IL-17A Levels Research Articles

Quercetin alleviates ulcerative colitis through inhibiting CXCL8-CXCR1/2 axis: a network and transcriptome analysis

IntroductionUlcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract in which mucosal healing is a crucial measure of therapeutic efficacy. Quercetin, a flavonoid prevalent in various foods and traditional Chinese medicines, exhibits notable pharmacological properties, including antioxidant and anti-inflammatory activities. Consequently, it warrants investigation to determine its potential therapeutic effects on UC. The objective of this study was to investigate the effects and underlying mechanisms of quercetin in a murine model of UC.MethodsA comprehensive approach integrating network predictions with transcriptomic analyses was employed to identify the potential targets and enriched pathways associated with quercetin in UC. Subsequently, the effects of quercetin on pathological morphology, inflammatory mediators, and mucosal barrier-associated proteins, as well as the identified potential targets and enriched pathways, were systematically investigated in a murine model of dextran sulfate sodium (DSS)-induced UC.ResultsNetwork analyses identified CXCL8 and its receptors, CXCR1 and CXCR2, as primary target genes for therapeutic intervention in UC. Further validation through transcriptomic analysis and immunofluorescence staining demonstrated significant upregulation of the CXCL8-CXCR1/2 axis in the intestinal tissues of patients with UC. Experimental investigations in animal models have shown that quercetin markedly alleviates DSS-induced symptoms in mice. This effect includes the restoration of colonic crypt architecture, normalization of goblet cell structure and density, reduction of inflammatory cell infiltration, and decreased concentrations of inflammatory mediators. Quercetin enhanced the expression of tight junction (TJ) proteins, including ZO-1, MUC2 (Mucin 2), and occludin, thereby preserving the integrity of the intestinal mucosal barrier. Additionally, it significantly diminished the levels of IL-17A, NF-κB, CXCL8, CXCR1, and CXCR2 in the colonic tissues of mice with UC.DiscussionThe ameliorative effects of quercetin on colon tissue damage in DSS-induced UC mice were significant, possibly due to its ability to inhibit the CXCL8-CXCR1/2 signaling axis. These findings provide a solid foundation for the clinical application and pharmaceutical advancement of quercetin.

Perturbed Microbial Ecology in Neuromyelitis Optica Spectrum Disorder: Evidence from the Gut Microbiome and Fecal Metabolome

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating immune-mediated ailment, which is influenced by genetic, epigenetic, and environmental elements. The escalating incidence of NMOSD in recent years implies alterations in environmental risk factors. Recent research has established a correlation between gut microbiomes and the development of NMOSD. MethodsMetagenomic shotgun sequencing and gas chromatography-mass spectrometry (GC-MS) were employed to assess alterations of the structure and function in the fecal microbiome, as well as levels of short-chain fatty acids (SCFAs) in fecal and blood samples, among individuals with neuromyelitis optica spectrum disorder (NMOSD) during the acute phase (n=25), the remission phase (n=11), and a group of healthy controls (HCs) (n = 24). We further explored the correlation between gut microbiota and the pathogenesis of NMOSD through fecal microbiota transplantation (FMT). The gut microbiome from human donors diagnosed with NMOSD or HCs was transplanted into germ-free mice, followed by an analysis of the alterations in the structure and functionality of the transplanted mice's gut microbiome. Additionally, the impact of microbiome transfer on the immunity and spinal cord of germ-free mice was assessed through various techniques, including ELISA, flow cytometry, western blot, histopathology, and transcriptome sequencing. Results(1) At the taxonomic levels of genus and species, there were significant differences in the α-diversity of the microbiome between HCs and NMOSD patients in the acute phase, with NMOSD patients having higher species diversity. (2) In the acute phase, the gut microbiota of NMOSD patients was characterized by Ruminococcaceae_unclassified, Campylobacter, Parabacteroides, Lactobacillus, Akkermansia, Streptococcus oralis, Clostridium leptum, Clostridium asparagiforme, Firmicutes bacterium CAG 238, and Lactobacillus fermentum. (3) The relative abundances of Coprobacter, Turicimonas, Gemmiger, Enterobacter, Roseburia sp.CAG 471, Veillonella tobetsuensis, Proteobacteria bacterium CAG 139, Ruminococcus bicirculans, Lactococcus lactis, Flavonifractor plautii, and Streptococcus cristatus were notably lower in patients experiencing remission compared to NMOSD patients in the acute phase, On the other hand, the relative abundances of Flavonifractor (P = 0.049) and Clostridium aldenense (P = 0.049) were significantly higher. Following medication, the gut microbiome distribution in NMOSD patients during remission closely resembled that of healthy controls (HCs). (4) Compared with HCs, acetate levels in the feces of patients with NMOSD in the acute phase were significantly lower. (5) In addition, we transplanted feces from NMOSD patients into germ-free mice and revealed a significant increase in the levels of IL-6, IL-17A, and IL-23 in the blood of mice belonging to the NMOSD fecal transplantation (NFMT) group. Additionally, the IL-10 level exhibited a significant reduction. Moreover, the proportion of Th17 cells displayed a significant increase, while the proportion of Treg cells exhibited a significant decrease in the spleens of NFMT mice. ConclusionPatients in the acute phase of neuromyelitis optica spectrum disorder (NMOSD) exhibited imbalances in their gut microbiota and a deficiency in short-chain fatty acids (SCFAs). Following drug treatment, the composition of intestinal microbes in NMOSD patients during the remission phase closely resembled that of the healthy control population. The FMT experiment provided evidence of the significant association between intestinal flora and the pathogenesis of NMOSD. Consequently, investigating gut microbiota and identifying novel microbial markers hold promise for the diagnosis and treatment of NMOSD patients.

Acyclovir provides protection against 6-OHDA-induced neurotoxicity in SH-SY5Y cells through the kynurenine pathway

Parkinson's disease is one of the most prevalent neurodegenerative disorders worldwide. The kynurenine pathway associated with oxidative stress and neuroinflammation is recognized to contribute to its pathophysiology, although the exact mechanism is not fully elucidated. In neuroinflammation, IDO-1 catalyzes the conversion of tryptophan to neurotoxic QUIN through the kynurenine pathway. Consequently, QUIN increases oxidative stress via nNOS and NMDA, which causes neurodegeneration. Few studies have reported on the effect of different antiviral drugs in Parkinson's disease; the exact mechanism is still unknown. The antiviral acyclovir has been shown to have neuroprotective properties and can cross the blood-brain barrier. We examined acyclovir's effects and potential mechanisms in the 6-OHDA-induced in vitro model of Parkinson's disease in SH-SY5Y cells using biochemical, immunocytochemical, and in silico methods. MTT assay demonstrated that acyclovir significantly decreased cell mortality induced by the neurotoxic 6-OHDA at dosages of 3.2 µM, 6.4 µM, 12.8 µM, 25.6 µM, and 51.2 µM. In immunocytochemical analysis, acyclovir treatment decreased α-synuclein and TNF-α expressions in cells. In biochemical analyses, while IL-17A and TOS levels decreased depending on varying doses (1.6 µM, 3.2 µM, 6.4 µM, 12.8 µM), TAC levels increased. Using in silico analyses to investigate the mechanism showed that acyclovir docked with TNF-α, IL-17A, IDO-1, nNOS, α-synuclein, and NMDA. The findings demonstrated that acyclovir had neuroprotective effects by modulating the kynurenine pathway and decreasing neurodegeneration via QUIN inhibition in an in vitro Parkinson's disease model. Although the mechanisms of acyclovir's effects in Parkinson's disease are unclear, the results obtained from the experiments are encouraging.

Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity

Necroptosis can promote antigen-specific immune responses, suggesting induced necroptosis as a therapeutic approach for cancer. Here we sought to determine the mechanism of immune activation but found the necroptosis mediators RIPK3 and MLKL dispensable for tumor growth in genetic and implantable models of breast or lung cancer. Surprisingly, inducing necroptosis within established breast tumors generates a myeloid suppressive microenvironment that inhibits Tcell function, promotes tumor growth, and reduces survival. This was dependent upon the release of the nuclear alarmin interleukin-1α (IL-1α) by dying cells. Critically, IL-1α release occurs during chemotherapy and targeting this molecule reduces the immunosuppressive capacity of tumor myeloid cells and promotes CD8+ Tcell recruitment and effector function. Neutralizing IL-1α enhances the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. Low IL1A levels correlates with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.

Maggot alleviates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting immune stress and complement activation

To explore the therapeutic mechanism of maggot for psoriasis-like lesions in mice from the perspective of immune stress and complement activation regulation. Thirty-six male C57BL/6 mice were randomly divided into control group, model group, maggot (1.25%, 2.5%, and 5%) groups, and Benvitimod (1%) group. Psoriasis-like lesions were induced by application of imiquimod cream, and the severity of skin lesions was assessed using the modified Psoriasis Area and Severity Index (MPASI) score. Auricular swelling of the mice was observed, and histopathological changes of the skin lesions were examined with HE staining. Scratching behavior of the mice was observed and the spleen index was calculated. Toluidine blue staining was used to detect mast cells in the skin lesions, and serum levels of IgG, IgM, the complements CH50, C1s, C3, C3a, C5 and C5a, and the inflammatory factors IL-23, IL-17A and TNF-α were determined with ELISA. In mice with imiquimod-induced psoriasis-like skin lesions, treatment with the maggot at the 3 doses significantly decreased MPASI score, alleviated auricular swelling and pathologies in the skin lesions, reduced scratching behaviors, spleen index, and the number of mast cells in the lesions. Treatment with high-dose maggot significantly lowered serum levels of IgG, C1s, C3a, C5a, IL-23, IL-17A and TNF- α and the levels of C1s, C3, C3a, C5 and C5a in the lesion tissue, and increased serum levels of CH50, C3, and C5. The therapeutic effect of maggot showed a dose-effect dependence. Maggot can alleviate psoriasislike skin lesions in mice by inhibiting immune stress and complement activation.

TNF-α Regulated Bidirectional Interaction Between Bone Marrow Mesenchymal Stem Cells and Articular Chondrocytes.

Articular chondrocytes (ACs) secrete a variety of extracellular matrix components to maintain the functions of articular cartilage. Degeneration of ACs leads to the degeneration of articular cartilage and consequently to osteoarthritis. The secretion of bone marrow mesenchymal stem cells (BMSCs) is capable of protecting ACs from degeneration, and thus BMSCs are widely applied to treat osteoarthritis. This study aims to explore whether BMSCs and ACs will affect the functions of each other through their secretions in the context of osteoarthritis. BMSCs and ACs isolated from rabbits were identified using flow cytometry and immunocytochemistry. Conditioned medium of BMSCs and ACs treated with 0, 5, 10, 20, and 40 ng/ml of tumor necrosis factor-alpha (TNF-α) were collected and used to treat ACs and BMSCs, respectively. The viabilities of ACs and BMSCs treated with condition medium were assessed using a Cell Count Kit-8 (CCK-8) kit. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and enzyme-linked immunosorbent assay (ELISA) methods were employed to evaluate the relative expression levels of genes and proteins, as well as the cytokine concentrations in the supernatant. Immunofluorescence and flow cytometry results indicated that the purity of isolated cells exceeded 95%. CCK-8 analysis showed that 6 hours of treatment with a conditioned medium did not affect the viability of BMSCs and ACs. However, treatment for 12 hours or longer significantly increased the viability of BMSCs (p < 0.05) and significantly decreased the viability of ACs (p < 0.01). RT-qPCR results demonstrated that the relative expression levels of Runx2 (1.15-3.91), Alp (1.06-2.84), TNF (BMSCs: 0.94-2.54; ACs: 1.03-2.64), IL6 (BMSCs: 0.98-2.78; ACs: 0.96-3.71), IL17A (BMSCs: 1.08-5.91; ACs: 0.90-4.20), and IL10 (BMSCs: 0.93-2.82; ACs: 0.89-2.25) genes in conditioned medium-treated BMSCs and ACs were dose-dependently elevated (p < 0.001) by TNF-α treatment. Immunoblotting analysis revealed that the expression levels of RUNX2 (0.53-0.86) and ALP (0.49-0.85) proteins were also dose-dependently elevated (p < 0.001) by TNF-α treatment. ELISA results showed similar TNF-α dose-dependent increases (p < 0.001) in the supernatant concentrations of pro-inflammatory cytokines TNF-α (BMSCs: 36.90 ± 0.75 to 199.38 pg/ml; ACs: 29.76 to 293.99 pg/ml), interleukin (IL)-6 (BMSCs: 4.96-48.24 pg/ml; ACs: 6.12-38.15 pg/ml), IL-17 (BMSCs: 3.06-28.99 pg/ml; ACs: 3.08-28.51 pg/ml), as well as the anti-inflammatory cytokine IL-10 (BMSCs: 6.34-65.02 pg/ml; ACs: 5.30-34.85 pg/ml). Together, these results indicate a TNF-α-regulated bidirectional interaction between BMSCs and ACs, deepening our understanding of the pathogenesis of osteoarthritis and aiding in its prevention and treatment.

Abstract B018: Multifaceted pro-metastatic role of IL-17 signaling in modulating the tumor microenvironment of colorectal cancer

Abstract Colorectal cancer (CRC) ranks second in mortality and advanced CRCs are resistant to current immunotherapies and prone to metastasis, which necessitates research into enhancing innate and adaptive anti-cancer immune responses. Chronic inflammation mediated by cytokines like IL6 and notably, IL17 activates the oncogenic pathways in cancer cells, promoting sporadic and inflammatory CRC. What is unknown, is the ability of cytokines to control tumor microenvironment (TME) via cell type specific mechanisms to increase cancer progression, metastasis and/or therapy resistance. Increased levels of IL17A in CRC portends poor prognosis indicating its potential involvement into metastasis. However, the role of IL17 signaling in TME in the process of CRC progression and metastasis remains enigmatic. We utilized different models of CRC progression and metastasis, as well as variety of genetic mice models and therapeutic interventions. First, using a model of colitis-associated cancer we found that “late” IL17A neutralization decreases tumor burden, possibly acting through regulation of ferroptosis, NK cells mediated cytotoxicity, as well as myeloid cells and chemokine network essential for the control of immunosuppressive TME. Next, models of CRC metastasis, including those based on MC38 cells and APTAK cancerous organoids, showed that IL17A neutralization reduces metastasis growth. Also, FACS analysis revealed that IL17A promotes the recruitment of tumor- associated macrophages and other key myeloid subsets into the metastatic liver environment. Further research, using mice with conditional knockout of IL17RC receptor in myeloid cells (Il17rc f/f -LysMCre) or hepatocytes (Il17rc f/f -AlbCre) also showed significance of IL17 signaling activation in CRC metastasis through two distinct mechanisms. Employing different techniques, from FACS, immunohistochemistry, to RNAseq and scRNAseq data analysis, we observed that local hepatic activation of IL17RC signaling recruits neutrophils and reduces infiltration of cytotoxic CD8+T and NK cells to the metastatic niche supporting tumor growth, while myeloid IL17RC signaling reshapes TME, including macrophages and neutrophils, enhancing CRC metastasis. Our research indicates that IL17 signaling plays a multifaceted pathogenic role in CRC progression by operating in at least several cell types, providing new insights into the basic biology of CRC metastasis and potentially illuminating the design and improvement of CRC treatment strategies. Citation Format: Katarzyna Chojnacka, Katrina Mae Reyes, Hana Tomizawa, Sergei Grivennikov. Multifaceted pro-metastatic role of IL-17 signaling in modulating the tumor microenvironment of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B018.

Anti-inflammatory effects of LCB 03-0110 on human corneal epithelial and murine T helper 17 cells.

Dry eye disease (DED) is a complicated disorder that impacts ocular surface and tear-film stability. Inflammation has recently been reported as the core mechanism and main therapeutic target of DED. Although anti-inflammatory drugs have been developed, they still have limited efficacy and various side effects. Recent reports have suggested that kinase inhibitors are beneficial for relieving inflammation. Therefore, this study aimed to investigate the anti-inflammatory effects of LCB 03-0110, a multi-tyrosine kinase inhibitor, on representative cell-based models (HCE- 2 and Th17 cells) of DED. While tacrolimus and tofacitinib, two different anti-inflammatory drugs that have entered clinical trials for DED treatment, did not induce any anti-inflammatory responses in HCE-2 cells, LCB 03-0110 significantly suppressed the phosphorylation of P38 and ERK and reduced the expression levels of IL-6 and IL-8 in HCE-2 cells treated with either LPS or poly(I:C). Moreover, LCB 03-0110 notably decreased the expression level of IL-17A in Th17 cells in a dose-dependent manner, whereas tofacitinib promoted IL-17A production at low concentrations but inhibited its expression at concentrations greater than 1 μM. In addition, LCB 03-0110 was found to be non-toxic to both HCE-2 and Th17 cells. In conclusion, these results suggest that LCB 03-0110 would be a promising drug candidate for the treatment of DED because of its advantages over tacrolimus and tofacitinib.

Therapeutic Effect of Lactiplantibacillus plantarun HFY11 Isolated from Naturally Fermented Yak Yogurt on Lincomycin Hydrochloride-Induced Diarrhea in Mice.

This study aimed to observe the therapeutic effect of Lactiplantibacillus plantarun HFY11 (LP-HFY11) on lincomycin hydrochloride-induced diarrhea in mice. The results showed that LP-HFY11 alleviated weight loss and intestinal and colon tissue lesions caused by diarrhea. The serum assay showed that LP-HFY11 decreased interleukin 17A (IL-17A), IL-6, 5-hydroxytryptamine, and malondialdehyde levels and increased total antioxidant capacity in mice with diarrhea. LP-HFY11 also downregulated the mRNA expression of cystic fibrosis transmembrane conductance regulator (CFTR), epidermal growth factor receptor (EGFR), and transforming growth factor beta 1 (TGFβ1) and upregulated the expression of recombinant sodium/hydrogen exchanger 1 (NHE1) and NHE4 in the colon tissues of mice with diarrhea. In conclusion, the study showed that LP-HFY11 could effectively inhibit diarrhea, and the effect was better than that of the drug Bifidobacterium tetragenous viable bacteria tablets (Bifidobacterium-TVBT).

TH17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling

BackgroundPost-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a mouse model of repeated social defeat stress (RSDS) that recapitulates certain features of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear. MethodsUsing a modified version of RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., TH17). ResultsOnly pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g.,IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes. ConclusionsOur data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of TH17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.

Successful Treatment of Pediatric Generalized Pustular Psoriasis (GPP) with Spesolimab: 5 Case Reports and Evaluations of Circulating IL-36 Levels.

Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening inflammatory cutaneous disease. IL-36 is a key treatment target in GPP. Spesolimab, a humanized monoclonal antibody of the IL-36 receptor, has demonstrated a good efficacy and a favorable safety profile in adults with GPP. However, data on its use in children are scarce. We treated patients aged 4-12 years with GPP with a single dose of spesolimab. The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total score, GPPGA pustulation sub-score, Generalized Pustular Psoriasis Area and Severity Index (GPPASI), and the Japanese Dermatological Association severity index for GPP were evaluated. The levels of IL-36α, IL-36β, and IL-36γ were detected by the magnetic bead-based immunoassays, and the levels of IL-17A, IL-17C, IFN-γ, TNF, IL-6, and IL-8 were measured by the Olink proximity extension assay technology. We included five patients (four boys and one girl) with a median age was 6.9 years old (range: 4.8 to 10.6 years), and a median age of onset of 1.7 years (range: 3 months-10 years and 5 months). After 1week of spesolimab administration, all patients had a total GPPGA score of 0/1 and pustulation subscore of 0, all patients had a GPPASI of 50, and four patients had a GPPASI of 75. Meanwhile, plasma levels of IL-36α, IL-36β, IL-36γ, IL-17A, IL-17C, IFN-γ, TNF, IL-6, IL-8 all decreased, and those of IL-36α, IL-36β, IL-17A, IL-17C, and IL-6 were statistically significant. There was no recurrence after 2 to 8 months of treatment. No other adverse event was recorded apart from one patient who experienced an upper respiratory infection in the first week. Spesolimab might be a prospective option for children aged 4 to 12 years.

Chemopreventative potential of Salsola tuberculatiformis Botch and Compound A in the differential regulation of IL-1Ra:IL-1α in UVB exposed skin keratinocytes

BackgroundSalsola tuberculatiformis Botsch, commonly known as Gannabos, is a Namibian shrub known for its contraceptive properties in rats and its ability to modulate adrenal steroidogenesis both in vitro and in vivo. Due to the labile nature of the active compounds in the shrub, a more stable synthetic analogue, Compound A, was synthesized. This compound has demonstrated similar contraceptive and steroidogenic properties as the original extract from S. tuberculatiformis. Additionally, Compound A has shown potent anti-inflammatory and anti-cancer effects in skin, raising the question of whether the S. tuberculatiformis extract might exhibit similar properties. PurposeThe study aimed to evaluate the anti-inflammatory and anti-carcinogenic properties of S. tuberculatiformis extract and Compound A, particularly their effects on UVB-induced inflammation, cell growth parameters, and oxidative status in HaCaT cells. MethodsThe biological activity of S. tuberculatiformis extract and Compound A was assessed using a cytochrome P450 assay. Anti/pro-inflammatory effects were evaluated by measuring IL-1α and IL-1Ra production using an ELISA assay. Additionally, the study monitored cell viability through ATP production, apoptosis via Caspase-3 activity, and oxidative stress using the DCFDA assay. ResultsS. tuberculatiformis extract inhibited IL-1α production at lower concentrations while increasing IL-1Ra at higher concentrations. This was associated with reduced cell viability and increased pro-oxidant (ROS) and pro-inflammatory activity (intracellular IL-1α). Compound A, on the other hand, reduced IL-1Ra and IL-1α levels by inducing apoptosis. However, at higher concentrations, Compound A significantly increased extracellular IL-1Ra levels and enhanced pro-apoptotic and pro-oxidant activity. The extract exhibited different anti-inflammatory effects compared to Compound A, as evidenced by the increased intracellular IL-1Ra: IL-1α ratio. ConclusionThe data suggest that S. tuberculatiformis acts as an anti-inflammatory agent at low concentrations by inhibiting intracellular IL-1α production, while at higher concentrations, it regulates pro-inflammatory signaling through IL-1Ra. These anti/pro-inflammatory effects may have potential relevance in wound healing. Compound A displayed a novel indirect anti-inflammatory effect by removing inflamed and damaged cells via apoptosis and ROS production. The pro-oxidant activity of Compound A, potentially due to aziridine formation, appears to accelerate the progression of damaged cells into apoptosis.

Bioinformatics Analysis and Immunogenicity Assessment of the Novel Multi-Stage DNA Vaccine W541 Against Mycobacterium Tuberculosis.

Vaccination is one of the effective measures to prevent latent tuberculosis infection (LTBI) from developing into active tuberculosis (TB). Applying bioinformatics methods to pre-evaluate the biological characteristics and immunogenicity of vaccines can improve the efficiency of vaccine development. To evaluate the immunogenicity of TB vaccine W541 and to explore the application of bioinformatics technology in TB vaccine research. This study concatenated the immunodominant sequences of Ag85A, Ag85B, Rv3407, and Rv1733c to construct the W541 DNA vaccine. Then, bioinformatics methods were used to analyze the physicochemical properties, antigenicity, allergenicity, toxicity, and population coverage of the vaccine, to identify its epitopes, and to perform molecular docking with MHC alleles and Toll-like receptor 4 (TLR4) of the host. Finally, the immunogenicity of the vaccine was evaluated in animal experiments. The W541 vaccine protein is a soluble cytoplasmic protein with a half-life of 1.1 h in vivo and an instability index of 45.37. It has good antigenicity and wide population coverage without allergenicity and toxicity. It contains 138 HTL epitopes, 73 CTL epitopes, 8 linear and 14 discontinuous B cell epitopes, and has a strong affinity for TLR4. Immune simulations have shown that it can effectively stimulate innate and adaptive immune responses. Animal experiments confirmed that the W541 DNA vaccine could effectively activate Th1- and Th17-type immune responses, producing high levels of IFN-γ and IL-17A, but could not significantly increase antibody levels. The W541 DNA vaccine can induce strong cellular immune responses. However, further optimization of the vaccine design is needed to make the expressed protein more stable in vivo. Bioinformatics analysis could reveal the physicochemical and immunological information of vaccines, which is critical for guiding vaccine design and development.

EGFR-TKIs induce acneiform rash and xerosis via Caspase-3/GSDME-mediated pyroptosis of keratinocytes and sebocytes

Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.

Appreciation of hematological and serological of IL-1a, IL-10 and DHEA- S hormone levels in serum of patients with Acne

There were eleven cytokines in the interleukin-1(IL) bunch. Similarly, it's an essential part. Interleukin-1α (IL-1α) is the most extensively studied of them all, and it is arguably the most widely used cytokine in the pathophysiology of skin eruptions. In the ongoing review, the patients in the Thi-Qar region will have their levels of IL-1α and IL-10 assessed. In the Al-Hussein Instructional Clinic in Iraq, we were in charge of the review. The review contained 100 blood tests from patients who had breakouts on their skin; there were 39 male and 61 female patients, ages ranging from 10 to 35. Depending on their age ranges, our patients were divided into three groups. The most prevalent age group (10–20) was 52/100 (52%) and was followed by the other groups.

Profiling of Toll-like Receptors and Related Signaling Mediators in the Pathogenesis of Morphea.

Morphea, also known as localized scleroderma, is a rare fibrosing inflammatory disease of unknown pathogenesis. Although the genetic basis for morphea is important, reports on the evaluation of Toll-like receptors (TLR) in this disease is quite limited. We aimed to evaluate TLR expression levels and serum IL-6, IL-17A, TGF-β1, FGF, and VEGF levels in patients with morphea and compare these results with healthy controls. The expression levels of TLRs in the lesional and non-lesional adjacent skin of patients with morphea and in normal skin of healthy controls were evaluated by RT-PCR, whereas serum levels of IL-6, IL-17A, TGF-β1, FGF, and VEGF were evaluated by ELISA. Based on our findings, TLR1 gene expression increased 34.3-fold in the lesional skin of patients with morphea. In addition, IL-6, IL-17A, TGF-β, FGF, and VEGF were found to be higher in the blood samples of the patient group than in the healthy group. TLRs are important parts of the pathogenesis of morphea, and a better understanding of them will lead to more directed, effective treatments. We believe that this study will be important for pioneering TLR-targeted therapeutic approaches in the treatment of morphea in the future.

Cytokine balance in pregnant women with preeclampsia

Studies were conducted to study the levels of pro- (IL-6, IL-18, IL-17A) and anti-inflammatory (IL-4) cytokines in the blood serum of pregnant women at different stages of gestation: 18-20, 28-30, and 33- 38 weeks. The study involved 76 patients at risk of developing preeclampsia. Of these, 34 women developed preeclampsia, making up the main group, and 42 pregnant women had no symptoms of preeclampsia and made up the comparison group. The control group consisted of 28 somatically healthy women with a physiologically normal pregnancy. The average age of the examined patients with preeclampsia was 26.2±4.3 years, and in the group of pregnant women with normal pregnancy it was 25.8±4.7 years. The purpose of the study was to study the levels of cytokines IL-4, IL-6, IL-17A, and IL-18 in women with uncomplicated pregnancy and preeclampsia. These cytokines play an important role in the immune response and may be associated with the development of preeclampsia. The results of the study may help further understand the mechanisms of the disease and develop strategies for its prevention and management. The levels of pro- (IL-6, IL-18, IL-17A) and anti-inflammatory cytokines (IL-4, IL-10) were studied in blood serum by ELISA using test systems of Vector-best JSC (Novosibirsk, Russia) in accordance with the manufacturer’s recommendations. Statistical processing of research results was carried out using variation statistics methods. The results are presented as the sample mean (M) and standard error (m). The significance of the differences in the mean values (P) of the compared indicators was assessed using the Student t test (t). A study conducted by the authors found the following patterns in interleukin (IL) levels in pregnant women at risk of developing preeclampsia (PE). The levels of IL-6, IL-17A, and IL-18 were significantly increased in pregnant women with PE. There was a tendency to decrease the levels of IL-4, and IL-10 in women at risk of developing preeclampsia. These findings may help guide further research and development of strategies to prevent and manage preeclampsia in pregnant women.

Specific features of cytokine synthesis in adolescent girls with oligomenorrhea and low body mass index

The article is devoted to the study of the cytokine component of immunity in teenage girls with oligomenorrhea, underweight and with normal body weight in comparison with teenage girls with a normal menstrual cycle and normal body weight, which is of great importance to pediatric gynecology. Studying of the cytokine profile in oligomenorrhea will allow early identification of the development of many gynecological pathologies, including polycystic ovary syndrome, endometrioid neoplasms, as well as for understanding the pathogenesis of these conditions and developing approaches to their diagnosis and treatment, which is of great practical importance. The authors conducted an immunological study of teenage girls with oligomenorrhea with underweight and normal body weight in comparison with teenage girls with a normal menstrual cycle and normal body weight. Purpose of the study: to study the levels of IL-6, IL-17A, IL-18 and IL-10 in adolescent girls with oligomenorrhea and underweight. Teenage girls (N = 52) aged 13 to 17 years with established menstrual irregularities were examined. The control group consisted of 24 practically healthy girls of the same age. From the study, it was established that girls with oligomenorrhea and underweight have a pronounced increased synthesis of proinflammatory cytokines IL-6, IL-17A and IL-18. In the same group of girls, an increase in the level of the anti-inflammatory cytokine IL-10 was detected, which may be an attempt by the body to compensate for inflammatory processes. However, IL-10 levels remain elevated, which may indicate an immune imbalance. The discovered imbalance in the cytokine profile emphasizes the complexity of the pathogenesis of oligomenorrhea in girls with underweight, and the identified levels of the studied cytokines can serve as biomarkers that will help in diagnosis, assessment of severity, and prediction of the course of the disease state.

The protective effect and immunomodulatory ability of orally administrated Lacticaseibacillus rhamnosus GG against Mycoplasma pneumoniae infection in BALB/c mice.

Mycoplasma pneumoniae represents one of the significant etiologies of community-acquired pneumonia in pediatric patients. However, clinical treatment of M. pneumoniae infection in children has encountered challenges due to the escalating resistance to quinolones. Numerous studies have highlighted the potential of probiotic lactobacillus administration in boosting immune responses to bacterial and viral respiratory infections. In this study, the protective efficacy of pre-oral administration of Lacticaseibacillus rhamnosus GG (LGG), Limosilactobacillus reuteri F275, Lactiplantibacillus plantarum NCIMB 8826, L. plantarum S1 or L. plantarum S2 was evaluated in the BALB/c mice model; it was observed that among these five strains of lactobacillus, the supplementation of LGG exhibited the most significant protective effect against M. pneumoniae infection. Moreover, when administered orally, both live LGG and heat-inactivated LGG have demonstrated efficacy in reducing the burden of M. pneumoniae in the lungs and alleviating pulmonary inflammation. Oral supplementation with LGG resulted in the inhibition of neutrophil recruitment into the lungs and increased recruitment of alveolar macrophages in M. pneumoniae-infected mice. Additionally, LGG supplementation led to increased production of IL-10 and secretory IgA (sIgA), while suppressing the levels of IL-1β, IL-6, IL-17A, and TNF-α in the lungs of mice infected with M. pneumoniae. The data suggests that supplementation with LGG can modulate immune responses, decrease pathogen load, and alleviate inflammatory injury in the lungs of M. pneumoniae-infected mice.

Eucalyptus oil nanoemulsion for enhanced skin deposition of fluticasone propionate in psoriatic plaques: A combinatorial anti-inflammatory effect to suppress implicated cytokines.

Psoriasis is a chronic inflammatory skin disease that affects patients' quality of life. This study aimed to enhance the efficacy of topical application of fluticasone propionate (FP) using a eucalyptus oil-based nanoemulsion, an oil possessing anti-inflammatory activity and extracted from the leaves, fruits, and buds of Eucalyptus globulus or Eucalyptus maidenii, to improve the skin deposition of FP and aid its anti-inflammatory effect. Box-Behnken design was employed to optimize NE formulations, which were characterized for globule size, zeta potential, polydispersity index, rheological behavior, microscopic morphology, ex vivo skin permeation/deposition, and in vivo efficacy using imiquimod-induced psoriatic lesions. The optimized formulation depicted a droplet size of 188 ± 22.4 nm, a zeta potential of -17.63 ± 1.66 mV, and a viscosity of 204.9 mPa s. In addition to the increased FP retention in different skin layers caused by the NE and the reduced PASI score compared to the marketed cream, the levels of inflammatory cytokines IL-1α, IL-6, IL17a were markedly lowered, indicating the improved anti-psoriatic curable efficacy of the optimized formulation in comparison to the FP-marketed product.