Inflammatory IL-6 Research Articles

New insights into the interplay between MALAT1 and miRNA-155 to unravel potential diagnostic and prognostic biomarkers of Behçet's disease.

The current study was deployed to evaluate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-155, along with the inflammatory markers, TNFα and IL-6, and the adhesion molecule, cluster of differentiation 106 (CD106), in Behçet's disease (BD) pathogenesis. The study also assessed MALAT1/miR-155 as promising diagnostic and prognostic biomarkers for BD. The current retrospective case-control study included 74 Egyptian BD patients and 50 age and sex-matched controls. Blood samples were collected, and then, serum samples were separated for further biochemical and molecular investigations. The gene expression of MALAT1 and miR-155 was measured using qRT-PCR, whereas the levels of TNFα, IL-6, and CD106 were estimated using ELISA technique. MALAT1 was significantly downregulated, whereas miR-155 was upregulated among BD patients, compared with control subjects. Levels of TNFα, IL-6, and CD106 were elevated in BD patients. Further downregulation in MALAT1 together with upregulation of miR-155 was observed in active BD patients, relative to the inactive group. Receiver-operating-characteristic analysis revealed that MALAT1 and miR-155 could discriminate BD patients from controls, on the one hand, and active from inactive BD patients, on the other hand. MALAT1 was negatively correlated with TNFα, IL-6, and CD106, while miR-155 was positively correlated with them. Logistic regression analyses demonstrated miR-155 as a significant independent predictor of BD susceptibility, and MALAT1 as an independent negative predictor of BD activity. For the first time, the current research enlightens the role of MALAT1 and miR-155 in BD pathogenesis via impacting IL-6/TNF-α/CD-106 signaling. As well, MALAT1 and miR-155 could be regarded as novel non-invasive biomarkers that may improve BD diagnosis and prognosis. Key Points •MALAT1/miR-155 exerts potential role in Behçet's disease. •MALAT1/miR-155 are promising biomarkers for Behçet's disease. •MALAT1/miR-155 targets IL-6/TNF-α/CD-106 signaling.

Therapeutic Potential of Cajanus cajan (L.) Millsp. Leaf Extract in Modulating Gut Microbiota and Immune Response for the Treatment of Inflammatory Bowel Disease

Background/Objectives: Inflammatory bowel disease (IBD) is a persistent inflammatory condition affecting the gastrointestinal tract, distinguished by the impairment of the intestinal epithelial barrier, dysregulation of the gut microbiota, and abnormal immune responses. Cajanus cajan (L.) Millsp., traditionally used in Chinese herbal medicine for gastrointestinal issues such as bleeding and dysentery, has garnered attention for its potential therapeutic benefits. However, its effects on IBD remain largely unexplored. Methods: In this study, the major compounds from Cajanus cajan leaf extract (CCLE) were initially characterized by LCMS-IT-TOF. The IBD model was developed in C57BL/6 mice by administering continuous 4% (w/v) dextran sodium sulfate (DSS) aqueous solution over a period of seven days. The body weight, colon length, disease activity index (DAI), and histopathological examination using hematoxylin and eosin (H&E) staining were performed in the IBD model. The levels of the main inflammatory factors, specifically TNF-α, IL-1β, IL-6, and myeloperoxidase (MPO), were quantified by employing enzyme-linked immunosorbent assay (ELISA) kits. Additionally, the levels of tight junction proteins (ZO-1, Occludin) and oxidative stress enzymes (iNOS, SOD1, CAT) were investigated by qPCR. Subsequently, flow cytometry was employed to analyze the populations of various immune cells within the spleen, thereby assessing the impact of the CCLE on the systemic immune homeostasis of IBD mice. Finally, 16S rDNA sequencing was conducted to examine the composition and relative abundance of gut microbiota across different experimental groups. In addition, molecular docking analysis was performed to assess the interaction between the principal components of CCLE and the aryl hydrocarbon receptor (AHR). Results: We identified seven bioactive compounds in CCLE: catechin, cajachalcone, 2-hydroxy-4-methoxy-6-(2-phenylcinyl)-benzoic acid, longistylin A, longistylin C, pinostrobin, amorfrutin A, and cajaninstilbene acid. Our results demonstrated that oral administration of CCLE significantly alleviates gastrointestinal symptoms in DSS-induced IBD mice by modulating the balance of gut-derived pro- and anti-inflammatory cytokines. This modulation is associated with a functional correction in M1/M2 macrophage polarization and the Th17/Treg cell balance in splenic immune cells, as well as shifts in the populations of harmful bacteria (Erysipelatoclostridium and Staphylococcus) and beneficial bacteria (Odoribacter, unidentified Oscillospiraceae, Lachnoclostridium, and Oscillibacter) in the gut. Furthermore, cajaninstilbene acid, longistylin A, and longistylin C were identified as potential AhR agonists. Conclusions: The present results suggested that CCLE, comprising stilbenes like cajaninstilbene acid, longistylin A, and longistylin C, protects the epithelial barrier’s structure and function against DSS-induced acute IBD by restoring gut microbiota balance and systemic immune response as AhR agonists. Overall, CCLE represents a promising natural product-based therapeutic strategy for treating IBD by restoring gut microbiota balance and modulating systemic immune responses.

Stem Cell-Derived Exosomes as a Therapeutic Option for Spinal Cord Injuries; a Systematic Review and Meta-Analysis.

Exosomes function as cell signaling carriers and have drawn much attention to the cell-free treatments of regenerative medicine. This meta-analysis aimed to investigate the efficacy of mesenchymal stem cell-derived (MSC-derived) exosomes in animal models of spinal cord injuries (SCI). A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science to attain related articles published by January 31, 2023. The eligible keywords were correlated with the spinal cord injury and MSC-derived exosomes. The evaluated outcomes were locomotion, cavity size, cell apoptosis, inflammation, neuro-regeneration, and microglia activation. A standardized mean difference was calculated for each sample and a pooled effect size was reported. 65 papers fully met the inclusion criteria. Treatment with MSC-derived exosomes ultimately improved locomotion and shrunk cavity size (p<0.0001). The administration of MSC-derived exosomes enhanced the expression of beta-tubulin III, NF200, and GAP-43, and increased the number of NeuN-positive and Nissl-positive cells, while reducing the expression of glial fibrillary acidic protein (p<0.0001). The number of apoptotic cells in the treatment group decreased significantly (p<0.0001). Regarding the markers of microglia activation, MSC-derived exosomes increased the number of CD206- and CD68-positive cells (p=0.032 and p<0.0001, respectively). Additionally, MSC-derived exosome administration significantly increased the expression of the anti-inflammatory interleukin (IL)-10 and IL-4 (p<0.001 and p=0.001, respectively) and decreased the expression of the inflammatory IL-1b, IL-6, and TNF-a (p<0.0001). MSC-derived exosome treatment resulted in a significantly improved locomotion of SCI animals through ameliorating neuroinflammation, reducing apoptosis, and inducing neuronal regrowth by facilitating a desirable microenvironment.

Nutritional, Antibacterial and Thrombolytic Prospects of Freshwater Paludomas conica Protein Hydrolysate and Its Anti-Inflammatory Potential in LPS-Induced RAW 264.7 Macrophage Cells.

Chronic inflammation and heme-iron overload can result from bacterial hemolysis. Along with the synthetic drugs, numerous traditional and functional food approaches are equally trialed to eradicate the problem. As a prospective new source of dietary protein hydrolysates, freshwater mollusks (Paludomas conica) have recently drawn huge interest from researchers. In this research, protein hydrolysate (PhPC) of Paludomas conica, prepared by the enzyme digestion method, was analyzed for proximate nutritional and minerals contents and deciphered its suppressive effects on inflammatory gene expression in LPS-stimulated RAW264.7 macrophage cells. The inhibitory action of protein denaturation is also unfolded with established invitro and invivo models. Anti-hemolytic, antibacterial, and thrombolytic effects of PhPC were respectively assessed by H2O2-induced hemolysis of RBCs, the disc diffusion method, and the clot lysis method. The proximate nutritional and mineral contents of PhPC revealed it to be an enriched source of nutrients, crude protein, carbohydrates, Calcium, and Magnesium. Heavy metals were found to be within the prescribed limit. The PhPC suppressed the expression of inflammatory genes, including COX-2, iNOS, IL-6, TNF-α, and IL-1, multifold in LPS-stimulated RAW264.7 macrophages. The inhibition concentrations (IC50) of PhPC in the bovine serum albumin denaturation inhibition test and membrane stabilization tests were 431.39 and 285.25 μg/mL, respectively. The PhPC was discerned to be active against Shigella flexneri, Pseudomonas aeruginosa, and Shigella dysenteriae; its maximum thrombolytic effect was displayed to be 23.72% ± 2.71%. The findings demonstrate that the nutritionally enriched PhPC could be affirmed as an exciting invertebrate anti-inflammatory agent Extending other biological functions needs to be further characterized with its pure protein or protein products.

Discovery of N-Phenyl-5-propyl-1H-pyrazole-3-carboxamide, with Selective Inhibition and Degradation of HDAC6 for the Treatment of Acute Liver Injury.

Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as a promising strategy for treating ALI by inhibiting necrosis and inflammation. In this study, a series of pyrazole derivatives were designed to specifically target HDAC6, among which compound 6 demonstrated high antinecroptotic activity (IC50 = 0.5 nM) and excellent selective HDAC6 inhibition (IC50 = 4.95 nM, HDAC1/HDAC6 = 251). Surprisingly, compound 6 also exhibited excellent HDAC6 degradation activity (DC50 = 0.96 nM) through mechanistic studies. Additionally, it demonstrated strong inhibitory effects on inflammatory proteins TNF-α, IL-1β, and IL-6, indicating significant anti-inflammatory activity. Moreover, in a mouse model of acetaminophen (APAP)-induced acute liver injury, compound 6 exhibited significant therapeutic and protective efficacy at a dose of 40 mg/kg. These findings confirm that compound 6 is a promising lead structure for combating ALI-related diseases and warrants further investigation.

Fetuin-A as a plausible biomarker for cardiac valve calcification in rheumatic heart disease patients from North India.

Rheumatic heart disease (RHD) remains a persistent public health challenge, particularly prevalent in developing and underdeveloped regions despite concerted global eradication efforts. The progressive stage of RHD, marked by valvular calcification, necessitates the imperative need to identify prognostic biomarkers. Fetuin-A, well-known for its role as a negative inhibitor of ectopic calcification, is investigated in our study as a potential biomarker for cardiac valve calcification in RHD patients. Individuals with confirmed presence of RHD via echocardiography, who exhibited moderate to severe cardiac valve involvement, were enrolled alongside age and sex-matched healthy controls. Enzyme Linked Immunosorbent Assay was performed to analyse serum concentration of fetuin-A in healthy controls and RHD patients. Cytokine profiling was carried out using Cytometric Bead Array. Sixty confirmed RHD patients along with age and sex-matched case-control were evaluated for their serum fetuin-A and serum cytokines levels. Our findings reveal significantly reduced serum fetuin-A levels in RHD patients (1.96 ± 0.608 ng/ml) compared to healthy controls (2.85 ± 0.55 ng/ml) (p < 0.0001). Cytokine profiling shows nearly two-fold elevations in interleukin (IL)-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-6, IL-10, IL-4 and IL-2 levels among RHD patients versus healthy controls, with IL-6 showing the maximum elevation in serum concentration. Pearson's correlation coefficient (r) values indicate a strong negative correlation between fetuin-A levels in RHD patients and various inflammatory cytokines, including IL-17A (-0.9754), IFN-γ (-0.8142), TNF-α (-0.8281), IL-10 (-0.9183), IL-6 (-0.8479), IL-4 (-0.9182) and IL-2 (-0.9430) (p < 0.05, statistically significant). This study suggests that fetuin-A can be explored as a plausible biomarker for cardiac valve calcification and has an inverse correlation with inflammatory cytokines involved in RHD.

HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses.

Post-translational modifications (PTMs) are critical regulators of protein function and cellular signaling. While histone deacetylation by histone deacetylases (HDACs) is well established, the role of specific HDACs in modulating non-histone protein PTMs, particularly in an infectious context, is poorly understood. Here, we reveal a pivotal role for HDAC6 in orchestrating periodontal inflammation through its dual regulatory effects on FoxO1 acetylation and phosphorylation. Using Porphyromonas gingivalis , a key periodontal pathogen, as a model pathogen, we observed that infection induces HDAC6 activation, driving inflammatory responses via modulating FoxO1 activity. HDAC6 depletion increased FoxO1 acetylation and phosphorylation, leading to its cytoplasmic sequestration and subsequent suppression of FoxO1- mediated pro-inflammatory cytokine production in macrophages. Mechanistically, HDAC6 deficiency not only directly enhances the acetylation of FoxO1 but also upregulates the expression of Rictor, a critical component of the mTORC2 complex, thereby promoting Akt phosphorylation and subsequently FoxO1 phosphorylation. This results in its cytoplasmic retention and attenuated inflammatory transcriptional activity. Functional studies demonstrated that HDAC6 depletion suppressed the production of key inflammatory mediators, including TNFα, IL-6, IL-12p40, and MIP-2, while promoting macrophage polarization toward anti-inflammatory M2 phenotypes. In vivo , using oral gavage infection and ligature-induced mouse periodontitis models, HDAC6 deficiency significantly reduced inflammatory cell infiltration in gingival tissues and protected against alveolar bone loss. These findings establish HDAC6 as a central regulator of periodontal inflammation, acting through the coordinated modulation of FoxO1 acetylation and phosphorylation. Beyond its role in oral pathology, HDAC6 may serve as a promising therapeutic target for managing inflammatory diseases linked to immune dysregulation.

High Meat Intake and Ferritin Levels in Relation to Cardiovascular Risk Among Individuals with Diabetes in Mongolia.

Mongolian diets are characterized by high meat consumption, which may contribute to dietary iron intake and influence ferritin levels and cardiovascular risk. Elevated ferritin levels have been associated with inflammation and cardiovascular disease (CVD) risk in various populations; however, the specific effects of high meat intake and ferritin levels on CVD risk in Mongolian individuals with diabetes remain unclear. This study aimed to assess the relationship between meat intake, ferritin levels, and cardiovascular risk markers in a diabetic Mongolian population. A cross-sectional study was conducted involving 171 Mongolian adults with diabetes. Meat intake was assessed using 24 h dietary recall interviews, and participants were categorized into tertiles of low, medium, and high intake. Blood samples were collected to measure ferritin, lipid profiles, and other CVD markers. The Framingham Risk Score was calculated for each participant. Participants in the highest tertile of meat intake exhibited significantly elevated ferritin levels compared to those in the lower tertiles (275.6 ng/mL vs. 119.6 ng/mL, p = 0.001). Elevated ferritin levels were observed in 40% of participants and were associated with higher LDL cholesterol (3.75 vs. 3.22 mmol/L, p = 0.002), total cholesterol (5.63 vs. 5.2 mmol/L, p = 0.012), and Framingham Risk Scores (13.97 vs. 11.4, p = 0.0001). However, ferritin levels showed no significant association with other cardiovascular or inflammatory markers, including BMI, HbA1c, CRP, and IL-6 (p > 0.05). Mediation analysis revealed that ferritin partially mediated the relationship between meat intake and cardiovascular risk (beta coefficient = 0.539, p = 0.001), though the indirect effect was not statistically significant. Interaction analysis indicated no significant effect modification of meat intake and ferritin levels on cardiovascular risk (p = 0.844). In this diabetic Mongolian population, high meat intake was associated with elevated ferritin levels, which may have reflected dietary iron intake rather than systemic inflammation or increased CVD risk.

Unlocking the Therapeutic Potential of Adipose-Derived Stem Cell Secretome in Oral and Maxillofacial Medicine: A Composition-Based Perspective.

The adipose-derived stem cell (ADSC) secretome is widely studied for its immunomodulatory and regenerative properties, yet its potential in maxillofacial medicine remains largely underexplored. This review takes a composition-driven approach, beginning with a list of chemokines, cytokines, receptors, and inflammatory and growth factors quantified in the ADSC secretome to infer its potential applications in this medical field. First, a review of the literature confirmed the presence of 107 bioactive factors in the secretome of ADSCs or other types of mesenchymal stem cells. This list was then analyzed using the Search Tool for Retrieval of Interacting Genes/Proteins (STRING) software, revealing 844 enriched biological processes. From these, key processes were categorized into three major clinical application areas: immunoregulation (73 factors), bone regeneration (13 factors), and wound healing and soft tissue regeneration (27 factors), with several factors relevant to more than one area. The most relevant molecules were discussed in the context of existing literature to explore their therapeutic potential based on available evidence. Among these, TGFB1, IL10, and CSF2 have been shown to modulate immune and inflammatory responses, while OPG, IL6, HGF, and TIMP1 contribute to bone regeneration and tissue repair. Although the ADSC secretome holds great promise in oral and maxillofacial medicine, further research is needed to optimize its application and validate its clinical efficacy.

The Effect of Dexmedetomidine on Inflammatory Factors and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial

PurposeDexmedetomidine is a sedative-analgesic that is widely used in sepsis. However, its effect on septic shock remains unclear. This study aimed to investigate dexmedetomidine's effect on inflammatory biomarkers in septic shock. MethodsThe present study was a randomized controlled clinical trial. Patients with inclusion criteria were randomly allocated into either the dexmedetomidine (n = 24) or morphine + midazolam group (n = 24). The primary outcome was changes in inflammatory factors, including IL-1, IL-6, TNF-α, ESR, and CRP. The serum levels of inflammatory factors were measured at baseline and the end of the intervention. Secondary outcomes included the change in norepinephrine dose, vital signs, and SOFA scores. FindingsOf the 48 subjects, 52.08% were male. After intervention, IL-1, IL-6, and TNF-α levels significantly differed between the 2 groups (p = 0.011 and p < 0.001 and p < 0.001, respectively). Heart rate and systolic blood pressure decreased over time, but the two groups had no significant difference (p-value > 0.05). In addition, there was no significant difference in norepinephrine dose and SOFA score between the 2 groups (p-value > 0.05). ImplicationsSedation with dexmedetomidine can attenuate the inflammatory factors in septic shock. Also, dexmedetomidine did not worsen the hemodynamic parameters in septic shock patients.

Dihydromyricetin/montmorillonite intercalation compounds ameliorates DSS-induced colitis: Role of intestinal epithelial barrier, NLRP3 inflammasome pathway and gut microbiota.

Dihydromyricetin (DHM), the primary active compound in vine tea possesses various pharmacological effects such as anti-inflammatory and antioxidant properties, along with high biosafety. However, its oral delivery remains a significant challenge. Montmorillonite (MMT), the primary component of bentonite, is a commonly used drug in the clinical treatment of gastrointestinal diseases and serves as an excellent drug carrier due to its intercalation capability. In this study, we intercalated DHM into the interlayer spaces of MMT via solution intercalation method combined with rotary evaporation and used it to treat ulcerative colitis in mice. SEM, XRD, and FTIR analyses confirmed the successful synthesis of the DHM/MMT intercalation compound. In vitro studies shown that DHM/MMT eliminated intracellular ROS and suppressed inflammatory genes IL-1β, IL-6, and TNF-α. Moreover, DHM/MMT demonstrated notable therapeutic effects in ulcerative colitis (UC) mice, significantly restoring the intestinal mucosa. Importantly, the therapeutic mechanism of DHM/MMT is closely linked to the inhibition of the NLRP3 signaling pathway. Additionally, this strategy modulated gut microbiota by increasing probiotics and suppressing harmful bacteria, thereby maintaining intestinal homeostasis. In conclusion, DHM/MMT presents a promising strategy for UC treatment.

Regulation of keratinocyte barrier function and inflammatory response by the EGFR-STAT3 Pathway: Potential therapeutic implications of osimertinib and afatinib

The epidermal growth factor receptor (EGFR) signaling pathway is crucial for skin barrier integrity and immune response. This study explores the impact of EGFR inhibitors, osimertinib and afatinib, on keratinocyte function, focusing on keratin (KRT1, KRT17) and tight junction protein (CLDN1, CLDN2, CLDN4) expression in HaCaT cells. Osimertinib significantly increased the mRNA and protein levels of keratins and inflammatory markers, IL-6 and TNF-α, via activation of the EGFR-STAT3 signaling pathway. Co-treatment with recombinant human EGF reversed these changes, suggesting the pathway’s modulatory role. These findings underscore the potential therapeutic applications of targeting the EGFR-STAT3 axis in skin barrier dysfunction and inflammatory skin disorders.

Tracheloside, the main constituent of the total lignan extract from Trachelospermi Caulis, inhibited rheumatoid arthritis via IL-17/MAPK signaling pathway

A quantitative analysis method was established using high-performance liquid chromatography (HPLC) to simultaneously determine five lignans in the total lignan extract (TLE) from Trachelospermi Caulis at 280 nm, including nortracheloside, tracheloside, nortrachelogenin, trachelogenin, and arctigenin. The method demonstrated good linearity for each lignan within their respective ranges, with precision, stability, and repeatability meeting the criteria for quantitative analysis. Tracheloside, the most abundant compound in the TLE, effectively inhibited the release of inflammatory factors IL-6 and IL-17, and suppressed the migration MH7A cells in vitro. Furthermore, tracheloside reduced the production of key inflammatory factors, including COX-2, IL-6, IL-17, MMP2, MMP3, MMP9, JNK, p-JNK, p38, and p-p38 in TNF-α induced MH7A cells, thereby inhibiting the IL-17/MAPK signaling pathway, and thus contributing to its anti-rheumatoid arthritis effects. This study represents the first report on the simultaneous quantification of five major lignans from Trachelospermi Caulis and the anti-inflammatory properties of tracheloside.

Bilirubin, a hepatoprotective agent that activates SIRT1, PGC-1α, and PPAR-α, while inhibiting NF-κB in rats with metabolic-associated fatty liver disease

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disorder characterized by fatty liver disease alongside overweight or obesity and/or type 2 diabetes mellitus (T2DM). Timely intervention is crucial for a potential cure. This study aimed to investigate the effects of bilirubin, an endogenous antioxidant, on lipid metabolism and inflammation in MAFLD. Specifically, it examined bilirubin’s impact on SIRT1, PPAR-α, and NF-κB in the livers of rats with MAFLD induced by a high-fat diet (HFD) and streptozotocin (STZ) administration. Forty eight-week adult male Sprague Dawley rats were divided into five groups (n = 8): Control, HFD-STZ, HFD-S-BR6, HFD-S-BR14, and C-BR14. In the last three groups, bilirubin administration was performed intraperitoneally for 6 and 14 weeks (10 mg/kg/day). We selected the key genes associated with MAFLD and subsequently performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses to explore the enriched biological processes and signaling pathways. Hence, the gene expression of SIRT1, PGC-1α, PPAR-α, and inflammatory genes (NF-κB, TNF-α, IL-6, and IL-1β) was measured using Real-time quantitative PCR. Stereological and histopathological alterations of liver structure as well as lipid profile, biochemical indices, and liver indices, were also assessed among different groups. The enrichment analysis identified that several signaling pathways and biological processes might be related to MAFLD. Bilirubin-treated rats contained higher PPAR-α, PGC-1α, and SIRT1 expression levels by approximately 5.7-, 2.1-, and 2.2-fold, respectively, compared to the HFD-receiving rats (p < 0.0001, p < 0.05, and p < 0.05). Whereas, the genes involved in the inflammatory cascades, including NF-κB, TNF-α, and IL-6, were downregulated by 0.6-fold (p < 0.05) following 14-week treatment of bilirubin, while only significantly decreased expression of NF-κB and IL-6 (approximately 0.6-fold, p < 0.05) were observed after 6-week treatment of bilirubin. Remarkably, bilirubin administration favorably reversed the effects of HFD on the liver’s volume and cell numbers and ameliorated the related structural changes. It also improved lipid profile, biochemical parameters, and liver indices of HFD-STZ rats. This study indicated that bilirubin acts as a protective/ameliorative compound against MAFLD, particularly through regulating the key genes involved in lipid metabolism and inflammation in HFD-STZ rats.

IWR-1 attenuates the promotional effect of IL-36γ in a mouse model of psoriasis

BackgroundPsoriasis is a chronic inflammatory skin disease. The Wnt/β-catenin signaling pathway is essential for the regulation of adult stem cells, homeostasis, and tissue regeneration; however, the relationship between this pathway and interleukin (IL)-36γ in the pathogenesis of psoriasis remains unclear.MethodsIn this study, psoriasiform model mice were established using imiquimod (IMQ) induction. Hematoxylin and eosin (H&E) staining was used to evaluate pathological morphologies, while immunohistochemistry was used to verify the expression patterns of β-catenin and the inflammatory factors IL-6, IL-17 A, and interferon (IFN)-γ.ResultsIL-36γ treatment increased psoriasis area and severity index scores, and enhanced proliferation of keratinocytes in IMQ-induced psoriatic mice. The effects of IL-36γ on the severity of psoriasiform lesions and epidermal hyperplasia were partly inhibited by IWR-1, which is an inhibitor of the Wnt/β-catenin signaling pathway. Furthermore, the levels of proinflammatory cytokines and molecules involved in the Wnt/β-catenin signaling pathway in psoriatic mouse skin, including IL-6, IL-17 A, IFN-γ, β-catenin, and Dickkopf-1 (DKK1), were upregulated by treatment with IL-36γ. Consistently, the effects of IL-36γ on the inflammatory response and the Wnt/β-catenin signaling pathway were alleviated by IWR-1.ConclusionsTaken together, our findings suggested that inhibition of the Wnt/β-catenin signaling pathway may be useful in the alleviation of IL-36γ-induced psoriasis-like lesions.

Major alteration of lung microbiome and the host responses in critically ill COVID-19 patients with high viral load

Patients with COVID-19 under invasive mechanical ventilation are at higher risk of developing ventilator-associated pneumonia (VAP), associated with increased healthcare costs, and unfavorable prognosis. The underlying mechanisms of this phenomenon have not been thoroughly dissected. Therefore, this study attempted to bridge this gap by performing a lung microbiota analysis and evaluating the host immune responses that could drive the development of VAP. In this prospective cohort study, mechanically ventilated patients with confirmed SARS-CoV-2 infection were enrolled. Nasal swabs (NS), endotracheal aspirates (ETA), and blood samples were collected initially within 12 h of intubation and again at 72 h post-intubation. Plasma samples underwent cytokine and metabolomic analyses, while NS and ETA samples were sequenced for lung microbiome examination. The cohort was categorized based on the development of VAP. Data analysis was conducted using RStudio version 4.3.1. In a study of 36 COVID-19 patients on mechanical ventilation, significant differences were found in the nasal and pulmonary microbiome, notably in Staphylococcus and Enterobacteriaceae, linked to VAP. Patients with VAP showed a higher SARS-CoV-2 viral load in respiratory samples, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1β, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. Metabolomic analysis revealed changes in 22 metabolites in non-VAP patients and 27 in VAP patients, highlighting D-Maltose-Lactose, Histidinyl-Glycine, and various phosphatidylcholines, indicating a metabolic predisposition to VAP. This study reveals a critical link between respiratory microbiome alterations and ventilator-associated pneumonia in COVID-19 patients with higher SARS-CoV-2 viral loads in respiratory samples, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1β, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. These findings provide novel insights into the underlying mechanisms of VAP, with potential implications for management and prevention.

Investigating bacteria-induced inflammatory responses using novel endometrial epithelial gland organoid models.

The endometrium plays a crucial role in early human pregnancy, particularly in embryo implantation, survival, and growth. However, invasion and infection by pathogens can lead to endometritis, infertility, and poor reproductive outcomes. Understanding the mechanisms of endometritis and its impact on fertility remains limited. An infection model using patient-derived endometrial epithelial gland organoids (EEGOs) was established to advance in vitro studies on endometritis and related infertility. An EEGOs infection model was constructed and characterized from human endometrium, treating the organoids with estrogen and progesterone to observe changes in the proliferative and secretory phases. The organoids were infected with E. coli, and the release of inflammatory cytokines in the supernatant was detected using ELISA. RNA-seq was employed to analyze the differences before and after E. coli treatment, and differential gene mRNA expression was validated using real-time quantitative PCR. Additionally, the effect of E2 in alleviating inflammation was assessed through markers of receptivity (PAEP, LIF, ITGβ), proliferation (Ki67), and barrier repair (ZO-1). The constructed human EEGOs exhibited long-term expansion capability, genetic stability, and characteristic hormonal responses, strongly expressing epithelial markers (MUC1, E-Cadherin). After E. coli infection, the expression levels of inflammatory cytokines TNF-α, IL-8, and IFN-γ increased significantly (P < 0.05). RNA-seq indicated that the MAPK signaling pathway was activated post-infection, with increased expression levels of heat shock proteins and transcription factor mRNA. E2 treatment post-infection significantly decreased the mRNA expression of inflammatory genes IL-1β, IL8, IL6 and TNF-α compared to the E. coli infected group (P < 0.05). Additionally, the expression of genes related to receptivity, proliferation, and barrier repair was enhanced in the E2-treated organoids. Our findings demonstrate that patient-derived EEGOs are responsive to bacterial infection and are effective models for studying host-pathogen interactions in bacterial infections. These organoids revealed the anti-inflammatory potential of E2 in alleviating E. coli-induced inflammation, providing insights into the mechanisms of endometritis and its impact on infertility. The study supports the use of EEGOs as valuable tools for understanding endometrial health and developing targeted treatments.

Pathogenic Mechanisms of Collagen TypeⅦA1 (COL7A1) and Transporter Protein Transport and Golgi Organization 1 (TANGO1) in Rheumatoid Arthritis: A New Therapeutic Target

Rheumatoid arthritis (RA) is an autoimmune disorder causing chronic inflammation primarily due to collagen regulation and transport imbalances. Collagen VII A1(COL7A1), a major component of anchoring fibrils, regulates inflammation via interacting with its transporter protein Transport and Golgi organization 2 homologs (TANGO1). The study revealed a significant increase in COL7A1 levels in both the plasma and PBMCs of RA patients. Additionally, a positive correlation between COL7A1 and ACCPA (anti-cyclic citrullinated peptide antibody) levels was observed among RA patients. TANGO1 mRNA expression was also found to be elevated in PBMCs. The knockdown of COL7A1 in RA synoviocytes using siRNA affected the expression of TANGO1 and inflammatory genes. Western blot analysis showed that COL7A1 si-RNA in TNF-α-induced SW982 cells reduced the expression of COL7A1, TANGO1, and NF-kBp65. The mRNA expression of inflammatory genes TNF-α, NF-kB p65, and IL-6 simultaneously decreased after the knockdown of COL7A1, as measured by qRT-PCR. An in silico analysis found 20 common interacting proteins of COL7A1 and TANGO1, with pathway enrichment analysis linking them to antigen presentation, class I and II MHC, and adaptive immunity pathways in RA. Among the common proteins, The DisGeNET database depicted that COL1A1, MIA3, SERPINH1, and GORASP1 are directly linked to RA. The molecular docking analysis of COL7A1 and TANGO1 revealed strong interaction with a −1013.4 energy-weighted score. Common RA-used drugs such as Adalimumab, Golimumab, and Infliximab were found to inhibit the interaction between COL7A1 and TANGO1, which can further impede the transport of COL7A1 from ER exit sites, indicating COL7A1 and TANGO1 as potential therapeutic targets to diminish RA progression.

Hormone Replacement Therapy Relieves Periodontitis by Inhibiting Alveolar Bone Loss and Inflammation.

Hormone replacement therapy (HRT) is a commonly used strategy for treating menopausal symptoms, while its relation with periodontitis remains unclear. This study aimed to explore the potential effects of HRT on periodontitis, mainly in aspects of bone loss and inflammation. The alveolar bone height (ABH), alveolar bone thickness (ABT), and bone mineral density (BMD) were measured in menopausal women with periodontitis who had received HRT or had not received HRT by cone beam computed tomography. Based on a rat model of periodontitis, the alveolar bone loss was evaluated by micro-computed tomography and bone-related biochemical markers. The expression/levels of inflammatory markers were measured to reflect periodontal inflammation. Although the differences were not all significant in each premolars/molars, the mesial/distal ABH and buccal/lingual ABT were lower, and the mesial/distal BMD was higher in patients in the HRT group than those in the control group. In a rat model of periodontitis, the alveolar bone loss was relieved by HRT. Additionally, HRT significantly weakened the elevation of inflammatory markers, including TNF-α, IL-1β, and IL-6 in periodontitis rats. HRT contributes to the remission of periodontitis by inhibiting alveolar bone loss and inflammation.

Microbiome-based therapies for Parkinson's disease.

The human gut microbiome dysbiosis plays an important role in the pathogenesis of Parkinson's disease (PD). The bidirectional relationship between the enteric nervous system (ENS) and central nervous system (CNS) under the mediation of the gut-brain axis control the gastrointestinal functioning. This review article discusses key mechanisms by which modifications in the composition and function of the gut microbiota (GM) influence PD progression and motor control loss. Increased intestinal permeability, chronic inflammation, oxidative stress, α-synuclein aggregation, and neurotransmitter imbalances are some key factors that govern gastrointestinal pathology and PD progression. The bacterial taxa of the gut associated with PD development are discussed with emphasis on the enteric nervous system (ENS), as well as the impact of gut bacteria on dopamine production and levodopa metabolism. The pathophysiology and course of the disease are associated with several inflammatory markers, including TNF-α, IL-1β, and IL-6. Emerging therapeutic strategies targeting the gut microbiome include probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). The article explored how dietary changes may affect the gut microbiota (GM) and the ways that can affect Parkinson's disease (PD), with a focus on nutrition-based, Mediterranean, and ketogenic diets. This comprehensive review synthesizes current evidence on the role of the gut microbiome in PD pathogenesis and explores its potential as a therapeutic target. Understanding these complex interactions may assist in the development of novel diagnostic tools and treatment options for this neurodegenerative disorder.