Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss.

Electroacupuncture pretreatment is considered as an optimal strategy for inducing cerebral ischaemic tolerance. However, the underlying neuroprotective mechanism of this approach has never been explored from the perspective of calcium homeostasis. Intracellular calcium overload is a key inducer of cascade neuronal injury in the early stage after cerebral ischaemia attack and the Na+/Ca2+ exchanger (NCX) is the main plasma membrane calcium extrusion pathway maintaining post-ischaemic calcium homeostasis. This study aims to investigate whether the regulation of NCX-mediated calcium transport contributes to the cerebroprotective effect of electroacupuncture pretreatment against ischaemic injury and to elucidate the underlying mechanisms involved in this process. Following five days of repeated electroacupuncture stimulation on Baihui (GV20), Neiguan (PC6), and Sanyinjiao (SP6) acupoints in rats, in vivo and in vitro models of cerebral ischaemia were induced through middle cerebral artery occlusion and oxygen/glucose deprivation (OGD), respectively. Firstly, we verified the neuroprotective effect of electroacupuncture pretreatment from the perspective of neurological score, infarct volume and neuronal apoptosis. Our findings from brain slice patch-clamp indicated that electroacupuncture pretreatment enhanced the Ca2+ efflux capacity of NCX after OGD. NCX1 expression in the ischaemic penumbra exhibited a consistent decline from 1 to 24 h in MCAO rats. Electroacupuncture pretreatment upregulated the expression of NCX1, especially at 24 h, and silencing NCX1 by short hairpin RNA (shRNA) administration reversed the protective effect of electroacupuncture pretreatment against cerebral ischaemic injury. Furthermore, we administered LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, prior to inducing ischaemia to investigate the upstream regulatory mechanism of electroacupuncture pretreatment on NCX1 expression. Electroacupuncture pretreatment activates PI3K/Akt pathway, leading to an increase in the expression of NCX1, which facilitates calcium extrusion and exerts a neuroprotective effect against cerebral ischaemia. These findings provided a novel insight into the prevention of ischemic stroke and other similar conditions characterized by brain ischaemia or hypoperfusion.

Here, we presented the study of the molecular mechanisms underlying the action of Wulingsan (WLS) in rats with metabolic-associated fatty liver disease (MAFLD) induced by a high-fat diet (HFD). High-performance liquid chromatography was employed to identify the chemical components of WLS. After 2 weeks of HFD induction, MAFLD rats were treated with WLS in three different doses for 6 weeks, a positive control treatment or with a vehicle. Lipid metabolism, liver function, oxidative stress, and inflammatory factors as well as pathomorphological changes in liver parenchyma were assessed in all groups. Finally, the expressions of autophagy-related markers, adenosine monophosphate-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)/unc-51-like kinase-1 (ULK1) signaling pathway-related genes, and proteins in liver were detected. The results revealed that WLS significantly ameliorated liver injury, the dysfunction of the lipid metabolism, the oxidative stress, and overall inflammatory status. Furthermore, WLS increased the expressions of LC3B-II, Beclin1, p-AMPK, and ULK1, along with decreased p62, p-mTOR, and sterol regulatory element-binding protein-1c levels. In conclusion, we showed that WLS is capable of alleviating HFD-induced MAFLD by improving lipid accumulation, suppressing oxidative stress and inflammation, and promoting autophagy.

After viral infection, the virus relies on the host cell's complex metabolic and biosynthetic machinery for replication. However, the impact of avian influenza virus (AIV) on metabolites and gene expression in poultry cells remains unclear. To investigate this, we infected chicken embryo fibroblasts DF1 cells with H9N2 AIV at an MOI of 3. Our aim was to explore how H9N2 AIV alters DF1 cells metabolic pathways to facilitate its replication. We employed metabolomics and transcriptomics techniques to analyze changes in metabolite content and gene expression. Metabolomics analysis revealed a significant increase in glutathione-related metabolites, including reduced glutathione (GSH), oxidized glutathione (GSSG) and total glutathione (T-GSH) upon H9N2 AIV infection in DF1 cells. Elisa results confirmed elevated levels of GSH, GSSG, and T-GSH consistent with metabolomics findings, noting a pronounced increase in GSSG compared to GSH. Transcriptomics showed significant alterations in genes involved in glutathione synthesis and metabolism post-H9N2 infection. However, adding the glutathione synthesis inhibitor BSO exogenously significantly promoted H9N2 replication in DF1 cells. This was accompanied by increased mRNA levels of pro-inflammatory cytokines (IL-1β, IFN-γ) and decreased mRNA levels of anti-inflammatory cytokines (TGF-β, IL-13). BSO also reduced catalase (CAT) gene expression and inhibited its activity, leading to higher reactive oxygen species (ROS) and malondialdehyde (MDA) level in DF1 cells. qPCR results indicated decreased mRNA levels of Nrf2, NQO1, and HO-1 with BSO, ultimately increasing oxidative stress in DF1 cells. Therefore, the above results indicated that H9N2 AIV infection in DF1 cells activated the glutathione metabolic pathway to enhance the cell's self-defense mechanism against H9N2 replication. However, when GSH synthesis is inhibited within the cells, it leads to an elevated oxidative stress level, thereby promoting H9N2 replication within the cells through Nrf2/HO-1 pathway. This study provides a theoretical basis for future rational utilization of the glutathione metabolic pathway to prevent viral replication.

Sarcoidosis is a heterogeneous granulomatous disease with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential biomarkers.

The possible protective effect of interleukin-32 (IL-32) in Mycobacterium tuberculosis (Mtb) infection has been indicated. However, few studies have been focused on IL-32 in tuberculosis patients. Additionally, the regulation of IL-32 production has rarely been reported. In the present study, the production, regulation, and role of IL-32 in tuberculous pleurisy (TBP) were investigated. We found that the content of IL-32 in tuberculous pleural effusion (TPE) was higher than the level in the malignant pleural effusion and transudative pleural effusion. The level of IL-32 mRNA in pleural fluid mononuclear cells (PFMCs) was higher than that in peripheral blood mononuclear cells (PBMCs) of patients with TBP, and this difference was mainly reflected in the splice variants of IL-32α, IL-32β, and IL-32γ. Compared with the PBMCs, PFMCs featured higher IL-32β/IL-32γ and IL-32α/IL-32γ ratios. In addition, lipopolysaccharide (LPS), Bacillus Calmette-Guérin (BCG), and H37Ra stimulation could induce IL-32 production in the PFMCs. IL-32 production was positively correlated with the TNF-α, IFN-γ, and IL-1Ra levels in TPE, whereas IFN-γ, but not TNF-α or IL-1Ra, could induce the production of IL-32 in PFMCs. Furthermore, IL-32γ could induce the TNF-α production in PFMCs. Monocytes and macrophages were the main sources of IL-32 in PFMCs. Nevertheless, direct cell-cell contact between lymphocytes and monocytes/macrophages plays an important role in enhancing IL-32 production by monocyte/macrophage cells. Finally, compared with the non-tuberculous pleural effusion, the purified CD4+ and CD8+ T cells in TPE expressed higher levels of intracellular IL-32. Our results suggested that, as a potential biomarker, IL-32 may play an essential role in the protection against Mtb infection in patients with TBP. However, further studies need to be carried out to clarify the functions and mechanisms of the IFN-γ/IL-32/TNF-α axis in patients with TBP.

Strict regulation of epithelial cells is crucial for maintaining intestinal barrier integrity and preventing intestinal diseases. While transcriptional regulation is well recognized as vital in this process, translational regulation is equally important. SETD2, a methyltransferase, is involved in transcriptional regulation to maintain intestinal epithelial barrier function. However, its role in translation remains largely unexplored. Here, we found SETD2 deficiency leads to the downregulation of ribosome biogenesis progress coupled with transcriptome-proteome discordance. Further ribosome profiling sequencing analyses showed reduced translational efficiency of cell adhesion and junction signatures in impaired intestinal epithelial barrier. Mechanistically, SETD2 ablation causes dysregulation and recruitment disorders of ribosome biogenesis factors, impairing the composition and distribution of ribosomal proteins. This disruption of ribosome biogenesis and homeostasis results in translational disorder of barrier maintenance genes, thereby compromising the intestinal barrier. Collectively, our findings unveil a previously unappreciated role of ribosome biogenesis and translational regulation in safeguarding intestinal epithelial barrier, and disclose a previously undiscovered role of SETD2 in modulating ribosome homeostasis.

This research investigated the therapeutic efficacy and potential targets of exosomes derived from umbilical cord mesenchymal stem cells (UC-MSC-Exo) in the context of chronic obstructive pulmonary disease (COPD). UC-MSC-Exo were isolated from the culture supernatant. A model of COPD was induced through exposure to cigarette smoke (CS) and airway lipopolysaccharide (LPS) instillation. Mice in the UC-MSC-Exo group received 100 µg of exosomes via tail vein injection. Lung function, computed tomography imaging of the lungs, bronchoalveolar lavage fluid cell count, plasma levels of inflammatory factors, as well as histological assessments using hematoxylin and eosin staining and Masson’s trichrome staining of lung tissue were employed to assess the therapeutic efficacy. Single-cell transcriptome sequencing was utilized to investigate the potential targets of UC-MSC-Exo in improving lung function and exerting anti-inflammatory effects in COPD mouse models. The UC-MSC-Exo group exhibited significant enhancements in pulmonary function parameters, attenuation of lung CT abnormalities, reduced BALF cell counts, and decreased levels of plasma inflammatory markers. Histological analysis confirmed decreased inflammatory infiltration and collagen deposition. Single-cell sequencing analysis suggested that UC-MSC-Exo might modulate CXCR4 expression, suppress inflammation, and facilitate lung regeneration by modulating macrophage functionality. This investigation introduces novel therapeutic avenues and potential targets for managing COPD.

Parkinson's disease (PD) is increasingly recognized as a brain network-disconnection syndrome. However, there is little consistent evidence on multimodal global topological alterations and their diagnostic value. We systematically searched PubMed, Embase and Web of Science up to March 2025 for articles reporting brain network topology in PD, to which we applied a multilevel random-effects meta-analyses with robust variance estimation to account for statistical dependencies. Our case-control meta-analysis included 80 studies (42 fMRI, 25 dMRI, 10 EEG, 4 sMRI, 3 others) involving 3736 PD patients and 2384 healthy controls. Compared to controls, PD patients showed lower structural and functional network segregation, especially when cognitively impaired. Structural network integration was also lower in PD, such deficits appearing to correlate with disease progression. Drug and network construction strategies were identified as potential moderating factors. Our diagnostic meta-analysis of 10 studies yielded a pooled diagnostic odds ratio of 16.4 and a pooled area under the curve of 0.86, with better diagnostic performance observed in studies using combined network metrics. These results support the clinical relevance of topological metrics in PD as potential biomarkers for disease characterization, prognosis and patient stratification, and underscore the importance of methodological harmonization and prospective validation in future research.

Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined. Using generalized linear mixed models, we analyze 218 TF ChIP-Seq datasets alongside GWAS data from 100,204 CRC cases and 154,587 controls of East Asian and European ancestries. We identify 51 TFs and TF-cofactor interactions, including VDR-cofactors, as key regulators of CRC risk. Integrating these TF insights with transcriptome-wide association studies (TWAS), we further evaluate associations between genetically predicted gene expression, alternative splicing, and alternative polyadenylation with CRC risk, using RNA-seq data from 364 Asian-ancestry and 707 European-ancestry individuals. Multi-ancestry TWAS identify 222 risk genes, including 95 novel genes and 48 potentially druggable targets. Single-cell analysis provides additional functional evidence supporting ~45% of these genes, and experimental validation confirms oncogenic roles for RHPN2, IRS2, and TXN. Our findings elucidate key TF-gene regulatory networks and uncover novel CRC risk genes.

BACKGROUND: Increasing evidence suggests that periodontitis may elevate the risk of acute myocardial infarction (AMI) through systemic inflammatory pathways. However, the strength and stability of this association remain controversial. OBJECTIVE: The primary objective of this systematic review and meta-analysis was to evaluate whether periodontitis is associated with an increased risk of AMI. The secondary objective was to identify which specific periodontal parameters are most strongly associated with AMI risk. METHODS: Following PRISMA guidelines, PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched from inception to September 25, 2025. Observational studies investigating the association between periodontitis and AMI were included. Two independent reviewers extracted data and assessed study quality using the Newcastle–Ottawa Scale (NOS). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity, sensitivity, subgroup, and publication bias analyses were also performed. RESULTS: A total of 17 studies comprising 146,001 participants (3,199 AMI cases) were included. Overall results demonstrated a significantly increased AMI risk in individuals with periodontitis (pooled OR = 1.84, 95% CI = 1.51–2.23, I² = 83.3%), and sensitivity analyses confirmed the robustness of the findings. Although publication bias was detected, the trim-and-fill method yielded consistent results (adjusted OR = 1.26, 95% CI = 1.03–1.55). Subgroup analyses revealed that several periodontal parameters were independently associated with AMI, including bleeding on probing (BOP; OR = 2.90), clinical attachment loss (CAL; OR = 1.76), probing depth (PD; OR = 1.15), radiographic bone loss (RBL; OR = 8.85), and remaining bone height (RBH; OR = 1.59). CONCLUSIONS: Periodontitis increases the risk of AMI by approximately 84%, independent of traditional cardiovascular risk factors. The severity of periodontal inflammation and tissue destruction is positively correlated with AMI risk. These findings highlight the importance of integrated prevention strategies for oral and cardiovascular health and the need for prospective clinical trials to confirm causality.

Radiotherapy remains a mainstay of cancer treatment. However, radiotherapy can also elicit acute and chronic adverse effects, including dermal inflammation and skin fibrosis. A comprehensive understanding of the underlying fibrotic processes remains elusive, and currently, no established treatment options exist. Canonical Wnt signaling has emerged as a significant player in fibrotic conditions. The Dickkopf (DKK) protein family comprises key modulators of Wnt signaling. To define the function of DKK3 in radiation-induced skin damage, we combined complementary in vivo and in vitro approaches, including a 3D human skin model, mice with cell-type-specific Dkk3 deletions, and irradiated human skin specimens. Our study revealed the pivotal role of DKK3 in regulating the response of the skin to radiation, with diminished DKK3 significantly mitigating radiation-induced skin damage. We found that radiation increases DKK3 expression in basal keratinocytes, leading to elevated ROS levels, TGF-β-mediated Wnt activation, epidermal hyperplasia, and subsequent skin fibrosis. Increased keratinocyte expression of DKK3 also drives macrophage polarization toward a CD163highCD206high profibrotic M2 phenotype, activating myofibroblasts and leading to fibrosis. Notably, DKK3 deficiency in keratinocytes markedly reduces radiation-induced dermal hyperplasia and fibrosis, identifying DKK3 as a key regulator of cutaneous radiation responses. These findings position DKK3 as a promising upstream modulator of TGF-β signaling for mitigating radiation-induced dermatitis and fibrosis, with potential relevance to other fibrotic diseases.

Colorectal cancer (CRC) development and progression are linked to genetic factors, environmental influences, and dysregulated signaling pathways.

Acute lung injury (ALI) is characterized by a considerable mortality rate and currently lacks viable therapeutic strategies. Alveolar type II epithelial cells (AT2 cells) play a critical role in lung injury repair, potentially through activation of the Wnt/β-catenin signaling cascade, which may enhance regenerative ability of lung tissue. In this study, we developed a mini-catalytically inactive Cas13X (mini dCas13X)-based adenosine-to-inosine (A-to-I) RNA editing approach, designated as β-catenin T41 editing to treat alveolar type 2 cells (CARTEL), with the objective of alleviating lung damage in ALI. We found that CARTEL proficiently performed base editing on β-catenin, achieving a high A-to-I conversion rate with minimal off-target effects. Moreover, CARTEL significantly inhibited the degradation of β-catenin, amplified Wnt/β-catenin signaling activation and facilitated cellular proliferation. In a murine model of lipopolysaccharide (LPS)-induced ALI, a single adeno-associated virus (AAV)-mediated administration of CARTEL effectively and primarily transduced AT2 cells, resulting in attenuated lung injury, enhanced AT2 cell proliferation, and improved pulmonary function, with no detected long-term risks. Collectively, these findings revealed that CARTEL-mediated RNA editing represents a promising therapeutic strategy to counteract lung injury occurring in diverse settings.

Primary liver cancer ranks among the most prevalent and refractory malignant tumors globally. This investigation delves into the role of Epstein-Barr virus nuclear antigen 2-binding protein (EBP2) in hepatocellular carcinoma (HCC). Significantly, EBP2 exhibits marked overexpression in HCC tissues, a finding that correlates with advanced tumor staging and unfavorable prognostic outcomes. In HCC cells, EBP2 silencing led to attenuated proliferation, enhanced apoptosis, and reduced migratory capacity, coupled with reversal of epithelial-mesenchymal transition (EMT). In vivo studies further demonstrated that EBP2 depletion potently suppressed tumor growth in xenograft models. Mechanistically, EBP2 interacts with CENPA to transcriptionally upregulate minichromosome maintenance protein family member 8 (MCM8), thereby stabilizing the MCM8/MCM9 complex and enhancing homologous recombination-mediated DNA repair. Functional rescue experiments revealed that MCM8 overexpression abrogated the suppressive effects of EBP2 knockdown on HCC cell proliferation and migration. In parallel, EBP2 regulates HMGB1 expression through the CENPA/YY1 transcriptional complex, thereby participating in the progression of HCC. Collectively, these findings highlight EBP2 as a crucial regulator of HCC progression via the dual axes-EBP2-CENPA-MCM8 and EBP2-CENPA/YY1-HMGB1, offering a promising therapeutic target for HCC intervention.

OBJECTIVE: To investigate the role of centrin-2 (CETN2) in platinum resistance and its underlying mechanisms in ovarian cancer. METHODS: We conducted a pan-cancer analysis of CETN2 expression and its associated genes using the STRING and TIMER databases. Data from the GEO and TCGA databases were employed for survival, clinical correlation, and prognostic analyses. Enrichment and co-expression analyses were performed to identify relevant pathways and genes. We also analyzed the tumor microenvironment, immune checkpoints, and drug sensitivity. For clinical validation, quantitative real-time PCR was used to measure CETN2 expression in patient samples and assess its correlation with chemotherapy response. Predictive models, including logistic regression and decision trees, were constructed. Their performance in predicting chemotherapy outcomes was evaluated using receiver operating characteristic (ROC) curves, and the prognostic impact of CETN2 was assessed via Kaplan-Meier survival analysis. RESULTS: CETN2 mRNA expression was significantly elevated in cisplatin-resistant samples. CETN2 was associated with the nucleotide excision repair (NER), oxidative phosphorylation, and cell cycle pathways and showed a negative correlation with several immune checkpoints. CETN2 expression demonstrated notable predictive value for chemotherapy response, particularly in platinum-sensitive ovarian cancer. It influenced stromal and immune-related scores in the tumor microenvironment, and differential expression levels correlated with significant variations in sensitivity to specific drugs. In clinical samples, CETN2 expression was linked to immune infiltration patterns. Protein expression of CETN2 was significantly higher in platinum-resistant patients compared to platinum-sensitive patients and showed predictive utility for chemotherapy outcomes. CONCLUSION: Upregulation of CETN2 may contribute to cisplatin resistance through pathways involving nucleotide excision repair, oxidative phosphorylation, and the cell cycle. CETN2 holds potential as a biomarker for platinum-based chemotherapy response and prognostic evaluation in ovarian cancer.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, and identifying robust biomarkers is crucial for improving diagnosis and understanding its pathogenesis.

Peripheral nerve injuries often lead to painful neuroma formation and chronic neuropathic pain, and the optimal surgical strategy for prevention remains debated. Targeted muscle reinnervation (TMR), regenerative peripheral nerve interfaces (RPNI), and nerve-in-muscle implantation (NIM) are surgical techniques developed to mitigate neuroma-related pain, but their relative efficacy has not been compared systematically. This preclinical study compared TMR, NIM, and two RPNI variants in a rat tibial nerve transection model to identify which approach best reduces neuroma formation and pain.

Emerging evidence suggests that ferroptosis resistance contributes to the ovarian cancer (OC) carcinogenesis. Here, the study identified a tumour promoting factor FSP1 and investigated the role of Salidroside in OC ferroptosis resistance. In vitro, Salidroside alleviated the ferroptosis resistance of OC cells, and promoted the ferroptosis features. In vivo, Salidroside could inhibit OC growth and stimulate the ferroptosis. Furthermore, Salidroside targeted the FSP1 to reduce FSP1 mRNA level, thereby assisted OC cells to ferroptosis. In public dataset, FSP1 expression was elevated in the OC single-cell transcriptome sequencing. In clinic, the FSP1 level was positively correlated to the O-RADS US grade. Taken together, these findings revealed an important role for Salidroside in OC ferroptosis resistance, which provided novel insight into ultrasonic diagnosis and traditional Chinese medicine in OC.

Plant-derived self-assembled nanoparticles, especially from food-medicine homology sources, are gaining attention, yet their structure-function relationships remain unclear. This study identified such nanoparticles from leaf decoction of Eucommia ulmoides, a key plant in traditional Asian medicine and diet, termed EUPs. These spherical particles (~287.8 nm) were primarily composed of polysaccharides and polyphenols, with 268 polyphenolic compounds detected via UPLC-QTOF-MS. Stepwise dissociation-ultrafiltration and spectroscopic analyses revealed that polyphenols were bound to the polysaccharide through noncovalent interactions, including hydrogen bonding and hydrophobic forces, forming a layered structure with sustained-release and thermo-responsive properties. Compared with free polyphenols, EUPs exhibited significantly prolonged anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages, reflected by the suppression of key inflammatory cytokines, including TNF-α, IL-6 and NO. Therefore, it aims to offer mechanistic insights into the multi-component synergistic anti-inflammatory effects of E. ulmoides and supporting the material basis of food-medicine homology.