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PubMed2026

Exercise-induced chronic adaptations and pro-inflammatory cytokine levels (IL-1β, IL-6, and TNF-α) in patients with depression: A systematic review and exploratory meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a leading cause of disability worldwide. Although exercise has been shown to alleviate depressive symptoms, potentially by affecting the body's inflammatory response, evidence in this area remains inconsistent. This study synthesized the most recent evidence from randomized controlled trials (RCTs) on the relationship between exercise-induced chronic adaptations and pro-inflammatory cytokine levels in patients with depression. METHODS: Eligible RCTs were identified from six electronic databases. Effect sizes were pooled using mean differences (MDs) and standardized mean differences (SMDs) with 95% confidence intervals (CIs). Two independent researchers assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: The review included 21 RCTs involving 1572 participants, six of which were included in the meta-analysis. No evidence of efficacy was observed for the chronic effects of exercise on the levels of the pro-inflammatory cytokines interleukin-1-beta (IL-1β) (MD = -0.01, 95% CI [-0.06, 0.04], p = 0.79), interleukin-6 (IL-6) (SMD = -0.30, 95% CI [-0.64, 0.04], p = 0.08), and tumor necrosis factor-alpha (TNF-α) (SMD = -0.18, 95% CI [-0.50, 0.14], p = 0.27) in patients with depression. However, the pooled results for certain markers were not robust. The certainty of evidence for each outcome was very low owing to inconsistency, indirectness, and imprecision. CONCLUSIONS: Evidence for exercise improving pro-inflammatory cytokine levels in patients with depression during the chronic phase remains exploratory and uncertain. Well-designed, adequately powered studies incorporating a broader range of immune biomarkers and dynamic multi-time-point assessments are urgently needed to determine whether exercise-induced chronic adaptations can modulate inflammatory pathways in depression.

Humans↗

PubMed2026

Eucalyptol mitigates isoproterenol-induced myocardial injury in rats via activation of p38 MAPK/JNK signaling, suppression of ER stress, and modulation of apoptotic pathway.

BACKGROUND: Myocardial injury (MI), a subset of cardiovascular diseases, remains a leading cause of deaths globally, driven by pathological inflammation, oxidative stress, and apoptosis. Despite advances in interventional cardiology, high relapse rates and therapeutic limitations underscore the urgent need for novel pharmacological agents. Phytochemicals, with their multi-target approach and favorable safety profiles, offer promising alternatives for mitigating ischemic injury. METHODS: The cardioprotective effects of 1,8-cineole, a monoterpene derived from Eucalyptus species, was investigated in a rat model of isoproterenol-induced myocardial injury. Serum levels of cardiac enzymes (creatine kinase (CK), lactate dehydrogenase (LDH)) and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were quantified. Preliminary histopathological analysis was performed to assess the extent of myocardial damage. Key molecular mechanisms were evaluated via western blotting and immunohistochemistry, examining pathways related to inflammation (NF-κB), apoptosis (Bcl-2/Bax, caspase-3), endoplasmic reticulum (ER) stress (GRP78, CHOP, PERK-eIF2α), and antioxidant defense (GSH, SOD, CAT). RESULTS: Our results demonstrate that 1,8-cineole significantly reduced the levels of serum cardiac enzymes (CK-MB, LDH), and histopathological damage. Mechanistically, 1,8-cineole also suppressed pro-inflammatory cytokine release (TNF-α, IL-6, and IL-1β) via inhibition of the NF-κB pathway. Furthermore, it attenuated cardiomyocyte apoptosis by modulating Bcl-2/Bax expression and inhibiting caspase-3 activation. Additionally, 1,8-cineole alleviated ER stress by downregulating GRP78, CHOP, and PERK-eIF2α signaling. Importantly, we identified enhanced Nrf2 nuclear translocation and subsequent upregulation of antioxidant enzymes (GSH, SOD, CAT) as key contributors to its cytoprotective effects. CONCLUSIONS: 1,8-Cineole exhibits potent cardio-protection in experimental myocardial injury by targetinginflammation, apoptosis, ER stress, and oxidative stress through modulation of p38 MAPK/JNK, suppression of inflammatory markers (TNF-α, IL-6, IL-1β) and apoptotic markers (Bax, p53). Its natural origin, bioavailability, and multi-mechanistic effectiveness make it a promising candidate for translational development as an adjunct therapy for myocardial injury.

Animals↗

PubMed2026

Does high fructose consumption trigger microglia activation and neuroinflammation? A systematic review.

This systematic review evaluated the effects of fructose intake on neuroinflammatory markers in rodent models. The search terms Fructose AND neuroinflammation OR Neurodegeneration OR chemokines OR interleukins OR microglia OR behaviour OR memory OR cognition were used in Google Scholar, Scopus and Web of Science. Thirteen animal studies investigating fructose-induced neuroinflammation that matched the eligibility criteria were included in the study. Across the studies, 16 inflammatory markers were identified and significantly altered following exposure to fructose. The findings consistently demonstrated elevated expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β, following fructose administration. Fructose consumption also dysregulated MCP-1, fractalkine, and CX3CR1 levels, thereby promoting inflammatory signalling and microglial activation. Furthermore, fructose exposure significantly increased IBA-1 and CD11b, indicating sustained neuroimmune activation. Alterations in important inflammatory pathways involving TLR4, NLRP3, NF-κB, MyD88, iNOS, and cyclooxygenases (COX-1 and COX-2) were also observed. In contrast, expression of the anti-inflammatory regulator peroxisome proliferator-activated receptor gamma (PPARγ) was reduced after fructose treatment. Overall, the findings suggest that chronic fructose consumption induces neuroinflammation through multiple inflammatory and immune-related mechanisms in the brain. These effects appear to be dose- and duration-dependent and may contribute significantly to neurodegeneration and cognitive impairment.

Microglia↗

PubMed2026

Atypical cytokine profiles in people on the autism spectrum: a comprehensive systematic review and meta-analysis including 54 cytokines.

Atypical peripheral blood cytokine concentrations have been shown in autism, but no clear pattern has been observed. This systematic review and meta-analysis summarised current state of findings, expanded the range of cytokines, accounted for study risk of bias, and examined relations between cytokines and autism traits. Literature comparing peripheral blood cytokine in autistic and non-autistic people was systematically searched in Ovid® Embase, MEDLINE and APA PsycINFO, Web of Science™ and Scopus, resulting in 98 studies and 54 cytokines (4236 autistic, 3333 non-autistic controls; age 2 to 65 years) in the meta-analysis. Study risk of bias was assessed using adapted Newcastle-Ottawa Scale. Compared to controls, autistic people had elevated levels of IL1-beta (Hedges' g = 0.620, 95%CI[0.32, 0.92]), IL4 (g = 0.245, 95%CI [0.07, 0.42]), IL6 (g = 0.365, 95%CI [0.011, 0.62]), IL8 (g = 0.384, 95%CI [0.15, 0.62]), IFN-gamma (g = 0.404, 95%CI [0.09, 0.72]), TNF-alpha (g = 0.31, 95%CI [0.11, 0.51]), CXCL1/GRO-α (g = 0.364, 95%CI [0.058, 0.670]) and MIF (g = 0.560, 95%CI [0.14, 0.98]). Over a third of studies were classified as having a high risk of bias; their removal revealed higher IL7 and IL1RA in autism relative to controls. Narrative synthesis produced no strong evidence for an association between cytokine and autism traits among autistic individuals. Altogether, our findings support a predominance of pro-inflammatory cytokines, while also indicating potential modulatory contributions from inhibitory cytokines, which reflect group-level differences between autistic and non-autistic individuals, but not variations of autism traits within the autistic population. However, higher-quality studies with low risk of bias are needed before firm conclusions can be drawn.

Humans↗

PubMed2026

Multi-omics analysis reveals stage-associated differences in gut immunity and microbiota between juvenile and adult common carp (Cyprinus carpio).

In vertebrates, the development of intestinal immunity is closely associated with dynamic changes in the gut microbiota. However, stage-associated differences in intestinal immunity and gut microbial communities remain poorly characterized in teleost fish. In this study, transcriptomic analysis combined with 16S rRNA gene sequencing was employed to characterize intestinal immunity and gut microbial communities in juvenile and adult common carp (Cyprinus carpio). Transcriptomic profiling revealed marked developmental differences in intestinal immune function. Juvenile carp exhibited a predominantly innate immune phenotype, characterized by elevated expression of pro-inflammatory cytokines, antimicrobial peptides, and lysozyme-related genes. This immune profile was accompanied by enhanced mucosal barrier function and a relatively pro-inflammatory intestinal environment. In contrast, adult carp displayed increased expression of genes associated with adaptive immunity, suggesting that adult common carp exhibit relatively stronger adaptive immune characteristics than juvenile fish. Gut microbiota analysis demonstrated significant stage-dependent differences in microbial diversity and community composition. Juvenile fish were enriched with bacterial taxa potentially associated with innate immune activation, whereas adult fish harbored distinct microbial communities linked to intestinal homeostasis and barrier maintenance. Furthermore, correlation analyses identified significant associations between specific microbial taxa and innate immune-related gene expression, suggesting a close association between gut microbiota composition and intestinal immune characteristics in juvenile and adult common carp. Collectively, these findings reveal stage-associated differences in intestinal immunity and gut microbial communities between juvenile and adult common carp, thereby providing insights into intestinal immune characteristics at different developmental stages in teleost fish.

Animals↗

PubMed2026

Human Monocytic Models Reveal Genotype-Dependent Inflammatory Programs in VEXAS Syndrome.

OBJECTIVES: VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets. METHODS: We conducted longitudinal deep phenotyping, including whole-blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses. RESULTS: Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes upregulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, FDR < 0.05) and was upregulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 upregulation, all following the same graded pattern, recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathological features, including RNASE1 upregulation. CONCLUSIONS: Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.

Journal Article↗

PubMed2026

TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses.

Asthma is a complex inflammatory airway disease with strong genetic determinants, yet the functional relevance of most asthma-associated non-coding variants remains unclear. Emerging evidence suggests that N6-methyladenosine (m6A) modification may serve as a critical epitranscriptomic link between genetic variation and immune regulation. In this study, we aimed to systematically identify functionally relevant m6A-regulated genes in asthma by integrating large-scale GWAS data, m6A-SNP annotations, and single-cell transcriptomic analyses, and to investigate their roles in monocyte-driven airway inflammation. We identified TET2 as a key m6A-regulated gene associated with both asthma and lung function, which was selectively upregulated in monocytes during asthma and accompanied by activation of inflammatory and PI3K signaling pathways. Mechanistic experiments further demonstrated that inflammatory stimulation induced ALKBH5 expression, reduced m6A modification of TET2 mRNA, and increased TET2 protein levels, thereby promoting PI3K/AKT signaling and pro-inflammatory cytokine production, whereas inhibition of TET2 or ALKBH5 attenuated these effects. Collectively, these findings demonstrate that ALKBH5-mediated m6A regulation of TET2 enhances PI3K/AKT signaling in monocytes, thereby promoting inflammatory responses in asthma. Our study establishes TET2 as a key m6A-regulated gene linking genetic susceptibility to monocyte-driven inflammation, and highlights the ALKBH5-m6A-TET2 axis as a potential therapeutic target for modulating aberrant immune responses in asthma.

Humans↗

PubMed2026

Eagle-Derived Weissella confusa EG05 Prevents LPS-Induced Enteritis Through Modulation of Inflammation, Gut Barrier, And Microbiota.

Intestinal enteric inflammation can seriously harm animal health and lead to massive economic losses in livestock production. Probiotics have become a promising alternative to antibiotics for preventing and controlling enteritis. In this study, a novel lactic acid bacterium (LAB) was isolated from eagle feces and identified as Weissella confusa EG05 (W. confusa EG05), and its probiotic characteristics and protective effects on lipopolysaccharide (LPS)-induced enteritis in mice were evaluated. In vitro experiments showed that W. confusa EG05 has strong antimicrobial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), good tolerance to acidic and bile salt conditions, high auto-aggregation ability and surface hydrophobicity, and no hemolytic activity. Whole-genome analysis further confirmed its safety and probiotic potential by revealing genes involved in adhesion, immune regulation, and stress tolerance. In mouse experiments, pretreatment with W. confusa EG05 alleviated LPS-induced intestinal pathological damage, inhibited the secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6), promoted the expression of anti-inflammatory cytokine IL-10, enhanced the activities of antioxidant enzymes, and up-regulated the expression of tight junction proteins (Occludin, ZO-1). In addition, W. confusa EG05 restored gut microbiota homeostasis disturbed by LPS, increasing the abundance of beneficial genera and decreasing harmful bacteria. Taken together, these results suggest that W. confusa EG05 can effectively prevent LPS-induced enteritis in mice by modulating the inflammatory response, enhancing antioxidant capacity, protecting the intestinal barrier and the reshaping gut microbiota. These results indicate that W. confusa EG05 exhibits prominent probiotic potential in mouse models, providing a strain resource for the future development of microecological preparations.

Weissella confusa EG05↗

PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗

PubMed2026

Maternal immune activation disrupts epigenomic and functional maturation of cortical excitatory neurons.

Elevated levels of maternal pro-inflammatory cytokines following severe infection during gestation can disrupt offspring neural development and increase the risk of neurodevelopmental disorders. The viral mimetic Poly(I:C) reproduces the effects of gestational influenza exposure, leading to behavioral outcomes that recapitulate neurodevelopmental disorder phenotypes. Although Poly(I:C)-induced maternal immune activation (PIC-MIA) alters the epigenome, behavior and cognition of offspring in adulthood, it remains unclear when these changes occur and how MIA influences the epigenomic regulatory programming across the transition from embryonic development to the mature brain. Here, we examined the effects of PIC-MIA on the epigenomic maturation of the frontal cortex, focusing on excitatory neuron-specific DNA methylation and transcriptomic dynamics throughout perinatal development. Mid-gestation PIC-MIA disrupted development of the excitatory neuron transcriptome, with the largest alterations observed at birth. PIC-MIA altered the development of the mature DNA methylation program of excitatory neurons at thousands of genomic regulatory regions that normally gain or lose methylation during development. Transcription factor binding site analyses of these differentially methylated regions revealed a significant enrichment of Tbr1 motifs within hyper-methylated deep-layer neuron-specific regions at birth. Notably, transcriptional targets of Tbr1 were down-regulated at birth despite up-regulation of Tbr1 transcription, suggesting PIC-MIA uncouples Tbr1 expression from its regulatory function in deep-layer neurons. Electrophysiological recordings of intrinsic and firing properties further confirmed a lasting disruption in deep-layer neuronal activity. Our results suggest that mid-gestation MIA may alter the development of deep-layer neurons through an epigenomic blockade of Tbr1 function, thereby perturbing normal cortical circuit formation.

Journal Article↗

PubMed2026

Kmt2c and Kmt2d histone methyltransferase deficiencies compromise macrophage function.

Methylation of histone (H) 3 lysine (K) 4 (H3K4) has a well-established role in innate immune responses, but the contribution of H3K4 methyltransferases Kmt2c and Kmt2d in innate immunity is incompletely understood. Using conditional knockout mouse models, we investigated how Kmt2c- and Kmt2d-deficiencies affect innate immune cell function. Through functional, transcriptomic, and metabolic analyses, we delineate the consequences of disrupted epigenetic regulation on macrophage biology. Our findings reveal that loss of Kmt2c or Kmt2d in macrophages leads to impaired pro-inflammatory cytokine response and phagocytotic capacity, as well as skewed energy metabolism toward glycolysis, highlighting the critical role of H3K4 methylation-dependent chromatin regulation in shaping innate immune cell behavior. This study provides the first comprehensive characterization of innate immune system dysfunction in mouse models with conditional Kmt2c and Kmt2d deletions and offers mechanistic insight into how epigenetic regulators control fundamental immune processes.

Animals↗

PubMed2026

Nebivolol treatment improves hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalizing mitochondrial indices.

OBJECTIVES: Serum from patients with hypertension (HT) causes endothelial cell (EC) damage, leading to senescence and dysfunctional phenotype. This study investigated whether serum from patients treated with the antihypertensive drugs could normalize EC activity. METHODS: This study involved 71 patients with newly diagnosed HT, who were randomly assigned to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. Serum samples collected before and 6 weeks after treatment were applied to ECs in vitro to assess their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress. RESULTS: Results showed that exposure of ECs to serum from patients treated for 6 weeks significantly altered EC function, with varying effects among the drugs. Serum from nebivolol-treated patients produced the most consistent benefits, reducing EC proliferation and HIF-1α expression, likely due to lower levels of angiogenic factors such as angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Additionally, this serum contained reduced levels of pro-inflammatory cytokines (E-selectin, P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα)) and lower TGF-β1, which are linked to HT-related EC senescence. Nebivolol treatment decreased senescence biomarkers such as SA-β-Gal, 53BP1, and p16, with SA-β-Gal reduction comparable to that of TGF-β1 neutralizing antibodies. Oxidative stress was reduced, indicated by lower oxidized DNA product levels. CONCLUSIONS: Nebivolol was the most effective at reducing the factors, associated with HT induced cellular senescence of endothelium, through reducing TGF-β1.

Humans↗

PubMed2026

[Study on mechanism of Wendan Decoction in intervening in nonalcoholic fatty liver disease based on proteomics and network pharmacology].

This study systematically explored the molecular mechanism of Wendan Decoction(WDD) in treating nonalcoholic fatty liver disease(NAFLD) by integrating network pharmacology, proteomics, and experimental validation. A mouse NAFLD model was established using a high-fat diet, and the mice were randomly divided into a blank control group, a model group, a positive drug group(simvastatin, 3.03 mg·kg~(-1)), and low-(3.035 g·kg~(-1)), medium-(6.07 g·kg~(-1)), and high-dose(12.14 g·kg~(-1)) WDD groups, with intervention lasting for 6 weeks. After the intervention, the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) were measured using an automatic biochemical analyzer. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were detected by ELISA. Liver histopathology was observed via hematoxylin-eosin(HE) staining and oil red O staining. Network pharmacology was used to predict potential targets and pathways, and proteomics was applied to identify differentially expressed proteins and related pathways. RT-qPCR and Western blot were performed to detect mRNA and protein expression of relevant genes. Animal experiments demonstrated that WDD dose-dependently ameliorated hepatic steatosis, inflammation, and lipid deposition, significantly reducing serum levels of ALT, AST, TG, TC, LDL-C, and pro-inflammatory cytokines(IL-1β, IL-6, and TNF-α), while significantly increasing serum HDL-C levels. Network pharmacology screening identified naringenin, baicalein, and other key active components, which were involved in pathways such as the peroxisome proliferator-activated receptor(PPAR), lipid, and atherosclerosis pathways. Proteomics further revealed differentially expressed pathways including the PPAR and advanced glycation end product-receptor(AGE-RAGE) signaling pathways. Integrated analysis highlighted the PPAR signaling pathway as the core mechanism. Molecular biology validation showed that WDD significantly regulated the mRNA expression of sterol regulatory element-binding protein-1c(SREBP-1c), fatty acid synthase(FASN), carnitine palmitoyl transferase 1A(CPT1A), acyl-CoA oxidase 1(ACOX1), and PPARα, as well as protein expression of PPARα, CPT1A, and PPARγ in mouse liver tissue. These results suggested that WDD might exert a multi-component, multi-target, and multi-pathway synergistic effect to improve lipid metabolism disorders and inflammatory responses with the PPAR signaling pathway as the central hub, thereby alleviating NAFLD progression.

Animals↗

PubMed2026

SSB deficiency-induced R-loop accumulation triggers podocyte inflammation in DKD.

INTRODUCTION: Diabetic kidney disease (DKD) is fundamentally a podocytopathy in which sterile inflammation plays a central pathogenic role, yet the upstream triggers that initiate inflammatory cascades in podocytes remain elusive. R-loops are critical regulators of genomic stability, and their pathological accumulation triggers DNA damage and innate immune activation. Whether R-loop dysregulation contributes to podocyte-driven inflammation in DKD is unknown. METHODS: We integrated single-cell transcriptomic profiling, dual machine learning algorithms, and functional experiments to dissect the R-loop regulatory network in the diabetic kidney. RESULTS: Integrated analysis of human diabetic kidney single-cell RNA-seq data revealed a globally compromised R-loop regulatory network selectively within podocytes. Intersection of podocyte-specific transcriptomic shifts with validated R-loop regulators identified 93 candidate genes, from which dual machine learning algorithms pinpointed SSB (Sjögren syndrome antigen B) as the principal podocyte-selective R-loop resolver and a superior diagnostic biomarker (AUC = 0.983). SSB expression was selectively downregulated in diabetic podocytes and showed the strongest positive correlation with the R-loop resolution module. Mechanistically, SSB loss impaired RNA splicing and stability pathways, leading to aberrant R-loop accumulation that activated the cGAS-dependent inflammatory signaling in podocytes. In two murine DKD models and high glucose-challenged podocytes, SSB was markedly reduced. Remarkably, SSB knockdown in podocytes alone sufficed to trigger R-loop accumulation and pro-inflammatory cytokine expression, whereas both RNase H1-mediated R-loop removal and cGAS co-depletion blunted this response. DISCUSSION: These findings suggest that an SSB-governed R-loop -cGAS -inflammatory signaling axis may link genomic instability to podocyte inflammation and contribute to DKD progression, nominating R-loop homeostasis as a previously unrecognized potential therapeutic target.

Podocytes↗

PubMed2026

Placenta-derived Exosomes Mitigate Hypoxia-Induced Trophoblast Apoptosis and Inflammatory Progression via SASH1.

SASH1 is a signal adaptor protein involved in cell growth, apoptosis, and immune regulation, and has been increasingly studied in tumor and immune cells. Emerging evidence suggests that SASH1 plays an important role in inflammatory responses and cellular homeostasis, processes that are closely associated with the development of PE. This study aimed to determine whether SASH1 contributes to trophoblast apoptosis and inflammatory responses in PE and whether P-EXOS exerts protective effects through SASH1 regulation. In this study, three PE-related transcriptomic datasets (GSE75010, GSE10588, and GSE60438) were analyzed to identify shared differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Machine learning algorithms were further applied to screen key candidate genes, and single-cell RNA sequencing data were used to characterize cellular heterogeneity in placental tissue and to determine cell type-specific expression patterns. SASH1 was identified as a consensus candidate gene and was significantly upregulated in trophoblast cells from PE samples. In vitro, a hypoxia-treated HTR-8/SVneo trophoblast cell model was established, combined with SASH1 knockdown, SASH1 overexpression, and co-culture with P-EXOS. Functional experiments showed that knockdown of SASH1 significantly suppressed hypoxia-induced trophoblast apoptosis and reduced the secretion of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, whereas SASH1 overexpression promoted apoptosis and inflammatory responses. In addition, P-EXOS treatment markedly reduced SASH1 expression at both mRNA and protein levels and attenuated hypoxia-induced trophoblast injury, while SASH1 overexpression largely abolished these protective effects. Taken together, these findings indicate that SASH1 plays a critical role in trophoblast apoptosis and inflammatory responses in PE. P-EXOS may alleviate hypoxia-induced trophoblastic injury by suppressing SASH1 expression, providing new insights into the molecular mechanisms and potential therapeutic targets for PE.

Trophoblasts↗

PubMed2026

Interleukin-1α Mediates Pancreatic Fibroblast Activation, Regulates Immune Cell Recruitment and Fibrosis in Acute and Chronic Pancreatitis.

Pancreatitis is a life-threatening inflammatory disease of the pancreas. The cytokine interleukin-1α has been demonstrated to act as an alarmin released by necrotic cells. In the present study, we investigated the influence of IL-1α on the immune response during acute and chronic pancreatitis. Following tissue injury, pancreatic acinar cells released IL-1α, which activates tissue-resident fibroblasts to differentiate toward a pro-inflammatory phenotype. By secreting chemokines and cytokines such as CXCL5, CCL2, and IL-6, these fibroblasts recruit immune cells to the pancreas. The absence of IL-1α reduces disease severity in acute pancreatitis and chemokine release. Furthermore, IL-1α primes fibroblasts to enhance the production of extracellular matrix-components by the up-regulation of pro-fibrotic receptors such as Il4ra, Il13ra1, and Tgfbr3. Therefore, the deletion of IL-1α significantly reduced the development of tissue fibrosis. A therapeutic blockade of the IL1R1-signaling by i.p. administration of the IL-1-receptor antagonist Anakinra showed the same effect; the severity of acute pancreatitis and fibrogenesis during chronic pancreatitis were reduced. In conclusion, the crosstalk between necrotic acinar cells and fibroblasts mediated by IL-1α plays a crucial role in acute inflammation of the pancreas and fibrogenic signaling. Blockade of IL1R1-signaling by Anakinra is therefore a promising therapeutic intervention for both acute and chronic pancreatitis.

Anakinra↗

PubMed2026

Probiotic supplementation increases fecal TLR4 agonists without improving disease activity in juvenile idiopathic arthritis: a randomized placebo-controlled trial.

Gut dysbiosis has been implicated in the pathogenesis of juvenile idiopathic arthritis (JIA), suggesting that microbiota-targeted interventions may influence immune signalling during early immune development. We conducted the PERMAJI multicentre randomized, double-blind, placebo-controlled trial to evaluate the effects of probiotic supplementation (VSL#3) on host-microbiota immune interactions and disease activity in children with oligoarticular or RF-negative polyarticular JIA. Participants were randomly assigned (1:1) to receive VSL#3 or placebo for 3 months in addition to standard therapy. Stool and serum samples collected at baseline and month 3 were used to assess gut microbiota composition, fecal innate immune agonists, intestinal permeability, and systemic cytokines. The primary clinical endpoint was the proportion achieving an ACR Pedi 30 response at 3 months. Forty-four children were enrolled between September 2017 and July 2022. Clinical responses did not differ between groups (ACR Pedi 30: 47% with VSL#3 vs 63% with placebo; p = 0.33), and conservative worst-case assumptions for missing data suggested lower response rates with VSL#3 (36% vs 68%; p = 0.03). Probiotic supplementation significantly increased fecal Toll-like receptor 4 (TLR4) agonist activity, whereas gut microbiota diversity, intestinal permeability, and systemic cytokine levels remained unchanged. These findings indicate that probiotic supplementation can modify microbial innate immune signalling without detectable changes in microbial community diversity and may increase exposure to pro-inflammatory microbial stimuli in early-life autoimmune disease. The results highlight the complexity of host-microbiota immune interactions and underscore the need for careful evaluation of microbiome-targeted therapies in paediatric autoimmune disorders.

Humans↗

PubMed2026

MASLD Exacerbates Chronic Low-dose PM2.5-induced Lung Injury, Inflammation, and Fibrosis.

BACKGROUND/AIM: Fine particulate matter (PM2.5) and metabolic dysfunction-associated steatotic liver disease (MASLD) are independent risk factors for respiratory disease. However, the combined impact of chronic, low-dose PM2.5 exposure and Western diet (WD)-induced metabolic dysfunction on pulmonary health remains poorly understood. We investigated whether this metabolic state exacerbates PM2.5-driven pathologies using an environmentally relevant PM2.5 dosage (~50 μg/m3). MATERIALS AND METHODS: C57BL/6J mice were fed a WD or normal diet (ND) for 28 weeks and concurrently received intratracheal instillations of PM2.5 (0.5 mg/kg diesel particulate matter) or vehicle three times per week. The MASLD phenotype was confirmed through metabolic and histological analyses. Pulmonary injury, fibrosis, and inflammation were assessed via histology (hematoxylin and eosin, and Masson's trichrome staining) and cytokine quantification in both bronchoalveolar lavage fluid using Luminex multiplex assay and lung tissue using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. RESULTS: The WD successfully induced MASLD characterized by weight gain, hepatic steatosis, and dyslipidemia. While PM2.5 exposure did not significantly worsen the primary features of MASLD, its combination with a WD markedly exacerbated pulmonary injury and fibrosis compared to PM2.5 exposure alone. This exacerbation was driven by a surge in pro-inflammatory chemokines, including C-X-C motif chemokine ligands 1 and 2 (CXCL1 and CXCL2), and C-C motif chemokine ligand 5 (CCL5), confirmed by Luminex analysis of lavage fluid and mRNA/protein quantification in lung tissue. CONCLUSION: Diet-induced metabolic dysfunction primes the lung for a hyper-inflammatory response to chronic PM2.5 exposure. These findings identify individuals with MASLD as a population with heightened susceptibility to air pollution-related respiratory diseases and underscore the critical interplay between metabolic health and environmental toxicology.

Animals↗