Introduction Chinese herbal medicine offers a multi-target approach to modulate key immune signaling pathways, yet its clinical translation remains underexplored. Periodontitis is a plaque biofilm-induced chronic inflammatory disease causing immune imbalance and periodontal tissue destruction. Drug resistance and systemic toxicity limit the use of conventional treatments. This review focuses on the clinical relevance of Chinese herbal medicine in regulating core signaling pathways, including nuclear factor kappa B (NF-κB), mitogen‑activated protein kinase (MAPK), and phosphatidylinositol 3-kinase / protein kinase B (PI3K/Akt), thereby providing a mechanistic and therapeutic perspective on its role in periodontitis and highlighting its therapeutic potential. Methods Recently published articles were reviewed by searching combinations of keywords in PubMed, Google Scholar and other databases (inception to 2025), including ‘periodontitis’, ‘Chinese herbal medicine’, ‘immune regulation’, ‘osteoclast’, ‘signaling pathway’ and specific botanical names. We focused on the regulatory effects of Chinese herbal medicine bioactive components and formulations on key pathological processes in periodontitis. Of 5,600 initially identified articles, 500 full texts were screened for relevance, and 75 were selected. Results This review investigated the pharmacological properties of the bioactive compounds of Chinese herbal medicine, which inhibit inflammation and apoptosis through multi-target mechanisms. These compounds, such as berberine, resveratrol, and curcumin, can significantly modulate NF-κB, MAPK, and PI3K/Akt signaling pathways. They can attenuate cytokine release, rebalance macrophage polarization, inhibit osteoclastogenesis, and promote osteogenic differentiation. Several Chinese herbal formulations showed synergistic effects when combined with conventional periodontal therapy, improving gingival inflammation, alveolar bone preservation, and symptoms. Discussion The combination of Chinese and Western medicine provides a low-toxicity, high-efficacy therapeutic strategy through multi-dimensional regulation of immune-inflammatory networks and bone homeostasis. This review discusses natural active components and integrates Chinese herbal medicine with modern medicine to promote the clinical transformation of Chinese herb, advancing personalized and precision medicine in periodontitis.

Background Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a common but preventable complication in hospitalized patients. However, VTE prophylaxis remains underutilized. This study aims to explore physicians’ knowledge, attitudes, practices (KAP) regarding VTE prevention in Chinese public hospitals and their interrelationships to inform improvement strategies. Methods A cross-sectional, multicenter online survey was conducted using a KAP-based questionnaire distributed to physicians in Chinese public hospitals. Data analysis integrated descriptive statistics, Pearson correlations, and structural equation modeling (SEM). Results Among 787 valid responses, KAP scores were positive (Knowledge: 4.00 ± 0.81; Attitude: 4.38 ± 0.78; Practice: 4.38 ± 0.82). Scores on knowledge of intermittent pneumatic compression usage (3.40 ± 1.24) and VTE risk assessment tools (3.98 ± 1.08) were relatively low, while only 23% and 40% of physicians reported being very familiar with them, respectively. About half strongly agreed on performing dynamic VTE/bleeding risk assessments and tailoring prophylactic measures accordingly. Poor patient awareness and adherence also hindered VTE prevention. Positive correlations were observed among KAP domains ( r = 0.35 – 0.59, P < 0.001). SEM demonstrated knowledge directly influenced practice ( β = 0.50, P < 0.05), while attitude facilitated knowledge-to-practice translation ( β = 0.25, P < 0.05). Conclusions Knowledge is pivotal for VTE prophylaxis implementation. Future targeted training should focus on addressing physicians’ knowledge deficiencies, enhancing awareness of dynamic risk assessment and improving patient education to strengthen institutional VTE prevention capabilities. Given the predominance of tertiary public hospital respondents, the generalizability of these findings should be interpreted with caution.

BACKGROUND:Ferroptosis dysregulation and immune evasion are central features of lung adenocarcinoma (LUAD) progression, yet the molecular mechanisms that coordinately govern both processes remain poorly understood. This study aimed to identify ferroptosis-associated genes in LUAD and characterize their functional and mechanistic roles in tumor progression and anti-tumor immunity. METHODS:Differentially expressed genes (DEGs) were identified from two GEO microarray datasets (GSE32863 and GSE118370) and intersected with a curated ferroptosis gene set from GeneCards. Expression and prognostic analyses were conducted using the TCGA-based GEPIA and KM Plotter databases. The functional role of CST1 was assessed in vitro via CCK-8, colony formation, ROS/Fe2+/GSH/MDA detection, and CD8+ T cell co-culture assays. Mechanistic studies employed WNT pathway inhibition with IWR-1. In vivo validation was performed using a syngeneic LLC tumor model in immunocompetent C57BL/6 mice. RESULTS:Nine ferroptosis-associated DEGs were identified in LUAD, among which CST1 was most consistently upregulated and significantly associated with shortened progression-free survival. CST1 knockdown suppressed LUAD cell proliferation, induced ferroptotic cell death as evidenced by elevated Fe2+, ROS, and MDA alongside GSH depletion, and enhanced CD8+ T cell chemotaxis and effector cytokine secretion. CST1 overexpression produced the opposing effects. Mechanistically, CST1 activated the WNT/β-catenin pathway, and pharmacological inhibition by IWR-1 reversed the pro-tumorigenic, ferroptosis-suppressive, and immunosuppressive phenotypes. In C57BL/6 mice, CST1 depletion reduced tumor growth, restored intratumoral ferroptosis markers, and increased CD8+ T cell infiltration. CONCLUSIONS:CST1 promotes LUAD progression by simultaneously suppressing ferroptosis and impairing CD8+ T cell-mediated immunity through WNT/β-catenin activation. These findings identify the CST1-WNT/β-catenin axis as a candidate therapeutic target in LUAD.

Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disorder with no effective cure, posing a major clinical challenge. Lysine 2-hydroxyisobutyrylation (Khib) is a recently identified post-translational modification found across diverse species and is involved in key metabolic processes associated with the regulation of protein function. However, its role in AD remains poorly understood. This study aimed to elucidate the involvement of Khib in AD pathogenesis as well as the underlying molecular mechanisms. We compared lysine acylation profiles between 10-month-old APP/PS1 transgenic mice and age-matched wild-type (WT) controls using western blot. Quantitative Khib proteomics was employed to identify differentially modified proteins and specific Khib sites relevant to AD. To examine functional effects, we introduced an adeno-associated virus (AAV) vector expressing clusterin (CLU) K436R—a mutation that mimics Khib deficiency—into the bilateral lateral ventricles of 8-month-old WT and APP/PS1 mice via stereotactic injection. Additionally, C8-D1A astrocytic cells were transduced with lentivirus expressing CLU K436R. Co-immunoprecipitation was used to analyze the interaction between CLU and Aβ. Khib levels were significantly elevated in the brains of 10-month-old APP/PS1 mice. Proteomic analysis identified CLU as a Khib-modified protein, with K436 as the primary modification site. CLU K436 Khib levels were significantly upregulated in APP/PS1 mice. Notably, the loss of Khib at this site in CLU K436R mutant APP/PS1 mice led to marked suppressions in the number of β-amyloid plaques, gliosis, and neuroinflammation, along with improved memory performance in vivo. In vitro, CLU K436R expression in C8-D1A astrocytes promoted glial activation and cell viability. Mechanistically, the K436R mutation influenced the CLU–Aβ interaction, thereby modulating Aβ metabolism. Our findings underscore a critical role for Khib in AD pathophysiology and reveal that Khib modification of CLU at K436 influences amyloid pathology, glial responses, and neuroinflammation. These results provide novel insights into the molecular mechanisms underlying AD and suggest that targeting Khib at CLU K436 may represent a promising therapeutic strategy. Alzheimer’s disease (AD) is a severe brain disorder that causes memory loss and cognitive decline, for which no cure is currently available. A newly identified protein modification called lysine 2-hydroxyisobutyrylation (Khib) is important for cellular functions. However, whether it is involved in AD remains unknown. We investigated whether Khib contributes to AD and if it influences disease progression. We compared protein modifications between AD-like mice (APP/PS1) and normal mice, identifying AD-linked Khib changes. We modified a protein linked to AD, clusterin (CLU), at a specific site (K436) to mimic reduced Khib levels, and then tested how this change affected brain function in both mice and brain cells. We also examined how CLU interacts with amyloid-beta (Aβ), a toxic protein that accumulates in AD. 1. Khib levels were higher in AD mice than in normal mice. 2. CLU showed increased Khib modification at site K436 in AD mice. 3. Reducing Khib modification levels at CLU K436 in AD mice decreased harmful brain changes, including amyloid plaque formation, inflammation, and memory deficits. 4. Similar experiments in brain cells confirmed that reducing Khib in CLU improved cell survival and function. 5. Khib modification of CLU may influence how it interacts with Aβ, thereby affecting disease progression. Khib modifications, particularly in CLU, are involved in AD development. Reducing Khib at a specific site in CLU improved brain function in AD models, thereby identifying a potential novel treatment strategy. These findings provide important insights for future AD research and therapy development.

Current therapies for Alzheimer’s disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system. Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD. LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming. Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.

IntroductionMicroRNAs (miRNAs) are promising biomarkers for the diagnosis and prognosis of neurodegenerative diseases. Over the past few years, miR-34a-5p and miR-126-3p have become some of the most characterized miRNA, the former being associated with cellular senescence and apoptosis and the latter with the maintenance of vascular endothelial function. The present study aimed to evaluate diagnostic performance of miR-34a-5p and miR-126-3p for cognitive dysfunction in CSVD patients. In addition, we investigated whether these miR-34a-5p and miR-126-3p have mediating effect of impaired glucose regulation (IGR) status on cognitive dysfunction. The final objective was to the identification of better diagnostic biomarkers and further investigation on their value of practical application in Chinese population.MethodsThe study included 300 patients with cerebral small vessel disease (CSVD), who were further stratified by oral glucose tolerance test into those with impaired glucose regulation (IGR, n = 151) and those with normal glucose metabolism (NGM, n = 149), with the NGM group serving as the internal control. Concurrently, all patients were stratified according to Montreal Cognitive Assessment scores into cognitive function subgroups (normal/mild/moderate/severe impairment). Plasma levels of miR-34a-5p and miR-126-3p were measured in all participants using reverse transcription-polymerase chain reaction (RT-PCR). Mediation analysis was employed to assess the mediating role of the relevant miRNAs in the pathway from IGR to cognitive dysfunction in CSVD patients. The diagnostic performance of these miRNAs for cognitive function and long-term prognosis in CSVD patients with IGR was compared in terms of specificity, sensitivity, and accuracy. Moreover, the miR-34a-5p target genes were screened, and functional and pathway enrichment analyses were performed.ResultsThe results show that, in the analysis based on cognitive stratification, plasma miR-126-3p expression levels were negatively correlated with the severity of cognitive impairment in CSVD patients, whereas miR-34a-5p levels showed a positive correlation. miR-126-3p exhibited a stepwise decrease with increasing cognitive severity, while miR-34a-5p significantly distinguished between normal and impaired cognitive status. Mediation analysis revealed that only miR-34a-5p demonstrated a significant mediating effect in the pathway from IGR to cognitive dysfunction (indirect effect = 0.4519, 95% BootCI: 0.0277–0.8879), and it exhibited superior diagnostic performance for cognitive impairment within the CSVD cohort. Following evaluation using the Youden index, miR-34a-5p at the 2-year follow-up demonstrated a balanced diagnostic performance with an area under the curve (AUC) of 0.803, a sensitivity of 65.3%, and a specificity of 84.0% at the optimal cut-off of 2.49, indicating its potential utility for risk stratification. Compared with its performance at baseline (AUC: 0.679, sensitivity: 58.3%, specificity: 75.0%), the diagnostic performance of miR-34a-5p at the 2-year follow-up showed improvements across all metrics, particularly in specificity. In contrast, miR-126-3p (an inverse indicator) showed a moderate sensitivity (64.6–70.5%) and specificity (60.7–63.2%), which may limit its standalone diagnostic application. Enrichment analysis indicated that miR-34a-5p could be involved in the pathological aspects of cognitive impairment by regulating pathways related to apoptosis, oxidative stress, and synaptic function.DiscussionThe IGR stage may represent a potential early pathological window of cognitive impairment in CSVD patients. Plasma miR-34a-5p is more valuable as diagnostic and long-term prognostic marker in IGR patients than miR-126-3p and may mediate association between IGR and cognitive decline via apoptosis, oxidative stress and synaptic pathway.

The effects of the SARS-CoV-2 virus (COVID-19) on the central nervous system predispose to cognitive dysfunction in older adults. However, limited information is available on how long this impact will last. This study aims to assess the cognitive decline in Chinese older adults after COVID-19 using a cross-sectional study. A nationwide cross-sectional study was conducted among 1698 individuals over 50 years old who completed an online questionnaire survey on their cognitive impairment. Based on the Subjective Cognitive Decline Questionnaire (SCD-Q), we designed a self-administration SCD-18 questionnaire that assess perceived subjective decline in attention, comprehension, memory, emotion, motivation and sleep. The scores of each evaluation index in the SCD-18 questionnaire ranges from 0 to 6, with higher scores indicating a greater possibility of cognitive dysfunction. We compared differences in relevant cognitive function between different participants and performed a multiple linear regression analysis to identify factors that might be associated with cognitive function. Older adults who were infected with COVID-19 had significantly higher SCD-18 scores than uninfected participants ( P = 0.005). Among the infected participants, the SCD-18 scores of females were significantly higher than that of males ( P = 0.007), especially in memory ( P <0.001), and rural participants had higher SCD-18 scores than urban participants ( P <0.001). Specifically, the SCD-18 scores of the infected participants for 1-6 months were significantly higher than that of the uninfected participants ( P = 0.003), especially in comprehension ( P = 0.011), memory ( P <0.001), motivation ( P = 0.016), and sleep ( P = 0.008). Participants infected for more than 6 months did not have significantly different SCD-18 scores from uninfected participants ( P = 0.118), suggesting that cognitive function gradually recovered. Regression analysis indicated that female and rural area were associated with cognitive impairment. The cognitive function of older adults due to the COVID-19 pandemic has changed over time. Female and rural area were the risk factors for cognitive decline. Therefore, further long-term interventions for vulnerable older adults with a history of COVID-19 should be considered to maintain cognitive health.

Rationale: Chronic kidney disease (CKD) is a progressively debilitating condition leading to kidney dysfunction and severe complications. While dysbiosis of the gut bacteriome has been linked to CKD, the alteration in the gut viral community and its role in CKD remain poorly understood. Methods: Here, we characterize the gut virome in CKD using metagenome-wide analyses of faecal samples from 425 patients and 290 healthy individuals. Results: CKD is associated with a remarkable shift in the gut viral profile that occurs regardless of host properties, disease stage, and underlying diseases. We identify 4,649 differentially abundant viral operational taxonomic units (vOTUs) and reveal that some CKD-enriched viruses are closely related to gut bacterial taxa such as Bacteroides, [Ruminococcus], Erysipelatoclostridium, and Enterocloster spp. In contrast, CKD-depleted viruses include more crAss-like viruses and often target Faecalibacterium, Ruminococcus, and Prevotella species. Functional annotation of the vOTUs reveals numerous viral functional signatures associated with CKD, notably a marked reduction in nicotinamide adenine dinucleotide (NAD+) synthesis capacity within the CKD-associated virome. Furthermore, most CKD viral signatures are reproducible in the gut viromes of diabetic kidney disease and several other common diseases, highlighting the considerable universality of disease-associated viromes. Conclusions: This research provides comprehensive resources and novel insights into the CKD-associated gut virome, offering valuable guidance for future mechanistic and therapeutic investigations.

Metabolic syndrome (MetS) is a conglomerate of metabolic abnormalities including hypertension, obesity, hyperglycemia, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). The relationship between MetS and Inflammatory Bowel Disease (IBD) has received a lot of attention lately. Epidemiological investigation has yet to determine if the two illnesses are causally related. To investigate the causal link between IBD and MetS levels, we screened publically available genome-wide association study (GWAS) data using Mendelian randomization (MR) analysis. The study aimed to comprehensively analyze the causal association of each component of MetS, including fasting blood glucose(FBG), HDL-C, triglyceride(TG), waist circumference(WC), and hypertension, on the risk of IBD and its subtypes via univariate, two-way, and multivariate MR (MVMR) methods. We selected independent genetic variants of MetS and IBD as instrumental variables (IVs) from published data from the IEU OpenGWAS project and IIBDGC (International Inflammatory Bowel Disease Genetic Consortium), used MR to infer potential causal effects between them, and used a variety of methods (random effect inverse variance weighting (IVW), weighted median, MR-Egger regression, etc.) to ensure the robustness of causal effects. Univariate two-sample MR (TSMR) revealed that WC was significantly linked to the risk of Crohn’s disease (CD) (OR = 1.659; 95

BACKGROUND:Critically ill patients face challenges in venous thromboembolism (VTE) prevention, with limited consensus on the efficacy of different anticoagulants and prevention methods. This study aims to systematically evaluate the quality of existing clinical practice guidelines (CPGs) and the efficacy and safety of various anticoagulation regimens for VTE prevention in such patients. METHODS:CPGs quality was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II and Reporting Items for Practice Guidelines in Healthcare (RIGHT) tools. A network comparison was conducted to evaluate the efficacy and safety of distinct low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) for thromboprophylaxis. RESULTS:Seventeen CPGs and 12 randomized controlled trials (7636 patients) were systematically reviewed. The scores for "stakeholder involvement" (58.8%) and "applicability" (60.7%) were relatively low in AGREE II. The RIGHT checklist identified insufficient reporting in "review and quality assurance" (44.1%) and "evidence" (57.1%). Four CPGs (NICE2019, ACCP2012, ASH2018, and ASH2019) demonstrated high clinical applicability. Network analysis revealed no significant differences among separate LMWHs (bemiparin, enoxaparin, nadroparin, dalteparin) or between different LMWHs and UFH in reducing deep vein thrombosis (DVT), pulmonary embolism, or VTE. However, pooled LMWHs analysis demonstrated a significant reduction only in DVT compared to UFH (odds ratio 0.71, 95% credible interval: 0.42-0.99). CONCLUSIONS:Although the 17 CPGs propose various strategies for VTE prevention, substantial differences exist in their quality and clinical applicability. Existing clinical evidence fails to demonstrate superior prophylactic efficacy among VTE prevention strategies in critically ill patients.

Cyclic diguanosine monophosphate (c-di-GMP) is a crucial secondary messenger that regulates bacterial cellulose (BC) synthesis. It is synthesized by diguanylate cyclase (DGC) containing a Gly-Gly-Asp/Glu-Glu-Phe (GGDEF) domain and degraded by phosphodiesterase (PDE) with a Glu-Ala-Leu (EAL) domain. In this work, a systematic analysis of ten GGDEF-EAL tandem domain proteins from Komagataeibacter xylinus CGMCC 2955 assessed their c-di-GMP metabolic functions and effects on BC titer and structure. Of these, five proteins exhibited DGC activity, and five exhibited PDE activity in vitro. GE03 was identified as a bifunctional protein. Most mutant strains deficient in GGDEF-EAL protein showed changes in BC metabolism, motility, and c-di-GMP levels. The combined knockout of identified PDE proteins increased the BC titer by 48.1% compared to the wild type. Overall, our findings advance our understanding of c-di-GMP signaling and its role in BC synthesis, introducing novel concepts and effective strategies for enhancing industrial BC production.

Genome-wide association studies (GWAS) have identified numerous risk loci for psychiatric disorders, yet their limited explanatory power and unresolved molecular mechanisms impede therapeutic development. While proteomics has emerged as a key tool for elucidating genetic risk mechanisms, prior studies have been constrained by single-trait analyses and limited sample sizes. In this study, we performed multi-trait analysis of GWASs (MTAG) analyses on ten major psychiatric disorders by leveraging the large scale GWAS summary statistics (N = 14,307 to 2,000,702). MTAG significantly enhanced discovery power for shared genetic architecture, increasing the effective sample size by 56.55 % on average and identifying an average of 68 additional genetic loci per disorder. We then performed multi-trait proteome-wide association studies (PWAS) by combining MTAG results with human brain proteomic data from ROS/MAP and Banner cohorts (N = 528), identifying 137 genetically regulated proteins associated with bipolar disorder (43), major depressive disorder (46), schizophrenia (60), ADHD (18), anxiety (30), and PTSD (52). Through causal inference analyses, we prioritized 54 potential causal proteins, including 26 candidates (such as LSM6, GOPC, P2RX7) absent in original GWAS findings. Drug repurposing analyses nominated 32 compounds, including belinostat and vorinostat, that counteract risk-associated expression patterns, alongside 164 clinically actionable drug-protein interactions. Our study provides a mechanistic framework linking genetic risk to brain protein dysregulation and proposes tractable therapeutic targets for psychiatric disorders.

BackgroundDysbiosis of the gut microbiota (GM) has been linked to inflammatory bowel disease (IBD), yet its associated molecular mechanisms remain poorly defined. Identifying causal host genes mediating GM-IBD interactions is therefore of great importance.ObjectiveTo identify GM-associated causal genes for IBD and to prioritize key targets and cell types underlying GM-host crosstalk.MethodsWe integrated GWAS datasets of GM, UC, and CD using a two-sample Mendelian randomization (MR) framework with IVW as the primary estimator. Causal SNPs were mapped to genes for enrichment analyses. Candidate genes were refined by intersecting MR-derived genes with bulk RNA-seq DEGs (training: GSE87473, validation: GSE75214) and prioritized using nested cross-validated machine-learning models. Single-cell RNA-seq (GSE116222) was used to localize key genes to specific cell types. The functional role of TNIK was validated in IL-10-/- IBD mice via AAV9-mediated overexpression. Immunohistochemical staining of Ki67 and Cleaved caspase 3 was conducted to evaluate epithelial proliferation and apoptosis in colonic tissues.ResultsMR analysis identified 307 and 360 GM-associated causal genes for UC and CD, respectively. TNIK (TRAF2 and NCK-interacting kinase) was highlighted as a key candidate gene. Seven TNIK-associated immune cell subsets showed altered infiltration in UC. Single-cell transcriptomics revealed TNIK dysregulation in colonocytes, goblet cells. T/NK cells in UC. TNIK overexpression in IL-10-/- mice reduced disease severity and downregulated IL-1β, IL-6, and TNF-α. Immunohistochemistry confirmed that TNIK overexpression enhanced Ki67 expression and reduced Cleaved caspase 3 expression.ConclusionBy integrating MR with transcriptomics and single-cell seq results, we identified TNIK as a potential GM-associated host kinase linking dysbiosis to epithelial and immune dysfunction in IBD. TNIK emerges as a promising node for IBD prognosis through barrier maintenance and immune regulation.

Background: Neuronal exocytosis is mainly driven by the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes. However, little is known about the organization principle of the SNARE complex. Methods: Protein condensates formed by SNARE complex were imaged by confocal microscope. Fluorescence recovery after photobleaching (FRAP) assay together with fusion and division assays at the cellular level and in vitro studies with purified proteins were performed to characterize the dynamic properties of protein condensates. The effect of SNARE complex phase separation on the recruitment of synaptic vesicles was detected by immunofluorescence. Results: We discover that phase separation drives SNARE complex formation and aggregation; in addition, nonintrinsically disordered regions (non-IDRs) of the syntaxin1 protein is necessary for the formation of these biological condensates. Functionally, phase separation of the SNARE complex can be regulated by the major cofactors of the fusion machinery and has the ability to recruit synaptic vesicles in neurons. Conclusions: Our study here establishes that phase separation is a promising way to mediate the formation and aggregation of the SNARE complex, and further identified that the non-IDRs of syntaxin1 is necessary for the phase separation of the SNARE complex. Our work answers an vital scientific question: does the SNARE complex function as multiple copies that are dispersed or clustered together to ensure sustained neurotransmitter release. In sum, phase separation provides an ideal working model for SNARE complex-mediated membrane fusion and neurotransmitter release. ### Competing Interest Statement The authors have declared no competing interest.

Chemotherapy and radiotherapy (chemo-/radiotherapy) have advanced as the main treatment modalities for nasopharyngeal carcinoma (NPC), improving patient survival rates. However, chemo-/radiotherapy resistance in NPC cells has emerged as a key factor contributing to poor prognosis. Recently, competing endogenous RNA networks (ceRNETs) have garnered attention for their potential clinical value in studying chemo-/radiotherapy resistance. In this review, we aimed to explore the molecular mechanisms of ceRNA-related molecules, including circular RNA (circRNA), long non-coding RNA (lncRNA), microRNA (miRNA), and other competing endogenous RNAs, in regulating the chemo-/radiotherapy resistance in NPC. Additionally, we discuss the potential applications of ceRNA as a prognostic indicator and therapeutic target for this resistance.

The ε4 allele of the Apolipoprotein E (APOE) gene is an important genetic risk factor for several neurodegenerative diseases, while the common pathogenic mechanism is still unclear. Impaired synaptic transmission is one of the common pathogenic features of neurodegenerative diseases. By using proteomics analysis, co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assay, we demonstrated that APOE interacts with VAMP2, a core component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, in an APOE4 > APOE3 manner. Further in vitro and in vivo results suggest that APOE4 blocks SNARE complex assembly, which is likely driven by liquid-liquid phase separation (LLPS), negatively regulating synaptic vesicle release. Our study shows that APOE4 negatively regulates synaptic vesicle release by blocking the soluble SNARE complex assembly. Our data shed a light on how APOE polymorphism contributes to the risk for neurodegenerative diseases, and provides a theoretical basis for the future APOE targeted treatment of neurological diseases.

Alzheimer’s disease is a pervasive neurodegenerative disease that is estimated to represent approximately 70% of dementia cases worldwide, and the molecular complexity that has been highlighted remains poorly understood. The accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles formed by tau hyperphosphorylation, and neuroinflammation are the major pathological features of Alzheimer’s disease (AD). Over the years, there has been no apparent breakthrough in drug discovery based on the Aβ and tau hypotheses. Neuroinflammation has gradually become a hot spot in AD treatment research. As the primary cells of innate immunity in the central nervous system, microglia play a key role in neuroinflammation. Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes are vital molecules in neuroinflammation. In the pathological context of AD, the complex interplay between TLR4 and the NLRP3 inflammasomes in microglia influences AD pathology via neuroinflammation. In this review, the effect of the activation and inhibition of TLR4 and NLRP3 in microglia on AD pathology, as well as the cross-talk between TLR4 and the NLRP3 inflammasome, and the influence of essential molecules in the relevant signaling pathway on AD pathology, were expounded. In addition, the feasibility of these factors in representing a potential treatment option for AD has been clarified.

The metabolism of long-chain polyunsaturated fatty acids (LCPUFAs) is closely associated with the risk and progression of colorectal cancer (CRC). This paper aims to investigate the role of LCPUFA in the crosstalk between intestinal microflora and macrophages, as well as the effects of these three parties on the progression of CRC. The metabolism and function of LCPUFA play important roles in regulating the composition of the human gut microflora and participating in the regulation of inflammation, ultimately affecting macrophage function and polarization, which is crucial in the tumor microenvironment. The effects of LCPUFA on cellular interactions between the two species can ultimately influence the progression of CRC. In this review, we explore the molecular mechanisms and clinical applications of LCPUFA in the interactions between intestinal microflora and intestinal macrophages, as well as its significance for CRC progression. Furthermore, we reveal the role of LCPUFA in the construction of the CRC microenvironment and explore the key nodes of the interactions between intestinal flora and intestinal macrophages in the environment. It provides potential targets for the metabolic diagnosis and treatment of CRC.

Food preferences play a pivotal role in dietary choices and body weight regulation, yet the causal relationships and complex pathways linking food liking to obesity remain elusive. Here, we employed a two-sample Mendelian randomization (MR) analysis and pleiotropic analysis to investigate the causalities and shared loci between 187 food preferences ( N  = 161,625) and five obesity-related phenotypes ( N  = 100,716 to 322,154). MR analysis revealed a causal association between two food-liking phenotypes and increased body mass index (BMI), specifically, onion liking (β, 0.286; 95% CI, 0.185 to 0.387; P = 2.80×10−8), and highly palatable food liking (β, 0.266; 95% CI, 0.140 to 0.391; P = 3.31×10−5). Multivariable MR analysis indicated that the effect of onion liking on BMI remained after conditioning on actual onion intake, suggesting a degree of independence in dietary preferences′ influence. Pleiotropic analysis under a composite null hypothesis detected 32 pleiotropic loci and six colocalized loci in these two trait pairs. Candidate pleiotropic genes associated with onion liking-BMI highlighted biological pathways primarily involved in the sensory perception of smell. These findings contribute to a better understanding of the intricate relationship between food preferences and obesity.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study is supported by the National Natural Science Foundation of China (82101601, 82071190, 82371438), the Affiliated Hospital of Guangdong Medical University High level Talent Research Launch Project (GCC2022001), the Innovative Strong School Project of Guangdong Medical University (4SG21230G), and the Open Fund of Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases (2023).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.