeptide treatment. Six black bean tetrapeptides were evaluated, including KIGT, KGVG, KTGV, SIKL, KLGT, and SLKL. In vivo efficacy was evaluated in an ovariectomized mouse model of osteoporosis via intragastric administration. Based on molecular docking, the mechanisms were explored using Western blotting and immunofluorescence and validated through pathway inhibitor and siRNA knockdown experiments.

Results: All six tetrapeptides significantly stimulated the osteogenic differentiation of MC3T3-E1 pre-osteoblasts, particularly during early osteogenesis. Notably, the peptides all exhibited osteogenic effects at low doses (0.1 μM), although their optimal concentrations varied. Mechanistic studies revealed a shared anabolic pathway among the tetrapeptides, in which lysine residues may play a pivotal role in mediating their similar interactions with bone morphogenetic protein-2 (BMP-2), thereby activating the BMP-2/Smad signaling. Furthermore, this potent osteoanabolic efficacy was confirmed in osteoporotic mice, where a 10-week treatment with black bean oligopeptides (<1 kD), KIGT, and KGVG (100 mg/kg) markedly attenuated bone loss.

Conclusion: Lysine-containing tetrapeptides derived from black bean exert direct osteoanabolic activity by targeting BMP-2/Smad signaling in osteoblasts. These findings support their potential as novel anabolic candidates against osteoporosis, paving the way for the development of oligopeptide-based therapies targeting bone health.

Introduction: Viruses are abundant biological entities within the gastrointestinal tract (GIT) of ruminants. Current understanding is extensive for bacterial and archaeal communities, but limited for viral communities.

Objectives: The study aimed to investigate viral diversity, virus-host interactions and ecological functions of viruses across GIT regions and ruminant species.

Methods: We collected 373 short-read and long-read metagenomes from 10 GIT regions of seven ruminant species, combining Illumina, PacBio HiFi, and Nanopore sequencing. Viral contigs were identified using sequence homology, viral hallmark gene and machine learning, and employed to uncover community assembly of spatial heterogeneity by analyzing virus-host linkage, lifestyle, and auxiliary metabolic genes (AMGs).

Results: We constructed a Ruminant Gastrointestinal Virome Catalog (RGVC) comprising 43,981 vOTUs, revealing that viral communities were remarkably diverse and mainly driven by the GIT regions rather than by the ruminant species. Virus-host linkage analysis identified 4603 putative prokaryotic hosts across 34 classes for 5954 host-linked viruses, along with robust correlation (R² = 0.91) observed between abundances of prokaryotic hosts and host-linked viruses across GIT regions. The lysogenic lifestyle was a dominant feature, with integrases being the predominant lysogenic-specific genes. We identified 864 high-confidence AMGs in lysogenic viruses that are annotated as key genes for polysaccharide degradation, glycolysis, and the Wood-Ljungdahl pathway, indicating a putative role for the viruses in supporting these host metabolic functions. The metabolic features of host-linked viruses were further verified by genomic context of selected AMGs of GH10, GPI and FHS with target function.

Conclusion: These findings suggest that the GIT viral communities exhibit spatial heterogeneity with distinct virus-host interactions, and offer new perspectives on maintenance of complex ecological and nutritional functions in ruminant GIT.

Introduction: Rapeseed (Brassica napus L.) is a major oilseed crop with considerable potential for improving saline-alkali soils, yet the molecular mechanisms underlying its salt tolerance remain unclear.

Objectives: This study investigates the functional roles and regulatory mechanisms of glycine-rich protein 3 (BnaGRP3) in rapeseed under salt stress.

Methods: We employed molecular genetics, phenotypic and biochemical evaluation of transgenic rapeseed and Arabidopsis, transcriptome sequencing, protein interaction assays including immunoprecipitation-mass spectrometry (IP-MS), yeast two-hybrid (Y2H), luciferase complementation (LCA), and bimolecular fluorescence complementation (BiFC) assays, gene expression analysis by RT-qPCR, and hydrogen peroxide (H₂O₂) permeability assays conducted in yeast.

Results: BnaGRP3 was induced by salt stress and enhanced salt tolerance. Transcriptome analysis revealed that BnaGRP3 modulated expression of ion transporters under salt stress, especially NHX1 and SKOR. BnaGRP3 physically interacted with four plasma membrane intrinsic proteins (BnaPIPs). Overexpression of these BnaPIPs improved salt tolerance in Arabidopsis and increased H₂O₂ tolerance when expressed in yeast. In addition, these BnaPIPs formed both homomeric and heteromeric complexes, suggesting they may facilitate H₂O₂ permeability.

Conclusions: BnaGRP3 enhances salt tolerance by maintaining Na⁺/K⁺ homeostasis and, through its interactions with BnaPIPs, may participate in the regulation of H₂O₂ balance·H₂O₂ potentially serves as a bridge linking BnaGRP3-mediated ion homeostasis and redox regulation. The previously uncharacterized BnaGRP3-BnaPIP module broadens the mechanistic framework of GRP-mediated salt stress responses, thereby expanding our understanding of salt tolerance mechanisms in Brassica napus.