Search Results (2,400)

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes. Full article

Ultraviolet (UV) irradiation stimulates melanogenesis in melanocytes and melanin transfer to keratinocytes, where the former is mediated by pleiotropic factors such as SCF, α-MSH, and endothelin-1 (ET-1) secreted by keratinocytes. Therefore, the interaction between melanocytes and keratinocytes after UVB exposure appears to be critical to stimulating melanogenesis. The factors that are responsible for inflammation, one of the key biological processes, are crucial to forming the chronic inflammatory microenvironment in solar lentigines (hereafter called age spots). While chronic inflammation is thought to be involved in hyperpigmentation, the molecular mechanisms through which microinflammation affects melanocyte activation in age spots have not been elucidated. In our study, immunohistochemical analysis showed that the expression of the inflammatory factor IL-6R is enhanced in age spots. Specifically, in cultured keratinocytes irradiated with 10 mJ/cm² UVB, the expression of IL-6R was upregulated in UVB exposure- and age-dependent manners, and the co-culture of melanocytes with UVB-irradiated keratinocytes further demonstrated that melanocyte dendrites increased in length and number in a keratinocyte-age-dependent manner. Moreover, the suppression of IL-6R function in keratinocytes by an IL-6R-specific neutralizing antibody, Tocilizumab, inhibited melanocyte dendricity. These results indicate that the age- and UVB-dependent upregulation of IL-6R in keratinocytes stimulates melanocyte dendricity, which may also contribute to excessive melanin deposition in age spots. Full article

Endometriosis involves oestrogen-dependent chronic inflammation and the abnormal proliferation of ectopic endometrial tissue. Conventional hormonal therapies suppress systemic oestrogen, but do not fully address local oxidative and inflammatory signalling. This review provides a mechanistic synthesis of recent molecular evidence. This evidence is on four FDA-recognized (Food and Drug Administration) medicinal plants. These are Curcuma longa, Zingiber officinale, Glycyrrhiza glabra, and Silybum marianum. The review highlights their capacity to modulate key intracellular pathways. These pathways are implicated in endometriosis. The review covers the integration of phytochemical-specific actions within NF-κB- (nuclear factor kappa-light-chain-enhancer of activated B cells), COX-2-(Cyclooxygenase-2), PI3K/Akt-(PI3K/Akt signaling pathway), Nrf2/ARE-(Nuclear factor erythroid 2–related factor 2) and ERβ-(Estrogen receptor beta) mediated networks, which jointly regulate cytokine secretion, apoptosis, angiogenesis and redox balance in endometrial lesions. Curcumin downregulates COX-2 and aromatase while activating Nrf2 signalling, shogaol from ginger suppresses prostaglandin synthesis and induces caspase-dependent apoptosis, isoliquiritigenin from liquorice inhibits HMGB1-TLR4–NF-κB (High Mobility Group Box 1, Toll-like receptor 4) activation, and silymarin from milk thistle reduces IL-6 (Interleukin-6) and miR-155 (microRNA-155) expression while enhancing antioxidant capacity. Together, these phytochemicals demonstrate pharmacodynamic complementarity with hormonal agents by targeting local inflammatory and oxidative circuits rather than systemic endocrine axes. This mechanistic framework supports the rational integration of phytotherapy into endometriosis management and identifies redox-inflammatory signalling nodes as future translational targets. Full article

Background: Pseudomonas aeruginosa infection is a major driver of morbidity and mortality in cystic fibrosis (CF), yet disease severity varies widely among people with CF (pwCF). This clinical heterogeneity suggests the involvement of host genetic modifiers beyond CFTR. We previously identified sphingosine 1-phosphate receptor 1 (S1PR1) as a candidate gene associated with susceptibility to P. aeruginosa. Here, we investigated its role in modulating airway epithelial responses to infection. Methods: Using CRISPR/Cas9, we generated S1PR1-knockout bronchial epithelial cells with (IB3-1) and without (C38) CFTR mutations. We assessed cell viability, cytotoxicity, and interleukin-8 secretion following exposure to P. aeruginosa exoproducts. S1PR1 protein expression was evaluated in lung tissue from pwCF and non-CF individuals using immunohistochemistry. Results: S1PR1-mutant cells produced truncated, non-functional peptides. In CFTR-mutant cells, S1PR1 loss reduced viability, increased cytotoxicity, and significantly enhanced interleukin-8 production in response to P. aeruginosa exoproducts. These effects were not observed in CFTR-competent cells. Notably, S1PR1 protein levels were markedly lower in lung tissue from pwCF compared to non-CF individuals. Conclusions: S1PR1 deficiency exacerbates epithelial damage and inflammatory responses to P. aeruginosa in CF models. These findings highlight S1PR1 as a potential contributor to infection severity and a promising target for therapeutic strategies in pwCF. Full article

Dehydroandrographolide (DA), a bioactive diterpenoid from Andrographis paniculata with diverse biological activity, was investigated for its antioxidant and anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and dextran sulfate sodium (DSS)-induced murine colitis. In vitro, DA inhibited the inflammatory response by modulating extracellular Signal-Regulated Kinase (Erk), c-Jun N-terminal Kinase (Jnk), p38 Mitogen-Activated Protein Kinase (P38), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 activation, and downregulated interleukin-6 (il-6) and interleukin-1β (il-1β) mRNA. It also had antioxidant effects by upregulating Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (Nqo-1) and heme oxygenase-1 (Ho-1), promoting protein kinase B (Akt) and 5′-adenosine monophosphate-activated protein kinase-α1 (Ampk-α1) phosphorylation. DA decreased cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNos) levels and alleviated intracellular reactive oxygen species (ROS) accumulation. In vivo, DA alleviated DSS-induced colitis in wild type (WT) mice by improving weight loss, disease activity index, colonic inflammation, and oxidative stress. The beneficial effects were linked to inhibiting Erk, Jnk, and P38 activation and enhancing Nrf2 signaling pathway. DA inhibited NOD-like receptor family pyrin domain-containing 3 (Nlrp3) inflammasome-mediated pryoptosis. However, DA’s protective effects were abolished in DSS-induced nrf2^−/− mice, suggesting its efficacy depends on Nrf2 signaling. Overall, DA alleviates oxidative stress, inflammatory responses, and pyroptosis in experimental colitis mice mainly by activating Nrf2 signaling pathway, highlighting its potential as a promising therapeutic option for inflammatory bowel disease. Full article

Differentiation of oligodendrocytes and myelination are enhanced by interleukin-4, an anti-inflammatory cytokine secreted from immune cells or injured neurons, and peroxisome proliferator-activated receptor γ serves as a central effector. While intracellular zinc concentrations have recently been reported to change dynamically during oligodendrocyte development, the role of zinc in interleukin-4-enhanced oligodendrocyte differentiation has not been studied. Using primary oligodendroglial cells and the oligodendroglial CG4 cell line, we show that intracellular zinc concentrations transiently increased 1 day after interleukin-4-induced differentiation and that intracellular as well as extracellular zinc chelators repressed the interleukin-4-dependent effects. Our analyses furthermore reveal that STAT6 activated the zinc transporter ZIP11 downstream of interleukin-4 in a phosphorylation-dependent manner and that siRNA-dependent knockdown of ZIP11 abolished the interleukin-4-enhanced oligodendrocyte differentiation. An antagonist of peroxisome proliferator-activated receptor γ similarly repressed the interleukin-4-dependent differentiation. However, agonists did not affect intracellular zinc concentrations. These findings indicate that interleukin-4 upregulates ZIP11 expression via activation of STAT6 and facilitates extracellular zinc uptake, which in turn activates peroxisome proliferator-activated receptor γ and thereby promotes oligodendrocytes differentiation. Our results argue that a modulation of zinc concentrations may be beneficial for promoting oligodendrocyte differentiation and remyelination under demyelinating conditions such as multiple sclerosis. Full article

Cluster of Differentiation (CD) 147, a transmembrane glycoprotein, plays a critical role in monocyte function by regulating invasion, migration and cytokine production. This study explored the impact of CD147 on monocyte chemotaxis and inflammatory responses following monocyte chemoattractant protein-1 (MCP-1) modulation using CD147 knockout (CD147^KO) THP-1 monocytes. CD147^KO THP-1 cells exhibited significantly enhanced migration towards MCP-1 and chemoattractants secreted by MDA-MB-231 breast cancer cells compared to wild-type (WT) THP-1 cells, while surface expression of the adhesion molecule CD44 remained unchanged. Despite their increased migration, CD147^KO cells showed no significant differences in CC chemokine receptor type 1 (CC1) or CC chemokine receptor type 2 (CCR2) protein expression. Upon MCP-1 stimulation, CD147^KO THP-1 monocytes exhibited elevated mRNA expression of interleukin (IL)-6 and IL-10, accompanied by a reduction in tumor necrosis factor alpha (TNF-α) at higher MCP-1 concentrations. IL-6 upregulation in CD147^KO THP-1 monocytes appears to be a candidate mediator of their enhanced migratory capacity. In summary, this study highlights the dual role of CD147 as a potential checkpoint in regulating THP-1 monocyte migration, with its function varying depending on the context and microenvironment. Additionally, CD147^KO THP-1 monocytes exhibited a shift in the balance between pro- and anti-inflammatory cytokine responses. Full article

Background/Objectives: Hip osteoarthritis (HOA) is a progressive joint disease characterized by cartilage loss, subchondral bone changes, and synovial inflammation. While tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and transforming growth factor-beta 1 (TGF-β1) are recognized as key mediators of joint pathology, their compartment-specific expression in the human hip synovium remains insufficiently characterized. Therefore, we aimed to investigate their localization and expression in the intimal and subintimal compartments of synovial tissue in patients with HOA compared to controls (CTRL). Methods: Synovial membrane samples were obtained from 19 patients with primary HOA undergoing total hip arthroplasty and 10 CTRL subjects undergoing arthroplasty for acute femoral neck fracture without HOA. Specimens were processed for hematoxylin and eosin (H&E) and immunofluorescence staining. Expression of TNFR1, IL-6, and TGF-β1 was quantified in the intima and subintima using ImageJ analysis. Group differences were assessed using two-way Analysis of variance (ANOVA) with Tukey’s test when assumptions were met; for heteroscedastic outcomes we applied Brown–Forsythe ANOVA with Dunnett’s T3 multiple comparisons. Results: Histological analysis confirmed synovitis in HOA samples, with intimal hyperplasia and mononuclear infiltration. IL-6 was significantly upregulated in the intima of HOA synovium compared with CTRLs, while subintimal expression remained unchanged. In contrast, TGF-β1 expression was reduced in the HOA intima, eliminating the normal intima–subintima gradient. For TNFR1, the within-HOA contrast (int > sub) was significant, whereas the intimal HOA vs. CTRL comparison showed a non-significant trend. Transcriptomic analysis supported IL-6 upregulation, while TNFR1 and TGF-β1 did not reach statistical significance at the mRNA level in an orthogonal, non-hip (knee-predominant) dataset. Conclusions: These findings demonstrate compartment-specific cytokine dysregulation in HOA, with increased intimal TNFR1 and IL-6 alongside reduced intimal TGF-β1. The synovial lining emerges as a dominant site of inflammatory signaling, underscoring its importance in disease progression. Full article

Nuclear receptors (NRs) are transcription factors regulated by ligands that direct metabolism, development, and immunity. The NR superfamily constitutes a principal category of pharmacological targets for human ailments. Retinoic acid receptor-related orphan receptors (RORs) α, β, and γ are part of the nuclear receptor superfamily. They are nevertheless classified as “orphan” receptors due to the contentious nature of identifying their endogenous ligands. RORγ nuclear receptor protein further consists of two isoforms, namely RORγ1 and RORγ2 or RORγt. RORγt is largely found in immune cells and has been primarily associated with chronic inflammatory conditions. The expression of STAT3 is a major driver of Th17 differentiation and induces RORγt expression through the JAK-STAT pathway. Type 3 innate lymphoid cells (ILC3s), Th17 cells, and γδT cells express RORγt, the master transcription regulator for the pro-inflammatory cytokine interleukin IL-17. In chronic inflammatory skin disorders, a significant increase in IL-17 has been observed, which plays a key role in both immune cell recruitment to the site of inflammation and the propagation of tissue damage. In this review, we will discuss how RORγt regulates IL-17-driven inflammation and explore potential strategies to target the RORγt-IL-17 axis as a viable therapeutic intervention in chronic inflammatory skin disorders. Full article

Residual inflammatory risk after acute coronary syndromes (ACSs) remains a critical contributor to atherosclerosis progression and plaque destabilization. Inflammatory biomarkers such as interleukin-1 receptor antagonist (IL-1ra), resistin, and C-reactive protein (CRP) may provide additional insights into coronary lesion complexity and vulnerability. The main aim of the study was to evaluate the association of interleukin-1 receptor antagonist (IL-1ra), resistin, and C-reactive protein (CRP) with coronary disease extent; functional significance of non-culprit lesions, assessed by fractional flow reserve (FFR); and plaque vulnerability, assessed by optical coherence tomography (OCT) in patients with acute coronary syndrome (ACS). This prospective study enrolled 93 ACS patients undergoing invasive coronary assessment for an ACS. Inflammatory biomarkers were measured at admission and 6 months post-event. Patients were stratified post hoc into tertiles by biomarker distribution. SYNTAX score, FFR, and OCT-defined thin-cap fibroatheroma (TCFA) were used to characterize lesion burden and morphology. Multivariate logistic regression was performed adjusting for conventional cardiovascular risk factors and ACS type. Higher tertiles of IL-1ra, resistin, and CRP were significantly associated with increased SYNTAX score (p < 0.05), FFR < 0.80 (68% in the highest tertile), and presence of TCFA (62% vs. 20%, p < 0.01). All biomarkers correlated with coronary disease severity. In multivariate logistic models, IL-1ra (OR 1.23 per 100 pg/mL, p = 0.03), resistin (OR 2.35 per 1 ng/mL, p = 0.001), and CRP (OR 1.11 per 0.001 ng/mL, p = 0.006) independently predicted high-risk coronary profiles. IL-1ra, resistin, and CRP are independently associated with lesion complexity, functional significance, and vulnerability in ACS. Inflammatory biomarker profiling may provide complementary anatomical and physiological assessment in future ACS risk stratification strategies. Full article

Inflammation contributes to the pathogenesis of ischaemic stroke both as a long-term causal factor and through the inflammatory cascade in acute stroke. Interleukin-1 beta (IL-1β) is a potent pro-inflammatory molecule, while interleukin-1 receptor antagonist (IL-1Ra) acts as its antagonist. Free fatty acids (FFAs) play a role in atherosclerosis formation and serve as substrates for inflammatory molecules. This study aimed to determine the potential interplay between FFAs, IL-1β, and IL-1Ra in stroke patients. A prospective analysis was conducted on 73 ischaemic stroke patients. All participants had their FFA, IL-1β, and IL-1Ra levels assessed. Significant correlations between IL-1β and certain FFAs were detected: C15:0 pentadecanoic acid (rho = 0.488), C15:1 cis-10 pentadecanoic acid (rho = 0.473), C17:1 cis-10 heptadecanoic acid (rho = 0.411), C18:0 stearic acid (rho = 0.302), C24:0 lignoceric acid (rho = −0.280), C24:1 nervonic acid (rho = −0.276), C18:2n6t linoleic acid (rho = −0.272), C17:0 heptadecanoic acid (rho = 0.241), and C13:0 tridecanoic acid (rho = 0.238). After multivariate analysis C15:0 pentadecanoic acid remained statistically significant. The strongest correlation was found between IL-1Ra and fatty acids: C15:1 cis-10-pentadecanoid acid (rho = −0.357), C18:2n6t linoleic acid (rho 0.341) and C24:1 nervonic acid (rho 0.302), but after multivariate analysis significantly correlated remained: C22:1n9 13 erucic acid (rho = 0.299), C18:3n6 gamma-linoleic acid (rho = 0.277), with close to significant correlation with C22:4n6 docosatetraenoate (rho = −0.241, p = 0.055). Certain FFAs may play a role in enhancing both pro- and anti-inflammatory responses in the early subacute phase of stroke, where inflammatory and resolving processes are ongoing. Fatty acids such as C15:0 pentadecanoic acid, C15:1 cis-10 pentadecanoic acid and C22:4n6 docosatetraenoate might be involved in pro-inflammatory responses, while C22:1n9 13 erucic acid and C18:3n6 gamma-linoleic acid in the anti-inflammatory pathways with the overlay of IL-1β and IL-1Ra. Full article

The growing global aging population is contributing to an increasing burden of benign prostatic hyperplasia (BPH), highlighting the need for novel, highly effective and low-toxicity therapies. In light of its well-documented anti-inflammatory and anti-tumor properties, we investigated the potential of the natural product Pulsatilla saponin D (PSD) in treating BPH. For the first time, we demonstrate that PSD significantly inhibits the proliferation of and induces apoptosis in the immortalized human normal prostatic stromal cell line, human prostate fibroblasts, and the human benign prostatic hyperplasia epithelial cell line. Mechanistic studies involving transcriptome analysis and RT-qPCR validation revealed that PSD likely exerts its effects by downregulating the expression of the androgen receptor and by modulating multiple signaling pathways synergistically, including the Phosphatidylinositol 3-kinase/Protein Kinase B, Tumor Necrosis Factor, Hypoxia-Inducible Factor-1 and Interleukin-17 pathways. Full article

The pathogenesis of Inflammatory Bowel Disease is complex and not completely understood, resulting from multifactorial interactions between genetic predisposition, environmental triggers, and dysregulation of both innate and adaptive immune responses. Cytokines, produced by dysregulated immune cells, trigger chronic intestinal inflammation leading to tissue damage, carcinogenesis, and disease perpetuation. Current advanced therapies—including tumor necrosis factor (TNF)-α antagonists, adhesion and trafficking inhibitors (such as anti-integrin agents and sphingosine-1-phosphate receptor modulators), interleukin inhibitors, and Janus kinase inhibitors—have improved patient outcomes, but targeting a single inflammatory pathway is often insufficient for long-term disease control. To further improve therapeutic efficacy, novel approaches are under investigation, including advanced combination therapies that simultaneously inhibit multiple pro-inflammatory pathways and microbiome-based treatments to restore intestinal homeostasis. In this evolving therapeutic scenario, precision medicine and advanced combination therapies appear promising for breaking through the current therapeutic ceiling. This review highlights current knowledge on the role of cytokines in IBD pathogenesis and explores how their modulation can modify and control disease course. Full article

High Mobility Group Box 1 (HMGB1) is a central pro-inflammatory mediator released from damaged or stressed cells, where it activates receptors such as the Receptor for Advanced Glycation Endproducts (RAGE). Dendritic polyglycerol sulfate (dPGS), a hyperbranched polyanionic polymer, is known for its anti-inflammatory activity. In this study, we examined how dPGS modulates HMGB1-driven signaling in RAW 264.7 macrophages and human microglia. Recombinant human HMGB1 expressed in Escherichia coli (E. coli) was purified by nickel-nitrilotriacetic acid (Ni-NTA) and heparin chromatography. Proximity ligation assays (PLA) revealed that dPGS significantly disrupted HMGB1/RAGE interactions, particularly under lipopolysaccharide (LPS) stimulation, thereby reducing inflammatory signaling complex formation. This correlated with reduced activation of the nuclear factor kappa B (NF-κB) pathway, demonstrated by decreased nuclear translocation and transcriptional activity. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR (RT-qPCR) showed that dPGS suppressed HMGB1- and LPS-induced transcription of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Enzyme-linked immunosorbent assay (ELISA) and Griess assays confirmed reduced TNF-α secretion and nitric oxide production. Electron paramagnetic resonance (EPR) spectroscopy further showed that dPGS altered HMGB1/soluble RAGE (sRAGE) complex dynamics, providing mechanistic insight into its receptor-disruptive action. Full article

Ras gene mutations are frequently observed in many types of cancers. However, there are currently no effective anticancer drugs against Ras-induced cancers. Therefore, identifying the downstream effectors of the Ras signaling pathway can facilitate the development of promising novel therapeutic approaches. We previously showed that oncogenic Ras induces the expression of the receptor tyrosine kinase c-Mer proto-oncogene tyrosine kinase (MerTK) in an interleukin-1 family member NF-HEV/IL-33-dependent manner and that IL-33 and MerTK contribute to oncogenic Ras-induced cell migration. In the present study, we purified the MerTK complex from NIH-3T3 cells transformed by the expression of oncogenic Ras, H-Ras (G12V). Mass spectrometric analysis identified STK38 (also known as NDR1) as a candidate binding partner for MerTK. STK38 is a serine/threonine protein kinase that plays diverse roles in normal and cancerous cells. In addition to MerTK knockdown, STK38 knockdown effectively attenuated the H-Ras (G12V)-induced migration of NIH-3T3 cells. STK38 kinase activity is required for oncogenic Ras-induced cell migration and MerTK tyrosine phosphorylation. Furthermore, MerTK or STK38 knockdown attenuated the activation of Rac1 and Cdc42. Taken together, these results revealed a novel role for STK38 in oncogenic Ras-induced enhanced cell migration, which may be useful for developing novel therapeutic strategies targeting Ras-mutated cells. Full article