Background: Mast cells communicate with cardiac fibroblasts in inflammatory disorders, but whether they are key regulators of fibrotic remodeling after myocardial ischemia/reperfusion (I/R) remains unclear. Arachidonate 5‑lipoxygenase (ALOX5; 5‑lipoxygenase) is the rate‑limiting enzyme for leukotriene (LT) biosynthesis, and mast cells are an important cellular source of LTs. The contribution of mast cell–derived ALOX5–LT signaling to post‑I/R myocardial fibrosis is not fully defined. Methods: We analyzed a human post–myocardial infarction single‑nucleus RNA‑sequencing dataset (EGAS00001006330) to quantify mast cell abundance and ALOX5 expression in fibrotic myocardium. We generated mast cell–specific ALOX5 knockout mice (ALOX5flox/floxCpa3Cre/+) and subjected the male mice to 30 min ischemia followed by 2 or 4 weeks of reperfusion. Cardiac function, mast cell infiltration, myocardial LT levels, and fibrosis were assessed. Mechanistic studies in bone marrow–derived mast cells (BMMCs) tested how tumor necrosis factor‑α (TNF‑α) regulates ALOX5 subcellular localization and LT production. The effects of LTs on cardiac fibroblast proliferation, migration, and myofibroblast differentiation as well as associated signaling pathways were evaluated. Findings: Human snRNA‑seq analysis showed increased mast cell representation and higher ALOX5 transcription in fibrotic regions after myocardial infarction. In mice, mast cell-specific ALOX5 deletion reduced mast cell accumulation, decreased local LT levels within fibrotic myocardium, attenuated myocardial fibrosis, and improved cardiac function after I/R. TNF‑α promoted ALOX5 colocalization with 5‑lipoxygenase–activating protein (FLAP) at the nuclear envelope in BMMCs, enhancing synthesis and release of LTB4 and cysteinyl leukotrienes (CysLTs). These LTs activated leukotriene receptors on cardiac fibroblasts and engaged NF‑κB, AKT, and STAT3 signaling to drive fibroblast proliferation, migration, and myofibroblast differentiation. Genetic deletion or pharmacological inhibition of ALOX5 in mast cells suppressed LT production and blunted fibroblast activation. Interpretation: TNF‑α–driven activation of the mast cell ALOX5–LT axis amplifies pro‑fibrotic fibroblast responses and contributes to adverse post‑I/R cardiac remodeling. Targeting mast cell ALOX5 represents a potential therapeutic strategy to limit leukotriene‑mediated fibroblast activation and reduce post‑I/R myocardial fibrosis.

Xuefu Zhuyu Capsule (XFZY) demonstrated potential in alleviating post-stroke depression (PSD), a condition whose underlying mechanisms may involve the gut-brain axis. This study aimed to explore the therapeutic effects of XFZY on PSD and its possible modulation of the gut microbiota-gut-brain axis in a rat model. Wistar rats were randomly assigned to sham, PSD, three XFZY dose (0.216, 0.432, 0.864 g/kg), and fluoxetine (1.80 mg/kg) groups (n = 12 per group). The PSD model was established using transient middle cerebral artery occlusion (t-MCAO) combined with chronic unpredictable mild stress (CUMS), followed by 28 days of XFZY administration. In a separate experiment, gut microbiota was depleted via antibiotic cocktails, with rats divided into sham, PSD, XFZY medium Dose (XFM), pseudo-germ-free (PGF) and PGF + XFM (PGFX) groups. Behavioral tests indicated that XFZY ameliorated depressive-like behaviors, with the medium dose (0.432 g/kg) showing the most significant effect. Histological analysis using hematoxylin and eosin (H&E) and Nissl staining revealed that XFZY alleviated colonic and neuronal damage. Furthermore, 16S rRNA sequencing and gas chromatography revealed that XFZY modulated gut microbiota composition, increased species richness, and elevated levels of short-chain fatty acids such as acetic acid, propionic acid, and butyric acid. Enzyme-Linked Immunosorbent Assay (ELISA) results showed that XFZY reduced pro-inflammatory cytokines - interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), while immunohistochemistry indicated enhanced intestinal barrier function and reduced neuroinflammation. Furthermore, after depletion of gut microbiota using antibiotic cocktails, these therapeutic effects of XFZY were abolished. In summary, XFZY may alleviate PSD by modulating the gut microbiota and regulating the gut-brain axis, offering a promising direction for future therapeutic research.

BackgroundDiabetes-induced cognitive impairment (DCI), with its incompletely elucidated pathological mechanisms, currently lacks FDA-approved therapeutic agents in clinical practice. The traditional Chinese medicine pair Zhimu-Huangbo (ZMHB) exhibits neuroprotective and immunomodulatory effects, but its role in DCI via neuroimmune crosstalk is unclear. PurposeThis study aims to elucidate the pathogenesis of DCI from the perspective of neuroimmune interactions and explore the therapeutic effect of ZMHB, to provide new strategies for the prevention and treatment of DCI.MethodsIn this study, a mouse model of type 2 diabetes mellitus (T2DM) was established using a high-fat diet combined with streptozotocin (STZ), followed by intervention with ZMHB for 8 weeks to evaluate its effect on cognitive function improvement. Single-cell sequencing was performed to screen the key pathological processes and potential mechanisms underlying the effects of ZMHB. Behavioral assessment and immunofluorescence staining were used to detect cognitive function, neuronal CCL3 expression, brain infiltration of CCR5⁺CD8⁺ T cells, and the intervention effect of ZMHB, with reverse validation conducted using a CCR5 antagonist. In addition, UPLC/Q-TOF/MS was applied to identify the active components of ZMHB, and the mechanism by which it inhibits CCL3 expression was further explored in vitro.ResultsThe results showed that ZMHB significantly ameliorated cognitive impairment and prevented neuronal apoptosis in T2DM mice and the Single-cell RNA-seq revealed that ZMHB markedly modulates T cell receptor and chemokine signaling pathways. Specifically, ZMHB downregulated T2DM mice neuronal CCL3 expression, thereby disrupting neuron-CD8+ T cell crosstalk and reducing brain infiltration of CCR5+ CD8+ T cells. Moreover, CCR5 antagonism prevented brain infiltration of CCR5+ CD8+ T cells and reversed cognitive impairment in T2DM mice. In vitro screening assays identified berberine as the principal bioactive constituent of ZMHB that attenuates neuronal CCL3 expression by inhibiting activation of the non-canonical NF-κB2 pathway.ConclusionThis study elucidates a novel neuroimmune pathological mechanism underlying DCI and confirms that ZMHB ameliorates DCI by targeting CCL3–CCR5-mediated neuron–CD8⁺ T cell crosstalk.

OBJECTIVES: The association between night shift work and chronic kidney disease (CKD) risk remains uncertain. We investigated the associations of current/lifetime night shift work with incident CKD, assessed joint effects with genetic susceptibility, and explored the mediating roles of obesity and metabolomic alterations. METHODS: Utilizing UK Biobank data, current (N=242 721) and lifetime (N=63 659) night shift duration/frequency were assessed via questionnaires. The primary outcome was incident CKD. Polygenic risk scores (PRS) for cardiometabolic diseases (diabetes, hypertension, and cardiovascular disease) were calculated. Plasma metabolomics (249 measures, N=122 681) were analyzed. RESULTS: Over 13.7 years of follow-up, 5654 incident CKD cases were identified. Compared to day workers, those who usually or always worked night shifts had a 25% higher CKD risk [adjusted hazard ratio (HR_adj) 1.25, 95% confidence interval (CI) 1.10–1.41] and developed CKD 2.06 years earlier (95% CI 0.75–3.25). Lifetime night shift exposure showed consistent dose–response relationships, with 16–17% increased risks for either ≥5 cumulative years (HR_adj 1.17, 95% CI1.01–1.36) or ≥3 monthly night shifts (HR_adj 1.16, 95% CI1.01–1.33). Participants with both usual/always night shift exposure and high PRS for cardiometabolic diseases exhibited the greatest CKD risk. Obesity-related parameters (body mass index and waist circumference) mediated 14.7–14.8% of the observed night shift–CKD association. A novel 9-metabolite signature reflective of night shift mediated 5.47% of this association, primarily through disrupted fatty acid metabolism. CONCLUSIONS: Night shift work exhibits a dose-dependent association with CKD risk, exacerbated by cardiometabolic genetic predisposition and partially mediated through metabolic dysregulation and obesity. These findings underscore the need for workplace interventions targeting shift scheduling and metabolic health among high-risk workers.

BACKGROUND:Abdominal aortic aneurysm (AAA) carries high rupture mortality, yet medical therapies remain limited. While dyslipidemia and inflammation are implicated in AAA pathogenesis, the individual and joint roles of key lipid fractions, LDL-C (low-density lipoprotein-cholesterol), Lp(a) (lipoprotein[a]), and remnant cholesterol (RC), with systemic inflammation, are not fully established, particularly in the context of widespread cholesterol-lowering medication use. METHODS:We performed a prospective analysis of 338 758 UK Biobank participants free of AAA at baseline. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for associations between biomarkers and incident AAA. RESULTS:Over a median follow-up of 13.65 years, 1694 incident AAA cases occurred. Among participants not taking cholesterol-lowering medication, concurrent elevations of LDL-C, Lp(a), and RC (>75th percentile) conferred the highest risk (adjusted HR, 2.53 [95% CI, 1.97-3.24]). Coexisting elevated Hs-CRP (high-sensitivity C-reactive protein) with this triple-lipid elevation further increased the risk (adjusted HR, 4.19 [95% CI, 2.97-5.91]). Among cholesterol-lowering medication users, significant associations persisted for LDL-C (adjusted HR, 1.19 [95% CI, 1.09-1.29]) and RC (adjusted HR, 1.22 [95% CI, 1.14-1.31]) but not for Lp(a) (adjusted HR, 1.03 [95% CI, 0.97-1.10]). In this group, the combination of elevated LDL-C, RC, and Hs-CRP was associated with the greatest risk (adjusted HR, 2.46 [95% CI, 1.86-3.26]). CONCLUSIONS:Combined elevations of multiple lipid fractions and systemic inflammation were associated with a substantially increased risk of AAA. Cholesterol-lowering medication was associated with an attenuated risk relationship for LDL-C and Lp(a) but not for RC or Hs-CRP. Comprehensive risk assessment integrating a full lipid profile and Hs-CRP can improve identification of high-risk phenotypes for targeted AAA prevention.

OBJECTIVES:We aimed to identify plasma proteins associated with incident Crohn's disease (CD) and ulcerative colitis (UC), develop and validate predictive models for CD and UC risk, and uncover novel protein-based drug targets. METHODS:The study included 46 523 participants from England in the UK. Biobank as the development set and 47 105 participants for internal replication. An external validation set comprised 5807 participants from Scotland and Wales. Plasma proteomic profiling was performed on 2911 proteins. RESULTS:In the development set, 49 and 34 proteins were significantly associated with incident CD and UC risk, respectively (Bonferroni P < .05). These findings were replicated in the internal replication set. Two-sample Mendelian randomization (MR) analysis identified three proteins (TIMP1, TNFRSF10A, and LTBR) with causal associations for CD and four proteins (CCL20, OSM, NOS2, and CD300E) for UC. Among these, TIMP1 and CD300E represent novel, undrugged targets, while the remaining five are currently druggable. The proteomic-based model, incorporating age, sex, and candidate proteins, demonstrated strong predictive performance in the external validation set, with a C-index of 0.94 (95% CI, 0.88-1.00) for CD and 0.82 (95% CI, 0.73-0.92) for UC. Integrating candidate proteins or the top 10 proteins into clinically based models significantly enhanced risk prediction for both CD and UC. CONCLUSIONS:This study identifies novel plasma protein associations with CD and UC, supported by genetic evidence, and highlights their potential as therapeutic targets. Plasma proteomics significantly improves risk prediction for incident CD and UC compared to traditional clinical models, offering new avenues for drug discovery and personalized risk assessment.

Objective: Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study aimed to examine the relationship between CKM syndrome severity and the incidence of overall cancer and 18 site-specific cancers, and to identify potential mediating plasma protein and metabolite signatures. Methods: We analyzed data from 351,239 participants in the UK Biobank, classified into five CKM syndrome stages (0-4). Plasma proteomic (2923 proteins) and metabolomic (168 metabolites) profiles were analyzed. Cox models evaluated associations, and mediation analyses identified biological mediators. Results: Over a median 13.5-year follow-up, 44,840 incident cancer cases were documented. Advancing CKM stages (0-3) showed a dose-response relationship with increased overall (per one-stage increase: adjusted HR, 1.05; 95%CI, 1.03-1.07) and eleven site-specific cancer risks (e.g., digestive, respiratory, urinary tracts) (per onestage increase: adjusted HR ranging from 1.06 to 1.46). Stage 4 remained associated with elevated risk, though attenuated versus stage 3. Multi-omics mediation analysis identified 22 proteins and 2 metabolites that partially mediated the association between CKM stages 0-3 and overall cancer risk, implicating immune and metabolic pathways. Functional enrichment analysis further highlighted the PI3K-Akt signaling pathway and inflammatory processes as key mechanistic contributors. Conclusions: CKM syndrome severity is independently associated with increased cancer risk, partially mediated by proteins and metabolites involved in inflammation, proliferation, and lipid metabolism. These findings support CKM staging as a multisystem disorder with significant oncological implications and highlight potential biomarkers for intervention.

Thrombocytopenia is a common hematological disorder characterized by reduced platelet counts and an increased risk of bleeding, for which current pharmacological treatments are often limited by adverse effects, drug resistance, or high costs. Traditional Chinese medicinal herbs such as ginseng, notoginseng, peony root, and astragalus have long been used for blood-nourishing and qi-tonifying purposes and are frequently prescribed for conditions associated with blood deficiency and hematopoietic dysfunction. This review systematically summarizes glycoside compounds derived from these herbs, focusing on their structural characteristics and pharmacological activities relevant to thrombocytopenia. Accumulating evidence indicates that glycosylation enhances the solubility, bioavailability, and stability of aglycones, thereby influencing their biological effects. Preclinical studies suggest that glycoside compounds may improve the hematopoietic microenvironment through anti-inflammatory, antioxidant, and immunomodulatory actions, potentially reducing immune-mediated platelet destruction. In addition, they may promote thrombopoiesis by modulating hematopoietic signaling pathways, such as PI3K/AKT, and by restoring immune balance, particularly via regulation of the Treg/Th17 axis. Collectively, these multi-target effects on hematopoiesis and immune regulation highlight glycoside compounds as promising lead candidates for the development of novel therapeutic approaches to thrombocytopenia.

Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.

Intervertebral disc degeneration (IVDD) is the predominant pathological contributor to chronic low back pain, a pervasive musculoskeletal condition affecting over 630 million people globally and imposing tremendous socioeconomic and public health burdens. The etiopathogenesis of IVDD is remarkably complex and multifactorial, involving intricate crosstalk among chronic inflammatory responses, extracellular matrix (ECM) catabolism, cellular senescence, aberrant programmed cell death (including apoptosis, pyroptosis, and ferroptosis), mitochondrial dysfunction, and oxidative damage. Compelling evidence indicates that the inflammatory microenvironment acts as a decisive driving force throughout the entire degenerative course of IVDD. Among the diverse inflammatory mediators, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) serve as core pro-inflammatory cytokines that initiate and perpetuate the degenerative cascade. These two pivotal cytokines collectively activate an array of canonical intracellular signaling pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome, and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) cascade. Such interconnected signaling networks trigger a self-reinforcing positive feedback loop, which exacerbates inflammatory reactions, disrupts the anabolic-catabolic homeostasis of the ECM, promotes oxidative stress and mitochondrial injury, induces multiple forms of disc cell death, and ultimately leads to progressive structural collapse and functional deterioration of the intervertebral disc. Conventional therapeutic strategies, dominated by nonsteroidal anti-inflammatory drugs and surgical interventions, are limited by systemic adverse reactions, suboptimal long-term efficacy, and the risk of adjacent segment degeneration. In contrast, traditional Chinese medicine (TCM) exhibits prominent advantages in the prevention and treatment of IVDD by virtue of its holistic regulation, syndrome differentiation, and multi-component, multi-target, multi-pathway pharmacological properties. This review systematically elucidates the molecular mechanisms by which inflammation-associated signaling pathways modulate disc cell fate and ECM metabolic homeostasis, and comprehensively summarizes the experimental progress over the past five years on TCM monomers and compound formulas for intervening in IVDD. Accumulating studies have confirmed that numerous natural active ingredients isolated from herbal medicines (ferulic acid, mangiferin, paeonol, astragaloside IV) and representative TCM compound prescriptions (Bushen Huoxue Formula, Shensuitongzhi Formula, Fuzi Decoction) exert synergistic protective effects by coordinately targeting core signaling hubs. These TCM agents demonstrate potent anti-inflammatory, antioxidant, anti-apoptotic, anti-pyroptotic, anti-ferroptotic, ECM-protective, and autophagy-regulating bioactivities, thereby effectively decelerating the pathological progression of IVDD. Despite remarkable progress, current investigations are still confronted by several critical limitations. Most studies are restricted to validating the regulatory effects of single TCM components on individual signaling pathways, leaving the systematic, dynamic, and synergistic mechanisms of TCM compound formulas within multi-pathway regulatory networks largely unexplored. Furthermore, clinical translation of TCM is severely hampered by the lack of efficient targeted drug delivery systems, unclear pharmacokinetic profiles, suboptimal local bioavailability, and incomplete long-term safety assessments. Therefore, future research should adopt an interdisciplinary paradigm integrating multi-omics technologies, artificial intelligence, organoid models, and organ-on-chip systems to systematically decipher the scientific basis of TCM against IVDD. Concurrently, the development of intelligent, site-specific delivery systems (hydrogels, nanoparticles, exosome-based carriers) is urgently needed to enhance the local accumulation and sustained release of TCM ingredients. By deepening mechanistic exploration and accelerating translational research, TCM is expected to evolve into safe, effective, and personalized precision therapeutic regimens for IVDD, offering novel and reliable solutions for the clinical management of chronic low back pain.

Background:Individuals with prediabetes or diabetes face elevated dementia risk, yet robust prediction tools and mechanistic insights remain limited. Aims:This study aimed to develop and validate a protein-based risk score for dementia prediction in this high-risk population while elucidating underlying biological pathways and therapeutic targets. Methods:Utilising data from 10 433 UK Biobank participants with prediabetes or diabetes and proteomic profiling (2911 plasma proteins measured), we developed a dementia protein risk score in a training set (n = 6514) and validated it in testing (n = 2790) and external cohorts (n = 1129). Results:In the training set, 23 out of 2911 proteins were selected. In the testing set, compared with the basic model (age and sex, C-index: 0.78; 95% confidence interval [CI] 0.74-0.82), the dementia protein risk score (C-index: 0.84; 95% CI 0.81-0.88) significantly improved the performance in predicting incident dementia (C-index increase: 0.06; 95% CI 0.02-0.12), while cardiovascular risk factors, ageing and dementia incidence risk factors (C-index: 0.80; 95% CI 0.76-0.83) and apolipoprotein E (APOE; age and sex included, C-index: 0.81; 95% CI 0.77-0.85) had no significant improvement. Six key proteins (glial fibrillary acidic protein [GFAP], neurofilament light polypeptide [NEFL], Brevican core protein [BCAN], protein MENT [MENT], APOE and growth/differentiation factor 15 [GDF15]) captured the most predictive power. Pathway analyses implicated extracellular matrix remodelling and cholesterol metabolism, whereas Mendelian randomisation identified causal roles for APOE, haematopoietic prostaglandin D synthase (HPGDS), BAG family molecular chaperone regulator 3 (BAG3) and GDF15. Nine proteins were prioritised as druggable targets, including HPGDS, with existing Food and Drug Administration-approved drugs. Conclusions:This study establishes a highly accurate protein-based risk score for dementia prediction (including 6-23 proteins) in individuals with prediabetes or diabetes, uncovering actionable biological pathways and therapeutic targets. The findings enable precision risk stratification and accelerate translational opportunities for dementia prevention in this population.

BACKGROUND:Diabetes-induced cognitive impairment (DCI), with its incompletely elucidated pathological mechanisms, currently lacks FDA-approved therapeutic agents in clinical practice. The traditional Chinese medicine pair Zhimu-Huangbo (ZMHB) exhibits neuroprotective and immunomodulatory effects, but its role in DCI via neuroimmune crosstalk is unclear. PURPOSE:This study aims to elucidate the pathogenesis of DCI from the perspective of neuroimmune interactions and explore the therapeutic effect of ZMHB, to provide new strategies for the prevention and treatment of DCI. METHODS:A type 2 diabetic mouse model was established by high-fat diet combined with streptozotocin (STZ) injection and treated with ZMHB for 8 weeks. Cognitive function was assessed by Morris water maze, brain transcriptional signatures were profiled by single-cell RNA sequencing (scRNA-Seq), and key findings were validated by immunofluorescence, flow cytometry and splenocyte migration assays. In vitro studies further delineated the active components and molecular mechanisms. RESULTS:ZMHB significantly ameliorated cognitive function and prevented neuronal apoptosis in T2DM mice. scRNA-Seq revealed that ZMHB profoundly reversed T cell receptor and chemokine signaling pathways, specifically, downregulating neuronal CCL3 expression, which disrupted neuron-CD8+ T cell crosstalk and reduced brain infiltration of CCR5+ CD8+ T cells. CCR5 antagonism similarly prevented CCR5+CD8+T cell brain infiltration and reversed cognitive impairment. Berberine was identified as the principal active component of ZMHB that suppresses neuronal CCL3 expression by inhibiting the non-canonical NF-κB2 pathway. CONCLUSION:This study reveals a novel neuroimmune mechanism underlying DCI and demonstrates that ZMHB ameliorates DCI by targeting the CCL3-CCR5 axis-dependent interaction between neurons and CD8+ T cells.

BackgroundAlzheimer’s disease (AD) is characterized by progressive cognitive decline. Kaixinsan, a classical traditional Chinese formula composed of Renshen, Yuanzhi, Fuling, and Shichangpu, has therapeutic potential for AD, but its multi-herb compatibility mechanism remains unclear.PurposeThis study aimed to decipher the synergistic mechanism by which Kaixinsan inhibits AD-associated neuronal apoptosis.Study DesignAn integrated experimental study combining APP/PS1 mice, single-cell RNA sequencing, network proximity analysis, multi-dimensional weighted modeling, and cellular validation was performed.MethodsKaixinsan efficacy was evaluated in APP/PS1 mice using behavioral tests, Aβ pathology assessment, and evaluations of neuronal morphology and neuronal apoptosis. Disease and component networks were constructed from neuronal differentially expressed genes and brain-distributed components. Network proximity analysis predicted synergistic component pairs, herbal pair synergy was ranked by multi-dimensional weighted modeling, and shortest-path analysis identified targets converging on HSP90AA1. Predictions were validated by CETSA, HSP90AA1 inhibition, target-specific inhibition, and Aβ25-35-induced neuronal apoptosis assays.ResultsKaixinsan improved cognitive function, reduced Aβ deposition, and attenuated neuronal apoptosis in APP/PS1 mice. HSP90AA1 was identified as the hub of the AD-associated neuronal network. Component pairs with Sab ≥ 0 showed synergistic anti-apoptotic effects, and Renshen + Yuanzhi was ranked as the most synergistic herbal pair. Twelve direct targets, including BACE1, EGFR, and JMJD6, converged on HSP90AA1 and were validated by CETSA. Inhibition of HSP90AA1 or key upstream targets largely abolished Kaixinsan-mediated neuroprotection.ConclusionKaixinsan inhibits AD neuronal apoptosis through coordinated multi-target regulation converging on HSP90AA1. This study provides a novel network proximity-based framework to decode the molecular synergy of TCM formulae.

The gut-brain axis is increasingly recognized as a critical pathway in Parkinson's disease (PD), but the gut-targeted mechanisms underlying the therapeutic effects of herbal formulas remain poorly understood. In this study, an enterogenic PD-like mouse model was established by long-term rotenone gavage and treated with Duzhong Fang (DZF) to investigate whether DZF acts through intestinally retained components to influence gut-brain α-synuclein pathology. DZF markedly improved motor dysfunction, increased nigral tyrosine hydroxylase (TH)-positive cell density, alleviated colonic inflammation, and reduced α-Syn accumulation in the vagus nerve and brain, while colonic α-Syn showed a decreasing trend. Mechanistically, DZF downregulated colonic TPH1 and 5-HT3A expression, reshaped gut microbiota composition, and modulated fecal metabolites related to tryptophan metabolism and the 5-HT biosynthetic pathway. Molecular docking predicted potential interactions between TPH1 and gut-retained gingerol-related compounds, including 6-shogaol, 10-gingerdione, 10-gingerol, and 4-gingerol. These findings suggest that DZF ameliorates rotenone-induced PD-like phenotypes and may act by modulating the intestinal TPH1/5-HT-related pathway and α-Syn pathology along the gut-brain axis. This study supports a gut-targeted, neural-regulated therapeutic paradigm for traditional Chinese medicine and provides potential lead compounds for gut-directed anti-PD intervention.

Abstract Background and aims Cardiovascular-kidney-metabolic (CKM) syndrome stages confer graded CVD risk, but the underlying stage-specific molecular mechanisms remain undefined. Methods In 355,724 UK Biobank participants (median follow-up 13.5 years), we mapped CKM stages (0-3) to incident CVD. Using proteomics (n=37,785) and metabolomics (n=190,112), we identified stage-specific biomarkers via LASSO and XGBoost-SHAP. Mediation analyses were performed to quantify the proportion of the CKM–CVD association that was statistically accounted for by these biomarkers. The proportion of the protective association between cardiovascular health (Life’s Crucial 9 [LC9]) and incident CVD that was mediated by the same molecules was quantified. Results CVD risk increased across CKM stages. Beyond 11 pan-stage proteins (e.g., RTN4R,LEP) and 29 pan-stage metabolites (e.g.,GlycA), stage-specific molecular signatures emerged, whose pathway enrichment revealed a shift from metabolic/extracellular matrix dysregulation (Stage 1) to inflammation (Stage 2) to hypoxia/fibrosis (Stage 3). The proportion of the CKM–CVD risk association statistically accounted for by these molecules shifted accordingly: ADM (42.9%) in Stage 1, FABP4 (24.6%) in Stage 2, and HAVCR1 (28.0%) in Stage 3. High CVH (LC9≥80) was associated with approximately 80% lower CVD risk in Stages 0–2; a proportion of this protective association was statistically accounted for by the same stage-specific molecules. Conclusions These findings reveal a stage-ordered molecular continuum—from ECM remodeling to inflammation to fibrosis—that redefines CKM-driven CVD risk, and the strong protection of high CVH in early stages was statistically accounted for in part by these stage-specific molecules, generating the hypothesis that CVH may reduce risk through these modifiable pathways and providing a molecular framework for future stage-adapted intervention trials.

Ginger, a substance utilized in both culinary and medicinal contexts, demonstrates significant protective effects on pulmonary health and mitigates lung injury. Although numerous studies propose that the timing of ginger consumption may result in varied therapeutic outcomes, these propositions have yet to be empirically validated. This study represents the first systematic exploration of the temporal effects and underlying mechanisms associated with morning versus evening ginger administration in both healthy and lung-injured murine models. In comparison to the control group, evening consumption of ginger markedly affected lung function, inflammatory cytokine levels, and clock gene expression in healthy mice, whereas morning consumption did not produce significant effects. Conversely, morning administration of ginger ameliorated the symptoms of bleomycin-induced lung injury and altered clock gene expression, while evening administration aggravated lung damage. In Per2-knockout (Per2-KO) mice, the distinct effects of morning versus evening ginger intake were nullified. Proteomic analysis identified Sytl2 and Cluap1 as potential key proteins mediating the differential responses to ginger based on the time of administration. The study's findings underscore the importance of considering intake timing in both clinical applications and daily use of ginger to optimize its safety and therapeutic efficacy.

Background Doxorubicin (DOX) is a potent chemotherapeutic widely used in cancer treatment, but its clinical application is limited by dose-dependent cardiotoxicity. The underlying mechanisms involve oxidative stress, mitochondrial dysfunction, and apoptosis; however, effective cardioprotective strategies remain inadequate. Purpose To evaluate the cardioprotective effects of Danshensu (DSS), a bioactive compound from Salvia miltiorrhiza, against DOX-induced cardiotoxicity and to delineate the mechanisms by which it restores DOX-impaired mitochondrial quality control. Methods Cardiotoxicity models were established in vivo using DOX-treated C57BL/6J mice and in vitro using neonatal rat cardiomyocytes (NRCMs). The publicly available snRNA-seq dataset GSE292067 was analyzed to delineate DOX-associated transcriptional alterations in human cardiomyocytes. Molecular docking and cellular thermal shift assay were used to identify the targets of DSS. DSS was administered at multiple doses and compared with the FDA-approved cardioprotective agent, dexrazoxane (ICRF-187). Cardiac function was assessed by echocardiography and invasive hemodynamics. Histopathology, immunoblotting, flow cytometry, fluorescence imaging, and mitochondrial functional assays were used to evaluate apoptosis, oxidative stress, mitochondrial dynamics, and mitophagy. Results DSS supplementation improved survival, ameliorated ventricular dysfunction, and attenuated cardiac atrophy and fibrosis in DOX-treated mice. In DOX-exposed NRCMs, DSS increased cell viability and area, mitigated oxidative stress, and suppressed apoptosis. Mechanistically, mitochondrial injury-associated pathways were significantly enriched in DOX-treated human cardiomyocytes. DSS directly bonded to JNK and inhibited ROS-stirred c-Jun N-terminal kinase (JNK) phosphorylation, thereby restoring Mfn1/2 expression and limiting Drp1 phosphorylation to rebalance mitochondrial fission-fusion dynamics; It also restrained excessive, Drp1-facilitated and PINK1/Parkin-mediated mitophagy. Collectively, these effects preserved mitochondrial integrity, lowered ROS, and ultimately reduced cardiomyocyte apoptosis. Conclusion DSS confers cardioprotection against DOX-induced injury by disrupting the vicious circle formed by ROS and JNK, which mediated impairment of mitochondrial quality control, attenuating oxidative stress, and reducing apoptosis. These findings highlight DSS as a promising therapeutic candidate for mitigating chemotherapy-associated cardiotoxicity.

SCOPE:The relationship of dietary copper intake with new-onset chronic kidney disease (CKD) remained unclear. We aimed to examine the association of dietary copper intake with new-onset CKD in a 30-year follow-up study from young adulthood to midlife. METHODS AND RESULTS:A total of 4038 U.S. adults aged 18-30 years and without reduced estimated glomerular filtration rate (eGFR) from the Coronary Artery Risk Development in Young Adults (CARDIA) study was included. During a 30-year follow-up, 642 (15.9%) participants developed new-onset CKD. Overall, there was a U-shaped relationship between dietary copper intake and new-onset CKD (p for nonlinearity = 0.034). When copper intake was assessed as quartiles, compared with those in the second quartile (2.03-<2.46 mg/day), the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for new-onset CKD were 1.29 (1.05, 1.66), 1.29 (1.02, 1.64), and 1.49 (1.16, 1.91) for participants in the first (<2.03 mg/day), third (2.46-<3.11 mg/day), and fourth (≥3.11 mg/day) quartiles, respectively. Similar U-shaped associations were observed for new-onset eGFR decline and albuminuria. CONCLUSIONS:There was a U-shaped relationship of dietary total copper intake with new-onset CKD, with the lowest risk at a dietary copper intake of 2.03-<2.46 mg/day. Emphasizing the importance of maintaining optimal copper intake levels for the primary prevention of CKD.

Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.

Diabetes involves multi-organ complications that seriously threaten human life and health, and has become a major public health problem of global concern. Unfortunately, clinical management strategies for diabetic complications are still in their “infancy”, restricted by a limited understanding of their complex pathological mechanism. As is well established, lipid metabolism disorder is the characteristic pathological factors of diabetes, but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure. Protein S-acylation (often referred to as S-palmitoylation) is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine (Cys) residues through palmitoyl acyl transferases (PATs, also known as DHHCs) and deacylation enzymes, which is involved in the pathological progression of a variety of complex diseases such as cancer, neurological disorders and metabolic syndrome. Notably, recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications, and targeted intervention in the protein S-acylation process significantly alleviates the progression of diabetes and its complications, suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications. Therefore, this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications, summarizes the influence of the diabetic environment on S-acylation related enzymes, as well as providing an in-depth analysis of current drugs, measures, and challenges in targeting S-acylation. Finally, the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned, with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.