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关键词： Eruca vesicaria essential oil   Acetamiprid   Nephrotoxicity   GC-MS analysis   Oxidative stress   Biochemical/molecular analysis  

摘要： Acetamiprid (Aceta) is a neonicotinoid insecticide utilized extensively worldwide, and its environmental and human health risks are of concern. Eruca vesicaria is an edible year-round plant that contains a lot of healthpromoting phytochemicals and is an excellent source of antioxidants. So, the present investigation was planned to assess the effect of E. vesicaria seed essential oil versus acetamiprid-induced toxicity in rats. Animals were partitioned into 4 groups of seven each: control, E. vesicaria seeds essential oil (ESEO;0.17 mL/kg), acetamiprid (Aceta;21.7 mg/kg), and ESEO plus Aceta, respectively. Doses were given orally and daily for 14 days. Results revealed that ESEO has many phytochemical components with high antioxidant activity. Data showed that treatment with Aceta increased lipid peroxidation and decreased the activities of "enzymatic and non-enzymatic antioxidants" in kidney homogenate. Also, disturbance of kidney and liver function biomarkers, lipid profile, and protein content were observed. These are confirmed by the histological, molecular (Cox-2, TNF-alpha, and PPAR-alpha), and renal damage biomarkers (KIM-1 and Cystatin C) examination. On the other hand, rats administered ESEO and then treated with Aceta showed significant amelioration in most of the examined indices. To sum up, ESEO has a potent anti-inflammatory, anti-apoptotic, and antioxidant activity that protects against the pronounced harmful effects of Aceta in rat kidneys due to its health-promoting phytochemicals.

关键词： TNF-alpha   OX40L   OX40   hidradenitis suppurativa   Nanobody   xenograft graft-versus-host disease   T cell-dependent antibody response   delayed-type hypersensitivity skin reaction  

摘要： Background: Chronic inflammatory conditions are among the leading causes of disability and mortality. Although therapies have been significantly improved with the introduction of target-specific biologics, many chronic inflammatory conditions can be only moderately controlled by inhibition of individual cytokines. Objective: We sought to compare individual versus simultaneous blockade of TNF-a and OX40L in controlling inflammation. Methods: Analysis was conducted of the murine xenograft graft-versus-host disease model, a novel cynomolgus monkey model of simultaneous T cell-dependent antibody response (TDAR) and delayed-type hypersensitivity (DTH) skin reaction, and samples of patients with hidradenitis suppurativa (HS). Results: Compared with individual inhibition, combined targeting of TNF-a and OX40L using mAbs more potently suppressed TDAR and DTH in cynomolgus monkey. We therefore created SAR442970, a bispecific pentavalent Nanobody containing 2 domains each binding to OX40L and TNF-a and 1 domain binding serum albumin to extend half-life. In xenograft graft-versus-host disease, disease control by SAR442970 was superior compared with treatment with monospecific anti-TNF-a or anti-OX40L Nanobodies. In cynomolgus monkey, SAR442970 potently suppressed TDAR and DTH. The transcriptional signature of inflamed monkey skin showed similarities to that of lesional skin of patients with atopic dermatitis and, even more so, HS and was inhibited by SAR442970 treatment. Increased numbers of cells expressing OX40 were observed in HS lesions, and bioinformatics analyses of single-cell and bulk RNA sequencing data identified cells expressing OX40 as T cells with a highly mobile phenotype. Conclusion: OX40-OX40L interaction is a key pathogenetic feature in HS, and patients with HS might benefit from combined TNF-a/OX40L blockade by SAR442970, which is currently investigated in a clinical phase 2 trial. (J Allergy Clin Immunol Global 2025;4:100483.)

关键词： IL-39   Inflammation   Autoimmune disease   Dysbiosis   Periodontitis   Autoantibody  

摘要： IL-39, a cytokine from the IL-12 family that appears to be produced primarily by B cells, consists of the IL-23p19 and Ebi3 subunits, which signal through IL-23R/gp130 to activate STAT1/STAT3. Some studies suggest elevated IL-39 levels in certain autoimmune conditions, such as relapsing-remitting multiple sclerosis (RRMS), ankylosing spondylitis (AS), and autoimmune thyroid disease (ATD), possibly indicating a link between IL-39 and autoimmunity mediated by B cells. Preliminary evidence indicates that IL-39 might stimulate NETosis in neutrophils and promote BAFF (B-cell activating factor) secretion, which theoretically, in turn, may activate IL-39 production, T-cell-independent IgA isotype switching and somatic hypermutation. Some reports have revealed correlations between IL-39 and disease-specific autoantibodies, including RF and ACPAs in rheumatoid arthritis (RA), anti-dsDNA in systemic lupus erythematosus (SLE), and anti-AQP4 antibodies in neuromyelitis optica spectrum disorder (NMOSD), although these associations require further confirmation. Theoretically, through NETosis, IL39 could potentially expose intracellular antigens and facilitate their citrullination via peptidyl arginine deiminase (PAD), which might contribute to autoimmunity initiation. Some data suggest that in P. gingivalis-associated dysbiosis, IL-36 gamma may increase IL-39 secretion by epithelial cells. As dysbiosis and inflammatory bowel disease (IBD) increase gut permeability and LPS exposure-a possible stimulus for IL-39 production-the relationships among IL-39, gut dysbiosis, and autoimmunity appear to warrant further investigation. While some studies have reported conflicting results regarding the immunological activity of IL-39 in humans, these theoretical considerations suggest the need for more rigorous, standardized research, as current investigations remain limited by small sample sizes and heavy reliance on animal models or in vitro studies rather than comprehensive human studies ex

关键词： Hesperidin   ifosfamide   Apoptosis   Renal toxicity   Antioxidant  

摘要： This study explored the protective effects of hesperidin (HES) against ifosfamide (IFA)-induced nephrotoxicity in rats using biochemical, histopathological, and immunohistochemical techniques. The rats were administered IFA at a dose of 500 mg/kg body weight, followed by oral HES treatment at doses of 200 and 300 mg/kg body weight. The results demonstrated that HES significantly reduced IFA-induced increases in urea and creatinine levels, indicating improved kidney function. HES was shown to mitigate IFA-induced lipid peroxidation, likely due to its antioxidant properties, and to enhance the activities of key antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as elevate glutathione (GSH) levels. Biochemical and immunohistochemical analyses further revealed that HES exhibited anti-inflammatory, antiapoptotic and anti-endoplasmic reticulum stress effects, suppressing the elevated levels of nuclear factor kappa-B (NF-kappa B), interleukin-1n (IL-1n), tumor necrosis factor-alpha (TNF-alpha), Caspase-3, 6, 9, Bax, Apaf1, p53, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 alpha (IRE1 alpha), glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF-6), and protein kinase R-like ER kinase (PERK), CHOP and alleviating level of Bcl-2 in IFA-exposed kidney tissue. Additionally, the immunohistochemical staining results for TIM-1 in rat kidney tissues showed minimal expression in the control and HES groups. However, the IFA-treated group exhibited a significant increase in TIM-1 expression. Co-administration of IFA with HES at 200 or 300 mg/kg resulted in a significant reduction in TIM-1 expression. In conclusion, these results demonstrate that HES efficiently alleviated kidney toxicity induced by IFA.

关键词： DvL   CAM assay   Immunohistochemistry   Pro-inflammatory  

摘要： Due to their interesting biological activities, a mannose-binding lectin isolated from Dioclea violacea seeds, known as DvL have attracted considerable attention. In this study, we performed macroscopic, histologic, and immunohistochemical analysis on chicken embryo chorioallantoic membranes (CAM) to investigate the effects of DvL on the angiogenic process. Data showed a potential angiogenic effect of DvL at the highest concentrations tested (50 and 100 mu g/mL). This effect was confirmed through increased neovascularization, inflammatory cells, and fibroblasts in histological analysis of the CAM. In addition, the immunohistochemistry of CAM showed that DvL induced secretion of TNF-alpha and VEGF, important cytokines involved in angiogenesis. Therefore, increased neovascularization may result from a pro-inflammatory response through VEGF and TNF-alpha secretion. In contrast, the DvL effects on the angiogenic process and the TNF-alpha and VEGF secretion were significantly reduced by co-incubation with mannose. Thus, protein-carbohydrate interactions between DvL and cell membrane glycans are likely the main events involved in this effect. Therefore, our results demonstrated that DvL is a potent angiogenic agent, suggesting its potential application as a prototype molecule for developing new drugs with healing properties.

关键词： Deoxynivalenol   Pyroptosis   Gasdermin D   IL-1 beta secretion  

摘要： Deoxynivalenol (DON), a trichothecene mycotoxin, exerts pro-inflammatory and immunomodulatory activity. Interleukin (IL)-1 beta serves a crucial part as a gate keeper of inflammation in DON-induced macrophages, but an overview of how DON exposure elicits IL-1 beta secretion from RAW264.7 cells has not been fully illustrated. Here we found that the cellular phenomenon, involved with a type of programmed cell death known as pyroptosis, contains: 1) increase of pro-IL-1 beta expression, 2) motivation of caspase-1, 3) caspase-1-dependent maturement of IL-1 beta, 4) caspase-1 fragmentation of gasdermin D (GSDMD), and 5) IL-1 beta secretion through GSDMD pore. Mechanistically, the present study certified that DON both as first and second signals engaged in IL-1 beta release is mediated by purinergic P2X7 receptor (P2X7R)-Src signaling. During this process, P2X7R signal is required for GSDMD pore forming course in ASC-independent manner. Moreover, blocking of K+ efflux, ROS formation, as well as cathepsin B activity decreases IL-1 beta export. Our data show that exposure to DON does cause pyroptosis and IL-1 beta secretion via P2X7R signal in RAW264.7 macrophages. Overall, these results provide new mechanistic clue for DON as a pro-inflammatory factor in innate immune signaling events.

关键词： Interleukin   IL-17D   Immune regulation   Chub mackerel  

摘要： Interleukin-17D (IL-17D) is a pro-inflammatory cytokine implicated in T helper 17 cell-mediated immune responses. Although its role in mammalian immunity is well established, its function in fish remains relatively unexplored. This study delves into the functional characteristics of IL-17D in chub mackerel (Scomber japonicus). We identified and characterized a chub mackerel IL-17D homolog (SjIL-17D) and investigated its spatial and temporal expression patterns, as well as the impact it has on downstream gene expression, apoptosis, cell proliferation, and nitric oxide (NO) production. SjIL-17D exhibited a wide tissue distribution, showing the highest expression in the blood, followed by the brain and skin. Upon immune challenges with polyinosinic:polycytidylic acid, lipopolysaccharide (LPS), Vibrio harveyi, and Streptococcus iniae, SjIL-17D expression was significantly upregulated in the blood. Functional analysis revealed that recombinant SjIL-17D (rSjIL-17D) stimulated the expression of pro-inflammatory cytokines, transcription factors, mitogen-activated protein kinases, and antiviral response genes in fish cell lines. Furthermore, rSjIL-17D attenuated LPS-induced apoptosis, promoted M1 macrophage polarization, and enhanced wound healing. Additionally, rSjIL-17D was found to stimulate NO production in macrophages and exhibit antiviral activity against viral hemorrhagic septicemia virus. These findings collectively demonstrate the crucial role that IL-17D plays in regulating immune responses in chub mackerel, providing valuable insights into the innate immune mechanisms of this economically important fish species.

关键词： Oral squamous cell carcinoma   Interleukin-1 receptor antagonist   Type I interferon response   Interferon alpha   Interferon beta  

摘要： Interleukin-1 receptor antagonist (IL1RA) is an anti-inflammatory and anti-tumor protein, and a member of the Interleukin-1 (IL-1) family. Our previous finding showed that IL1RA is a tumor marker for oral squamous cell carcinoma (OSCC), but the exact mechanism is unknown. The present study aims to investigate the biological role of IL1RA in the progression of OSCC in vitro and in vivo and the underlying molecular mechanism. IL1RA was lowly expressed in OSCC specimens and cells, and its overexpression significantly inhibited the proliferation and migration of OSCC cell lines CAL27 and HN6. In nude mice bearing OSCC xenografts, in vivo overexpression of IL1RA significantly reduced tumor growth without influencing epithelial-mesenchymal transition (EMT). Differentially expressed genes (DEGs) in OSCC cells overexpressing IL1RA were identified by RNA sequencing (RNA-seq), and they were significantly enriched in cancer-associated signaling pathways like type I interferon response. IL1RA upregulated interferon alpha (IFNA) and interferon beta (IFNB), known for their anti-cancer properties, in OSCC cells and specimens. In conclusion, IL1RA inhibits the malignant progression of OSCC by mediating the type I interferon response.

关键词： THRIL   TNF-alpha   FTO   HuR   NSCLC  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is a crucial cytokine involved in cancer progression, affecting the proliferation and survival of tumor cells. However, the exact mechanisms underlying its action remain poorly understood. Here we found that high concentration of TNF-alpha decreased TNF-alpha and heterogenous nuclear ribonucleoprotein L related immunoregulatory LncRNA (THRIL) expression, thereby inhibiting non-small cell lung cancer (NSCLC) cells proliferation while facilitating apoptosis. Clinically, the expression of THRIL was upregulated in NSCLC cells and tissues. THRIL knockdown resulted in decreased proliferation and increased apoptosis in NSCLC cells. Mechanistically, TNF-alpha diminished the m6A methylation of the THRIL transcript by enhancing the expression of FTO in A549 cells, which was subsequently recognized and degraded by YTHDF2. Furthermore, we identified that THRIL specifically interacted with HuR, forming a functional THRIL-HuR complex that enhanced TNF-alpha mRNA stability, thereby influencing endogenous TNF-alpha expression. Collectively, our findings reveal a novel regulatory feedback loop between TNF-alpha and THRIL, demonstrating that TNF-alpha inhibits the proliferation of NSCLC cells via the FTO/YTHDF2/THRIL axis. This highlights THRIL as a potential biomarker and therapeutic target in NSCLC.

关键词： Anthemis   Sesquiterpene lactone   IL6   TNF   Carbonic anhydrase   Network pharmacology  

摘要： The present study investigated the phytochemical composition and biological activities of extracts from the aerial parts of Anthemis austriaca, A. cretica subsp. albida, A. pauciloba, A. tinctoria and A. wiedemanniana. About 150 compounds belonging to hydroxybenzoic acids, hydroxycinnamic acids, phenylethanoid glycosides, acylquinic acids, acylhexaric acids, flavonoids and sesquiterpene lactones were identified. A. tinctoria also displayed significant antiradical activity, obtained from its MeOH and 70 % MeOH extracts. EtOAc and MeOH extracts of A. pauciloba revealed the highest anti-acetylcholinesterase activity (3.51 and 3.50 mg GALAE/g;p > 0.05). Extracts had a higher affinity towards human carbonic anhydrase isoenzymes I (CAI) than CAII, and the best inhibition effect was exerted by EtOAc extract of A. wiedemanniana a (IC50 7.02 mu g/mL). Network pharmacology analysis identified IL6 and TNFa as key targets of these plant-derived molecules, underscoring their multi-target potential. Anthemis extracts' efficacy in blunting LPS-induced IL6 and TNF alpha gene expression in isolated mouse colon has confirmed these predictions. Molecular docking studies further confirmed that these compounds interact with multiple transcription factors (TFs), suggesting broad pharmacological activity. These results indicated that the five Anthemis species could be a promising source of bioactive molecules.