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PubMed2026

Understanding specificity in immune-brain pathways: A systematic review of differential associations between individual cytokines and brain structure and function measured through magnetic resonance imaging in humans.

Research shows that cytokines are associated with psychiatric disorders, including major depression, and multiple aspects of brain structure and function. Accumulating data suggest that different cytokines may have unique profiles of biological activity, particularly in their neuromodulatory roles, but it is currently unclear whether they have unique associations with specific neural circuits in humans. In this paper, we systematically review magnetic resonance imaging studies conducted with depressed or healthy control human participants under age 65 that examine associations between peripheral cytokines and brain structure and function, with the goal of evaluating evidence for the specificity of these cytokine-brain associations. We find that across multiple measures of brain structure and function, the majority of studies reviewed reported unique associations between individual cytokines and brain outcomes. A synthesis of findings across studies also suggests a preliminary hypothesis of specific associations of interleukin-6 levels in circulation with the default mode network and tumor necrosis factor-alpha with the salience network, which could be tested in future research. We conclude the review with future directions for research that can strengthen understanding of these associations.

Humans↗

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

11-O-galloylbergenin alleviates LPS-stimulated inflammation in RAW 264.7 macrophages by targeting Grb2, RhoA, and Cdc42 in the RAS signaling pathway.

OBJECTIVE: This study aimed to explore the anti-inflammatory mechanism of 11-O-galloylbergenin in macrophages. METHODS: Lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were treated with 11-O-galloylbergenin. Cytotoxicity was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cytokine secretion was measured by enzyme-linked immunosorbent (ELISA) assay. Data-independent acquisition (DIA)-based proteomics, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, western blotting, and molecular docking were also performed. RESULTS: 11-O-Galloylbergenin (≤50 μg/mL) was non-cytotoxic and significantly suppressed tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) secretion. Proteomics analysis identified 209 differentially expressed proteins (DEPs) that showed opposite expression trends before and after 11-O-galloylbergenin treatment. Seven of these DEPs were enriched in the RAS pathway: RhoA, Cdc42, Grb2, RalB, Calm3, Gnb2, and Pla2g4a. Western blotting confirmed that 11-O-galloylbergenin downregulated RhoA, Cdc42, and Grb2 expression. Molecular docking revealed good binding affinity of 11-O-galloylbergenin to RhoA, Cdc42, and Grb2. CONCLUSION: 11-O-Galloylbergenin alleviates LPS-stimulated inflammation in RAW 264.7 macrophages by inhibiting the RAS signaling pathway.

Animals↗

PubMed2025

Elucidation of the immunotoxicity of PEDOT: PSS on RAW264.7 macrophages by oxidative stress, inflammatory response, and NF-κB pathway activation.

Poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT: PSS) nanoparticles, widely used conductive polymers, pose environmental and health risks due to their nanoscale dispersion. However, the characteristics of PEDOT: PSS in aquatic systems and the underlying mechanisms of its toxicity in animal and cell models remain poorly understood. This study aimed to investigate the toxicological effects of PEDOT: PSS nanoparticles on macrophages, with a focus on RAW 264.7 cells. After an acute exposure to PEDOT: PSS nanoparticles at different concentrations (5, 10, 20 μg/mL), we observed significant impairments in cell viability, proliferation, migration, adhesion, and phagocytosis, as well as morphological alterations. Concurrently, there was a marked upregulation of inflammatory markers, including reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), indicating the induction of oxidative stress and inflammation. Mechanistically, PEDOT: PSS nanoparticles activated the nuclear factor kappa B (NF-κB) signaling pathway, a key regulator of inflammatory responses, suggesting that they may mediate inflammatory responses and cell damage via activation of the NF-κB signaling pathway. These findings reveal the toxic mechanism of PEDOT: PSS nanoparticles in macrophages and provide new insights into their biological safety implications.

Animals↗

PubMed2026

Metabolomic Signatures of Inflammation in Chronic Kidney Disease.

RATIONALE & OBJECTIVE: Inflammation is associated with adverse kidney, cardiovascular, and mortality outcomes. Investigation of the metabolic milieu as it relates to inflammation may provide important insights into these disease processes. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: African American Study of Kidney Disease and Hypertension (AASK), Atherosclerosis Risk in Communities (ARIC) study, and Boston Kidney Biopsy Cohort (BKBC) participants with available metabolomics and inflammatory protein data. PREDICTORS: Baseline blood levels of 718 metabolites. OUTCOMES: Baseline and longitudinal changes in blood levels of tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins 6, 8, and 10 (IL-6, IL-8, IL-10), uromodulin (UMOD), and epidermal growth factor (EGF). ANALYTICAL APPROACH: Multivariable linear regression and linear mixed-effects models. RESULTS: Among 491 AASK participants (mean age 54 years; 37% women; mean glomerular filtration rate, 45 mL/min/1.73 m2), 367 cross-sectional associations between metabolites and inflammatory proteins were significant after correction for multiple comparisons. The direction of association was mostly positive for TNFR1 (97%), TNFR2 (97%), IL-8 (77%), and IL-10 (100%); negative for UMOD (80%) and EGF (97%); and variable for TNF-⍺, IFN-γ, and IL-6. Pathways were distinct for several inflammatory proteins (eg, tryptophan metabolism for TNFR2). Forty-five associations between metabolites and longitudinal change in inflammatory proteins were identified. Notable metabolites included tigylcarnitine and N 2,N 5-diacetylornithine, which were associated with 2-year increases in TNFR1 and/or TNFR2, and 1,5-anhydroglucitol, where lower levels were associated with decreases in UMOD. In ARIC (n = 3,773) and BKBC (n = 413), replication of cross-sectional associations was excellent for TNFR1 (ARIC 83%; BKBC 85%) and TNFR2 (ARIC 64%; BKBC 79%) but poor for IL-8 (ARIC 3%; BKBC 3%). LIMITATIONS: Metabolite data limited to baseline visit; potential for residual confounding. CONCLUSIONS: Using an untargeted approach, multiple metabolites were cross-sectionally and longitudinally associated with inflammatory proteins in persons with chronic kidney disease.

Chronic kidney disease↗

PubMed2026

A Novel PTPN2 Isoform Differentially Regulates Immune Response.

Genome-wide association studies implicate the PTPN2 gene locus (18p11.21) in risk for several autoimmune diseases, including inflammatory bowel disease. Through genetic fine mapping, we identified the single-nucleotide polymorphism rs80262450 in the PTPN2 gene as the putative causal variant. Analysis of GTEx tissue samples and genetically engineered myeloid cell lines carrying risk and nonrisk alleles of rs80262450 demonstrated increased expression of the PTPN2 splice isoform 4 (PTPN2.4), suggesting that the rs80262450 enhances disease susceptibility by favoring production of PTPN2.4. Furthermore, we found that PTPN2.4 contains a nuclear export sequence (NES) that leads to its retention in the cytoplasm. Differential localization of PTPN2.4 isoform results in a distinct protein binding profile revealed by mass-spectrometry analysis, and its overexpression increased TNF-α. PTPN2.4 knockdown reduced pro-inflammatory cytokines in human macrophages. Mutations within the NES motif abolished the unique localization and function of PTPN2.4. Lastly, increased expression of PTPN2.4 was found in Crohn's disease tissues, demonstrating its involvement in the disease. Together, we identified the pathogenic isoform PTPN2.4 as a novel driver of intestinal inflammation and a potential target to attenuate inflammation in IBD.

Humans↗

PubMed2026

Obeticholic Acid and Edaravone Protect Against Cisplatin-Induced Hepatotoxicity Through Modulation of Keap1/Nrf2/ARE, TNF-α/NF-κB, and AKT/GSK-3β Pathways.

Hepatotoxicity is one of the most crucial side effects of chemotherapy administration. Obeticholic acid (OCA) is a semisynthetic bile acid and farnesoid X receptor (FXR) agonist derived from chenodeoxycholic acid, with reported antioxidant and anti-inflammatory effects in liver disorders. This study investigated the hepatoprotective effect of OCA against commonly used chemotherapy cisplatin (CP)-induced hepatotoxicity in rats, as well as the modulatory effects of edaravone (EDA), a potent free radical scavenger, on its effects. Rats were divided into five groups: control (received vehicle), CP (7.5 mg/kg), EDA (30 mg/kg) + CP, OCA (30 mg/kg) + CP, and EDA + OCA + CP. The results of the present study demonstrated that both OCA and EDA significantly mitigated liver damage caused by CP, as evidenced by restoring liver enzymes and histological structure, reestablishment of oxidant/antioxidant status, suppression of inflammation, and attenuation of pro-death signaling. The study highlights the role of key molecular pathways, including Keap1/Nrf2/HO-1,HO-1, TNF-α/NF-κB, and AKT/GSK-3β, in the hepatoprotective mechanisms of OCA. Collectively, these findings suggest that OCA and EDA, particularly in combination, attenuate CP-induced hepatotoxicity and are associated with coordinated modulation of oxidative stress, inflammatory signaling, and AKT/GSK-3β-associated pro-survival/pro-death pathways.

Animals↗

PubMed2026

Pairwise Comparative Safety and Effectiveness of Anti-TNF Blockers, Vedolizumab, and Ustekinumab During Pregnancy: A Systematic Review and Meta-Analysis.

PURPOSE: Biologic therapies, including tumor necrosis factor (TNF) blockers, vedolizumab (VDZ), and ustekinumab (UST), are generally considered safe during pregnancy in patients with inflammatory bowel disease (IBD), though comparative data remain limited. This meta-analysis examines their safety and effectiveness. METHODS: A systematic search of MEDLINE, EMBASE, CINAHL, Cochrane, and Web of Science was conducted through July 2025. Eligible studies reported maternal or neonatal outcomes in pregnant IBD patients treated with biologics. Studies were pooled using a random-effects model to calculate risk ratios (RRs) with 95% confidence intervals. Heterogeneity was assessed using I2. Primary outcomes were preterm birth and disease activity; secondary outcomes included pregnancy and neonatal outcomes. RESULTS: Nine observational studies (n = 6,054) were included. Compared to TNF blockers, VDZ was associated with a higher risk of preterm delivery (RR = 1.35, 95% CI 1.04-1.75, I2 = 0%) and active disease (RR = 1.55, 95% CI 1.01-2.40, I2 = 50%). UST was associated with a higher risk of active disease (RR = 1.30, 95% CI 1.06-1.60, I2 = 0%) and congenital anomalies (RR = 2.08, 95% CI 1.30-3.32, I2 = 0%) compared to TNF blockers. Compared to UST, VDZ was linked to increased risks of preterm birth (RR = 2.60, 95% CI 1.03-6.57, I2 = 0%) and low birth weight (RR = 2.38, 95% CI 1.01-5.60, I2 = 0%). No significant differences were observed for live births, abortions, hospitalizations, or neonatal infections. CONCLUSION: TNF blockers showed a favorable safety and effectiveness profile, VDZ and UST performed broadly similar, and all three biological classes appeared compatible with safe use in pregnancy to maintain effective disease control. Observed differences reflect that VDZ and UST cohorts likely had longer disease duration, prior biologic exposure, and more active disease. The results of this meta-analysis support the continuation of biologic therapy for disease control in pregnant patients with IBD. Treatment decisions should be individualized and tailored to each patient's clinical context.

Female↗

PubMed2026

Proteomic insights into the immunomodulatory effects of Ca/Sr co-doped sol-gel coatings for titanium implants.

Ionic functionalization of biomaterial coatings has emerged as a powerful strategy to regulate early host responses at the implant interface. However, how combined Ca/Sr incorporation governs the adsorbed proteome and downstream immune signaling remains poorly understood. This study analyses, employing in vitro tests and proteomics, the effect of adding Sr and Ca to Si-based coatings designed to bioactivate Ti implants. Hybrid Si-based coatings were synthesized by the sol-gel route with a fixed Ca content (0.5 wt%) and increasing Sr contents (0.5, 1.0, 1.5 wt%), and their physicochemical properties, ion release kinetics, and hydrolytic stability were characterized. The coatings remained highly crosslinked despite Ca/Sr incorporation, whereas the highest Sr content increased hydrolytic degradation to around 70% after 56 days. Proteomic analysis identified 183 adsorbed proteins, of which 56 were differentially adsorbed on Ca/Sr-coatings, mainly associated with immune and coagulation pathways. In vitro, RAW 264.7 showed increased gene expression of TNF-α and TGF-β; with an enhanced TNF-α secretion by the addition of Ca and Sr. In parallel, MC3T3-E1 indicated that Ca/Sr-coatings were not cytotoxic and did not impair cell proliferation. However, ALP activity was reduced in the co-doped groups, indicating that the immunomodulatory effects induced by Ca/Sr incorporation were not accompanied by enhanced early osteogenic differentiation. The Ca/Sr combination induced alterations in the adsorption of immune-related proteins, which correlated with the in vitro findings. The deeper insight into how Ca/Sr mixtures modulate protein adsorption on biomaterial surfaces may be key to understanding the immunomodulatory capacity of these bioactive cations.

Animals↗

PubMed2026

TNF-NF-κB signaling mediates immune-biomineralization crosstalk during shell repair under ocean acidification in Mytilus edulis.

Ocean acidification (OA) impairs biomineralization in bivalves, but its effects on immune-biomineralization crosstalk during shell repair remain unknown. Here, we exposed adult Mytilus edulis bearing standardized shell perforations to three pH levels (8.1, 7.9, and 7.7) for up to 40 days. OA slowed early repair and caused microstructural disorganization and an approximately 87% reduction of compressive strength at pH 7.7, yet the damaged area appeared largely closed by day 15, suggesting a decoupling between morphological closure and functional recovery. In addition, transcriptomic profiling of hemocytes and mantle tissue, based on an average of 6.5 Gb of clean reads per sample mapped to the M. edulis reference genome (NCBI Assembly GCF_000511035.1), revealed that these shell-level defects were accompanied by coordinated immune and metabolic reprogramming. Hemocytes, the primary immune effector cells of bivalves, exhibited pH- and time-dependent shifts with moderate acidification (pH 7.9) promoting inflammatory transcripts, whereas severe acidification (pH 7.7) suppressed these signals while upregulating stress-associated pathways; both treatments consistently downregulated lysosomal proteases and NF-κB negative regulators. The mantle, a primarily mineralizing organ, paradoxically upregulated immune-related genes while suppressing oxidative phosphorylation and extracellular matrix pathways. This tissue-level imbalance, with hemocytes recruited but functionally constrained and mantle metabolically suppressed yet immunologically activated, points to TNF-NF-κB pathway modulation as a key mediator of shell repair under acidification. Our findings demonstrate that visible shell closure masks underlying structural and mechanical failure, and that immune regulation, rather than simple suppression or activation, critically shapes the repair outcome. These results advocate for multifunctional indicators beyond closure area to assess shell integrity in acidified marine environments.

Animals↗

PubMed2026

Sex-dependent protective effects of microglial tumor necrosis factor on post-stroke inflammation and myelin injury.

Tumor necrosis factor (TNF) is rapidly induced after ischemic stroke, but its proposed cell-specific and sex-dependent functions during post-stroke inflammation remain insufficiently understood. Here, we investigated the role of microglia-derived TNF in the acute and subacute response to permanent middle cerebral artery occlusion (pMCAO). Tnf expression was transiently upregulated after stroke, becoming significant at 4 h, peaking at 12-24 h, and returning to baseline by 5 days. In situ hybridization confirmed strong Tnf expression in the infarct and peri-infarct regions. Whole-brain transcriptomic profiling showed that global TNF deficiency reshaped the early post-ischemic response, shifting it from microglia-associated phagocytic and wound-healing pathways toward an interferon-related inflammatory signature. To define the specific contribution of microglial TNF, we used inducible Cx3cr1CreER:Tnffl/fl mice. Microglial TNF deletion had no effect on infarct volume in males at 24 h or 5 days after pMCAO, but significantly increased infarct size in females at both time points. In both sexes, brain TNF levels peaked at 24 h and were significantly reduced in Cx3cr1CreER:Tnffl/fl mice, confirming microglia as a major source of early post-ischemic TNF. However, downstream consequences diverged by sex. At 5 days, male Cx3cr1CreER:Tnffl/fl mice showed reduced microglial reactivity and 18 kDa translocator protein (TSPO) signal, with no change in T-cell infiltration, and exhibited increased density of mature oligodendrocytes. In contrast, female Cx3cr1CreER:Tnffl/fl mice displayed enhanced microglial reactivity, increased TSPO binding, higher peri-infarct T-cell infiltration, and reduced oligodendrocyte density and myelin integrity. Together, these findings identify microglial TNF as a sex-dependent regulator of post-stroke inflammation and myelin injury.

Animals↗

PubMed2026

Methyltransferase METTL1 regulates MSC mRNA stability via m7G modification in acute pancreatitis.

Acute pancreatitis (AP) is a serious inflammatory disease with significant morbidity, yet its underlying molecular mechanisms remain incompletely understood. This study reveals a novel epitranscriptomic pathway in AP pathogenesis centered on METTL1-mediated N7-methylguanosine (m7G) RNA modification. We found that METTL1 expression and global m7G levels were significantly elevated in serum from AP patients, pancreatic tissues of sodium taurocholate-induced AP mice, and in vitro models of LPS-polarized macrophages and STC-injured pancreatic acinar cells. Through integrated multi-omics analysis combining m7G methylome mapping and transcriptome profiling, we identified Musculin (MSC) as a key target whose mRNA stability is enhanced by METTL1-mediated m7G modification. Functional experiments demonstrated that MSC upregulation activates TNF signaling through phosphorylation of NF-κB, JNK, and MAPK proteins, thereby promoting macrophage M1 polarization and pancreatic acinar cell injury. The pathological significance of this pathway was confirmed in vivo, where pancreas-targeted knockdown of Mettl1 significantly attenuated AP severity. Furthermore, mechanistic studies using a catalytic-dead METTL1 mutant established that both the methyltransferase activity of METTL1 and subsequent TNF signaling activation are essential for driving inflammatory responses. Our findings delineate a previously unrecognized METTL1-m7G-MSC-TNF signaling axis that promotes AP progression, highlighting the therapeutic potential of targeting METTL1-mediated epitranscriptomic modification in inflammatory diseases.

Animals↗

PubMed2026

Expression and mutation characteristics of mitochondrial genes in PBMCs of SLE patients: Implications for SLE pathogenesis.

This study aimed to investigate mitochondrial gene mutations and expression in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients, focusing on MT-ND5, and assess expression changes under lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and dexamethasone stimulation. Peripheral blood was collected from female SLE patients. Mitochondrial DNA (mtDNA) from PBMCs was sequenced using the HiSeq PE150 platform. Quantitative reverse transcription PCR and western blotting were used to evaluate mRNA and protein expression of the most frequently mutated mitochondrial genes. Cultured PBMCs were treated with LPS, TNF-α, or dexamethasone to examine regulatory effects. A total of 589 mtDNA mutation sites were detected in SLE patients. Among 13 protein-coding genes, MT-ND5, MT-CYB, MT-CO1, MT-ND4, and MT-CO3 exhibited the highest mutation frequencies. Expression analysis revealed significantly reduced mRNA and protein levels of these genes in SLE PBMCs compared with controls, with further decreases after stimulation with LPS, TNF-α, or dexamethasone. SLE PBMCs display extensive mitochondrial mutations and downregulation of key genes, particularly MT-ND5. Inflammatory and therapeutic stimuli exacerbate this suppression, suggesting mitochondrial dysfunction contributes to SLE susceptibility and progression.

Humans↗

PubMed2026

Positive conversion of latent tuberculosis screening in patients with inflammatory bowel disease on antitumor necrosis factor alpha drugs: a systematic review and meta-analysis.

Inflammatory bowel disease (IBD) patients undergoing antitumor necrosis factor-alpha (anti-TNF) therapy are at increased risk of developing tuberculosis (TB), making screening before anti-TNF initiation mandatory. Repeated screening during treatment is not yet recommended because of a lack of studies to support this practice. We aimed to determine the proportion of patients who develop latent TB during anti-TNF therapy. We systematically searched studies from MEDLINE, Embase, and Lilacs, and performed a single-arm meta-analysis investigating the positive conversion rate in IBD patients under anti-TNF therapy with previous negative TB screening. We calculated the combined proportion with 95% confidence interval, using the random-effects model. A P value less than 0.05 was considered statistically significant for subgroup differences. We included 13 studies from nine countries with 1153 patients. The overall positive conversion rate was 9.20%. Portugal had 18.01% of positive conversion, Spain 4.51%, and the USA 1.11%. Tests for subgroup differences were statistically significant for subgroup analysis by country and consistency of test used (performig same test as baseline). Subgroup analyses by continent, study design, or specific test (tuberculin skin test or interferon-gamma release assay) showed no statistical difference. Meta-regression analysis showed a significant positive association between positive conversion and TB incidence. In conclusion, IBD patients on anti-TNF therapy can have a positive conversion rate of 9.20%. Higher conversion rates were seen in European and Asian studies compared with those in the Americas (particularly the USA). TB prevention strategies should, therefore, be individualized and based on geographic location and risk factors.

Humans↗

PubMed2026

Inflammatory Cytokines Impair Glucagon Expression and Secretion in Pancreatic α-Cells.

AIMS: Insulin resistance and obesity-associated inflammation are key drivers in the pathogenesis of Type 2 diabetes mellitus (T2DM). Whilst inflammatory cytokines are well known to impair β-cell function, their impact on pancreatic α-cells and glucagon (GCG) regulation remains poorly understood. In this study, we investigated the effects of the pro-inflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ on GCG expression and secretion. MATERIALS AND METHODS: The viability and endocrine function of α-cell line αTC1 and isolated islets were investigated by WST-1 assay, LDH assay, qRT-PCR, Western blot analysis and ELISA. The transcriptional activity of the GCG promoter was analysed by reporter gene assays. The cellular composition of isolated islets was assessed by immunohistochemistry. RESULTS: We found that exposure of the α-cell line αTC1 to a mix of these cytokines activates cellular stress responses characterised by induction of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Moreover, cytokine treatment markedly reduced GCG gene expression and secretion through repression of GCG promoter activity. Mechanistically, this was associated with a disrupted transcriptional network. These findings were confirmed in isolated mouse islets, where cytokine exposure significantly reduced GCG expression and secretion in islets of both male and female donors. CONCLUSIONS: Taken together, these findings indicate that inflammatory cytokines are potent modulators of α-cell function as well as GCG secretion and provide novel insights into inflammation-driven dysregulation of the endocrine function of pancreatic islets.

Glucagon-Secreting Cells↗

PubMed2026

Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM), but their effects on inflammatory and oxidative biomarkers are not fully defined. MATERIALS AND METHODS: We searched PubMed, Ovid MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to 19 February 2026 for randomised controlled trials (RCTs) in adults with T2DM comparing a GLP-1RA or dual GIP/GLP-1 agonist with placebo or active therapy, and reporting C-reactive protein (CRP or high-sensitivity CRP [hs-CRP]), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), malondialdehyde (MDA) or adiponectin. Random-effects meta-analyses were conducted using standardised mean differences (SMDs). RESULTS: Forty-one RCTs were included. GLP-1RAs significantly reduced CRP/hs-CRP (27 studies, 1991 participants; SMD -0.37, 95% CI -0.59 to -0.14) and MDA (3 studies, 272 participants; SMD -0.98, 95% CI -1.65 to -0.30), and increased adiponectin (16 studies, 1327 participants; SMD 0.30, 95% CI 0.13 to 0.46). Pooled effects on IL-6 (17 studies, 1068 participants; SMD -0.14, 95% CI -0.37 to 0.10), TNF-α (16 studies, 1164 participants; SMD -0.25, 95% CI -0.61 to 0.12) and MCP-1 (7 studies, 450 participants; SMD -0.27, 95% CI -0.58 to 0.03) were not statistically significant, although MCP-1 decreased in sensitivity analyses. Across biomarkers, heterogeneity was moderate to high. Two tirzepatide RCTs (562 participants) showed a significant reduction in IL-6 (SMD -0.28, 95% CI -0.47 to -0.09) and a non-significant trend towards lower CRP/hs-CRP. CONCLUSIONS: In adults with T2DM, incretin-based therapies consistently lower CRP/hs-CRP, reduce oxidative stress (MDA) and increase adiponectin, while effects on IL-6 and TNF-α are more variable. These data support a selective anti-inflammatory and metabolic regulatory profile of GLP-1-based therapy, but heterogeneity and limited data for some biomarkers warrant cautious interpretation and further mechanistic studies. TRIAL REGISTRATION: PROSPERO number: CRD420261321430.

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

Therapeutic Potential of Terpenes in Lung Cancer: Modulation of 4-Oxo- Retinoic Acid, TNF-α, NF-κB, and HDAC2 Pathways.

Non-small cell lung cancer (NSCLC) includes various epithelial malignancies, such as squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Despite advancements in surgical resection, chemoradiotherapy, and multimodal therapies, NSCLC prognosis remains challenging due to its complex molecular landscape, drug resistance, and high treatment costs. Recent research highlights the potential of natural compounds, particularly terpenes and terpenoids, derived from essential oils (EOs), to enhance NSCLC treatment. These compounds exhibit anticancer properties and modulate key pathways like the 4-oxo-retinoic acid pathway, TNF-α signaling, NF-κB activation, and histone deacetylases (HDACs). Retinoids, a subclass of terpenes, show both chemopreventive and therapeutic benefits, especially when combined with other agents, though challenges in dosing and delivery methods limit their clinical application. Terpenes may also synergize with emerging therapies, such as antiangiogenic treatments and immunotherapy, to improve outcomes. Biomarkers, including genomic, epigenomic, and proteomic markers, play a critical role in predicting responses to terpene-based treatments, supporting personalized medicine. The integration of terpenes into existing regimens, in combination with conventional therapies, holds promise in overcoming clinical challenges, improving patient outcomes, and advancing natural compound use in modern oncology. Future research should focus on optimizing terpene therapies and addressing clinical hurdles.

Humans↗