Search Results (110)

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by vascular abnormalities, immune dysfunction, and progressive fibrosis. One of the most common manifestations of SSc is interstitial lung disease (ILD), known by a progressive course leading to significant morbidity and mortality. Aim: to investigate autoantibodies, cytokines, and genetic markers in SSc-ILD through a systematic review and analysis of a Kazakh cohort of SSc-ILD patients. Methods: A PubMed search over the past 10 years was performed with “SSc-ILD”, “autoantibodies”, “cytokines”, and “genes”. Thirty patients with SSc were assessed for lung involvement, EScSG score, and modified Rodnan skin score. IL-6 was measured by ELISA, antinuclear factor on HEp-2 cells by indirect immunofluorescence, and specific autoantibodies by immunoblotting. Genetic analysis was performed using a 120-gene AmpliSeq panel on the Ion Proton platform. Results: The literature review identified 361 articles, 26 addressed autoantibodies, 20 genetic variants, and 12 cytokine profiles. Elevated levels of IL-6, TGF-β, IL-33, and TNF-α were linked to SSc. Based on the results of the systemic review, we created a preliminary immunogenic panel for SSc-ILD with following analysis in Kazakh patients with SSc (n = 30). Fourteen of them (46.7%) demonstrated signs of ILD and/or lung hypertension, with frequent detection of antibodies such as Scl-70, U1-snRNP, SS-A, and genetic variants in SAMD9L, REL, IRAK1, LY96, IL6R, ITGA2B, AIRE, TREX1, and CD40 genes. Conclusions: Current research confirmed the presence of the broad range of autoantibodies and variations in IRAK1, TNFAIP3, SAMD9L, REL, IRAK1, LY96, IL6R, ITGA2B, AIRE, TREX1, CD40 genes in of Kazakhstani cohort of SSc-ILD patients. Full article

Chronic high-fat diet (HFD) feeding in male rats causes significant metabolic as well as inflammatory disturbances, including obesity, insulin resistance, dyslipidemia, liver and kidney dysfunction, oxidative stress, and hypothalamic dysregulation. This study assessed the therapeutic effects of chlorogenic acid (CGA), a natural polyphenol, administered at 10 mg and 100 mg/kg/day for the last 4 weeks of a 12-week HFD protocol. Both CGA doses reduced body weight gain, abdominal circumference, and visceral fat accumulation, with the higher dose showing greater efficacy. CGA improved metabolic parameters by lowering fasting glucose and insulin and enhancing lipid profiles. CGA suppressed orexigenic genes (Agrp, NPY) and upregulated anorexigenic genes (POMC, CARTPT), suggesting appetite regulation in the hypothalamus. In abdominal white adipose tissue (WAT), CGA boosted antioxidant defenses (SOD, CAT, GPx, HO-1), reduced lipid peroxidation (MDA), and suppressed pro-inflammatory cytokines including TNF-α, IFN-γ, and IL-1β, while increasing the anti-inflammatory cytokine IL-10. CGA modulated inflammatory signaling via upregulation of miR-146a and inhibition of IRAK1, TRAF6, and NF-κB. It also reduced apoptosis by downregulating p53, Bax, and Caspase-3, and restoring Bcl-2. These findings demonstrate that short-term CGA administration effectively reverses multiple HFD-induced impairments, highlighting its potential as an effective therapeutic for obesity-related metabolic disorders. Full article

Oximes have been reported to exhibit useful pharmaceutical properties, including compounds with anticancer, anti-arthritis, antibacterial, and neuroprotective activities. Many oximes are kinase inhibitors and have been shown to inhibit various kinases. Herein, a panel of oxime derivatives of tricyclic isatins was synthesized and evaluated for inhibition of cellular inflammatory responses and binding affinity to several kinases. Compounds 5a and 5d (a.k.a. NS-102), which have an unsubstituted oxime group, inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in human THP-1Blue monocytic cells and interleukin-6 (IL-6) production in human MonoMac-6 monocytic cells, with IC₅₀ values in the micromolar range. These compounds also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Compounds 5a and 5d exhibited nanomolar/submicromolar binding affinity toward several kinase targets. The most potent inhibitor, 5d (3-(hydroxyimino)-5-nitro-1,3,6,7,8,9-hexahydro-2H-benzo[g]indol-2-one), demonstrated high binding affinity for 12 kinases, including DYRK1A, DYRK1B, PIM1, Haspin, HIPK1-3, IRAK1, NEK10, and DAPK1-3. Molecular modeling suggested modes of binding interaction of selected compounds in the DYRK1A and PIM1 catalytic sites that agreed with the experimental binding data. Our results demonstrate that tricyclic isatin oximes could be potential candidates for developing anti-inflammatory drugs with neuroprotective effects for treating neurodegenerative diseases. Full article

Hidradenitis suppurativa (HS) and atopic dermatitis (AD) are both inflammatory dermatoses that can significantly impact patient quality of life, however, limited research exists regarding their association. The purpose of this comprehensive review is to compare the inflammatory pathogenesis of HS and AD, explore the associations between these diseases, and discuss standalone and concomitant disease treatment options. Although HS and AD are understood to be primarily driven by the Th1 and Th2 inflammation pathways, respectively, these conditions both utilize the Janus Kinase/Signal transducer and activator of transcription (JAK/STAT) pathway to promote inflammation. Newer research also suggests that IL-36 and IL-1 receptor-associated kinase 4 (IRAK4) may be two additional inflammatory signals shared between the HS and AD disease pathways. These shared mechanisms are reflected in patient presentations as HS and AD are often concomitantly present and demonstrate a bidirectional association in the current literature. Treatment options for concomitant disease are limited, but leverage the shared immune pathogenesis of both diseases. Dupilumab has been reported to improve both HS and AD symptoms in select patients. JAK inhibitors are currently FDA-approved for the treatment of AD, and early trials have suggested benefits from JAK inhibitors such as upadacitinib, povorcitinib, and topical ruxolitinib for HS. Possible future avenues for research on treating both HS and AD include IRAK-4 inhibitors such as zabedosertib and BAY1830839, and diet and gut microbiome modifications. Full article

The landscape of clinical trials aimed at targeting specific proteins has experienced significant advancements, presenting promising opportunities for the development of effective therapeutics across a range of diseases. These trials focus on the investigation of modulation of protein functions, utilizing innovative technologies such as PROTACs (Proteolysis-Targeting Chimeras) and other protein degraders. These innovative approaches aim to address previously undruggable targets, enhancing the specificity and efficacy of treatments. The current landscape of clinical trials encompasses a diverse array of therapeutic areas, including oncology, autoimmune diseases, and neurological disorders. For instance, drugs like ARV-471 and ARV-110 are in advanced phases for treating metastatic breast cancer and prostate cancer, respectively, by targeting estrogen and androgen receptors. Early-phase trials explored the potential of targeting proteins like IKZF1/3 in multiple myeloma and IRAK4 in autoimmune diseases. The conducted trials not only emphasize the therapeutic potential of protein degradation but also highlight the challenges associated with bioavailability, stability, and delivery mechanisms. As these clinical trials advance, they possess the potential to transform treatment paradigms, providing renewed hope for patients facing complex and refractory conditions. Full article

Sepsis, a life-threatening condition characterized by immune dysregulation and organ damage, remains a significant clinical challenge. Natural antioxidant compounds (NAOs) such as quercetin, EGCG, resveratrol, curcumin, and chlorogenic acid have shown promising anti-inflammatory and anti-apoptotic effects in preclinical models of sepsis and related conditions, yet the molecular mechanisms underlying their actions remain incompletely defined. In this study, we performed comprehensive molecular docking analyses to investigate the binding affinities and interaction profiles of these NAOs with three key proteins central to inflammatory and apoptotic signaling: Toll-like receptor 4 (TLR-4), interleukin-1 receptor-associated kinase 1 (IRAK1), and caspase-3. Our results demonstrate that all five compounds exhibit favorable binding affinities with these targets, forming multiple hydrogen bonds and hydrophobic interactions with critical active site residues. Notably, curcumin and EGCG consistently displayed the strongest binding affinities across the three proteins, with docking scores comparable to or surpassing those of reference inhibitors. Resveratrol demonstrated highly stable binding poses, particularly with caspase-3, while quercetin and chlorogenic acid showed moderate but reproducible affinities. Overall, this study provides new mechanistic insights into how NAOs may target central mediators of inflammation and cell death. Experimental validation is essential to confirm these interactions, assess binding affinities, and fully elucidate the therapeutic potential of NAOs in sepsis. Full article

Replacing fishmeal (FM) with plant-based protein sources remains a significant challenge, particularly for carnivorous fish. This study investigates the effect of dietary Lentinus edodes fermentation (LEF) supplementation on Japanese eel (Anguilla japonica) fed with fermented soybean meal (FSM) as a partial FM replacement. The positive control consisted of 64% FM (Con), and the negative control (FSM group) included 52% FM plus 12% FSM. Two experimental diets were formulated by adding 2% LEF (LEF2 group) and 3% LEF (LEF3 group) to the negative control diet. The experimental diet was administered to Japanese eels weighing 62.50 ± 2.14 g for 12 weeks. The experimental fish were randomly assigned to four groups, with three replicates of 100 fish per group. The results indicated that growth performance and feed efficiency were significantly reduced in the FSM group, but were significantly improved by LEF supplementation (p < 0.05). LEF supplementation did not significantly affect muscle crude fat and protein content compared to the FSM group (p > 0.05), but significantly increased muscle amino acid content and levels of certain fatty acids (linoleic acid, γ-linolenic acid, eicosatrienoic acid, DHA) (p < 0.05). LEF supplementation reduced serum TC and LDL-C levels, increased HDL-C levels, significantly increased CAT and T-SOD activities, and reduced MDA levels in both serum and liver (p < 0.05). ALT and AST activities were significantly elevated in the FSM group, accompanied by liver histological abnormalities, which were improved by LEF supplementation. LEF supplementation increased the thickness of the muscularis, villus height, and goblet cell count in the intestine (p < 0.05). Compared to the control, the FSM group significantly upregulated spleen tnf-α gene expression and downregulated the expression of anti-inflammatory factors (ifn-α, ifn-γ, socs1, mavs). LEF supplementation ameliorated the reduced immunocompetence induced by FM replacement with FSM by enhancing the expression of immune-related genes (irak4, ifn-α, ifn-γ, irf3, irf11, socs1, mavs, traf3) in the spleen. These results suggest that the beneficial effects of LEF supplementation on growth performance and feed efficiency may be attributed to its improvement of liver damage and intestinal histology, as well as its enhancement of antioxidant capacity and immunity. Full article

(1) Background: Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor in adults, constituting 45.6% of tumors. We explored the impact of gene methylation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) and the Transforming Growth Factor Beta (TGFB) gene complex using the TCGA dataset for GBM patients. (2) Methods: We implemented a multivariate Cox proportional hazards model to directly compare hazard ratios for TGFB1/2/3 and MGMT methylation in relation to OS, considering male versus female, age at diagnosis, and age interactions with TGFB2 gene methylation and sex variables. Reactome analysis was performed to identify enriched pathways negatively correlated with TGFB2 methylation. (3) Results: The GBM patients had high levels of TGFB2 gene methylation; this primarily benefited the young adult male patients, and multivariate analysis exhibited a significantly improved OS prognosis HR (95% CI range) = 0.04 (0.006–0.274); p = 0.001) relative to the TGFB1^highMe (HR (95% CI range) = 0.657 (0.454–0.951); p = 0.026) and MGMT^highMe (HR (95% CI range) = 0.667 (0.475–0.936); p = 0.019) groups of GBM patients. The Reactome pathways collectively represented T-cell activation, differentiation, effector functions, antigen presentation, and Toll-like receptor pathways. Gene level mRNA expression highlighted four positive prognostic genes upregulated in tumor tissues, and their expression was validated in independent single-cell RNA-seq experiments. These genes were highly expressed in macrophages (HIF1A, TRIM22, IRAK4, PARP9). In contrast, MALT1 mRNA expression was the only gene product with a negative prognostic impact on OS in GBM patients (HR (95% CI range) = 1.997 (1.1–3.625); p = 0.023). (4) Conclusions: Increased levels of TGFB2 gene methylation predict improved OS, especially in young adult male GBM patients, above that of MGMT gene methylation, and should be considered during the administration of mRNA-based TGFB2 therapies. Full article

Correct immunological dialogue between the maternal uterus and conceptus is essential during implantation, and Toll-like receptors (TLRs) participate in maternal immune tolerance during pregnancy. This study aimed to analyze the effect of early pregnancy on Toll-like receptor pathways in the ovine endometrium. Ovine endometria were obtained on day 16 of the estrous cycle (N16) and days 13, 16, and 25 of pregnancy (P13, P16, and P25), and expression profiles of TLR members, including TLRs, tumor necrosis factor receptor-associated factor 6 (TRAF6), interleukin 1 receptor-associated kinase 1 (IRAK1), and myeloid differentiation primary response gene 88 (MyD88), were detected by quantitative real-time PCR, Western blot analysis, and immunohistochemistry analysis. The data of this study showed that the expression of TLR2 and TLR5 was gradually increased during early pregnancy compared to N16, and TLR3 expression was greater at P16 and P25 than at N16 and P13. However, the expression levels of TLR4 and TRAF6 were weaker at P13 and P16, and the expression of MyD88 was inhibited by early pregnancy. Furthermore, early pregnancy regulated IRAK1 expression. These findings corroborated that the TLR pathway was modulated in the ovine endometrium during early pregnancy, which may be involved in maternal immunoregulation. Full article

Background: Articular chondrocytes are specialized cells in synovial joint cartilage, responsible for maintaining and regenerating the extracellular matrix. Inflammation disrupts the balance between matrix synthesis and degradation, leading to cartilage breakdown. This process, commonly observed in conditions such as osteoarthritis, results in chondrocyte dysfunction and accelerates joint degeneration. Since TRPA1 channels are implicated in inflammatory processes, this study investigates the expression of TRPA1 channels in freshly dissociated rat articular chondrocytes and their modulation by anti-inflammatory agents. Methods: We used the whole-cell patch-clamp method to assess TRPA1 channel expression and modulation. Results: Freshly dissociated chondrocytes exhibit ion currents attributable to TRPA1 channel expression, with higher magnitudes observed in medium-sized cells. These currents decrease over time in primary culture. Treatment with pro-inflammatory agents (IL-1α, IL-1β, and LPS) increases TRPA1′s current magnitude. IL-1β treatment directly induces transient TRPA1 currents. Several signaling components activated during inflammation contribute to the IL-1β-induced enhancement of TRPA1 current density, including IL-1 R1, the adaptor protein MyD88, and the downstream kinases IRAK1 and IRAK4. Conclusions: Our findings demonstrate that healthy rat chondrocytes express functional TRPA1 channels and that inflammatory processes modulate their expression. Full article

Background: Among the various forms of root resorption, External Apical Root Resorption (EARR) has garnered particular attention due to its prevalence and potential complications associated with orthodontic interventions. Methods: An electronic search of literature was performed between September 2024 and December 2024 to identify all articles investigating the Role of Genetic Polymorphisms in External Apical Root Resorption Among Orthodontic Patients: Implications for Treatment Outcomes. The search was conducted using MEDLINE (National Library of Medicine)-PubMed with restrictions concerning the date of publication. In particular, we focused on the period 2014–2024 using the following keywords: gene polymorphisms AND orthodontic treatment AND apical root resorption OR external apical root resorption. This was followed by a manual search, and references were used to identify relevant articles. Results: The review showed that certain variations of the following genes may be positively associated with OIEARR: Osteopontin gene, P2RX7, IL-1β, IL-6, IL1RN, OPG, RANK, STAG2, RP1-30E17.2, SSP1, SFRP2, TNFSF11, TNFRSF11A, TNFRSF11B, VDR, CYP27B1, ACT3N, TSC2, WNT3A, LRP1, LRP6. Conversely, the IRAK1 gene has a protective function against the development of OIEARR. Conclusions: Despite these advancements, it is still not feasible to establish new guidelines and clinical protocols based on the existing research findings. The integration of genetic considerations into orthodontic practice has the potential to revolutionize treatment strategies, ensuring that they are not only effective but also respectful of each patient’s unique biological landscape. Full article

Melatonin (MLT), produced by the pineal gland and other tissues, is known for its anti-inflammatory effects, particularly in regulating inflammatory markers and cytokines in intestinal cells. Our study aimed to investigate how MLT influences the expression of inflammatory genes through histone modification in canine ileum epithelial cells (cIECs). In our experiment, cIECs were cultured and divided into a control group (CON) and an MLT-treatment group. MLT did not significantly affect cell growth or death in cIECs compared to the CON. However, MLT treatment led to an upregulation of CD40, ZAP70, and IL7R and a downregulation of LCK, RPL37, TNFRSF13B, CD4, CD40LG, BLNK, and CIITA at the mRNA expression level. Moreover, MLT significantly altered the NF-kappa B signaling pathway by upregulating genes, such as CD40, ZAP70, TICAM1, VCAMI, GADD45B, IRAK1, TRADD, RELA, RIPK1, and RELB, and downregulating PRKCB, LY96, CD40LG, ILIB, BLNK, and TNFRSF11A. Using ChIP-qPCR, we discovered that MLT treatment enhanced histone acetylation marks H3K9ac, H3K18ac, H3K27ac, and methylation marks H3K4me1 and H3K4me3 at the ZAP70 and CD40 gene loci (p < 0.05). Additionally, the enrichment of RNA polymerase II and phosphorylated Ser5 pol-II at these loci was increased in MLT-treated cells (p < 0.05), indicating heightened transcriptional activity. In conclusion, our findings suggest that MLT mitigates inflammation in cIECs by modulating the transcription of ZAP70 and CD40 through histone modifications, offering potential therapeutic insights for inflammatory bowel diseases. Full article

The endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) modulates inflammatory and neuroinflammatory signaling through toll-like receptors (TLRs) in human and mouse macrophages, human blood cells and alcohol-preferring (P) rat brains. Although it is recognized that 3α,5α-THP inhibits TLR4 activation by blocking interactions with MD2 and MyD88, the comprehensive molecular mechanisms remain to be elucidated. This study explores additional TLR4 activation sites, including TIRAP binding to MyD88, which is pivotal for MyD88 myddosome formation, as well as LPS interactions with the TLR4:MD2 complex. Both male and female P rats (n = 8/group) received intraperitoneal administration of 3α,5α-THP (15 mg/kg; 30 min) or a vehicle control, and their hippocampi were analyzed using immunoprecipitation and immunoblotting techniques. 3α,5α-THP significantly reduces the levels of inflammatory mediators IL-1β and HMGB1, confirming its anti-inflammatory actions. We found that MyD88 binds to TLR4, IRAK4, IRAK1, and TIRAP. Notably, 3α,5α-THP significantly reduces MyD88-TIRAP binding (Males: −31 ± 9%, t-test, p < 0.005; Females: −53 ± 15%, t-test, p < 0.005), without altering MyD88 interactions with IRAK4 or IRAK1, or the baseline expression of these proteins. Additionally, molecular docking and molecular dynamic analysis revealed 3α,5α-THP binding sites on the TLR4:MD2 complex, targeting a hydrophobic pocket of MD2 usually occupied by Lipid A of LPS. Surface plasmon resonance (SPR) assays validated that 3α,5α-THP disrupts MD2 binding of Lipid A (Kd = 4.36 ± 5.7 μM) with an inhibition constant (Ki) of 4.5 ± 1.65 nM. These findings indicate that 3α,5α-THP inhibition of inflammatory mediator production involves blocking critical protein-lipid and protein-protein interactions at key sites of TLR4 activation, shedding light on its mechanisms of action and underscoring its therapeutic potential against TLR4-driven inflammation. Full article

(1) Background: Buffaloes are crucial livestock species for food and service in tropical and subtropical regions. Buffalo genetics, particularly in indigenous Chinese breeds such as the Xiangxi white buffalo (XWB), remains an intriguing area of study due to its unique traits and regional significance. (2) Methods: This investigation utilized the whole-genome sequences of twenty XWBs (newly sequenced), along with eighty published whole-genome sequences of other buffalo breeds (including Guizhou white buffalo, river buffalo, and Chinese buffalo in the Yangtze River). Using whole-genome sequencing analysis technology, the population structure, genomic diversity, and selection signatures of XWB were determined. (3) Results: This study revealed that the XWB, being phylogenetically positioned in the middle and lower reaches of the Yangtze River, exhibited substantial genomic diversity. Employing four selection sweep detection methods (CLR, iHS, π-ratio, and F_ST), several genes were positively identified for adaptive traits in the XWB, including coat color phenotypes (ASIP, KIT), the nervous system (GRIK2), reproduction (KCNIP4), growth and development (IFNAR1, BMP6, HDAC9, MGAT4C, and SLC30A9), the body (LINGO2, LYN, and FLI1), immunity (IRAK3 and MZB1), and lactation (TP63, LPIN1, SAE1). (4) Conclusions: In conclusion, this study enhances our understanding of the genetic distinctiveness and adaptive traits of XWB, highlighting selection signatures crucial for future breeding and conservation and ensuring sustainable use of this vital livestock resource. Full article

Arthritis has a high global prevalence. During the early ancient human era, bee (Apis) venom therapy was employed in Egypt, Greece, and China to alleviate ailments such as arthritis and neuralgia. In addition, bee venom has long been used as a traditional medicine for immune-related diseases in Korea. Wasp (Vespa) venom is a folk medicine of the Jingpo people in Yunnan, China, and has been widely used to treat rheumatoid arthritis. In spite of this, the underlying mechanisms of bee and wasp venoms for the treatment of arthritis are yet to be fully understood. In recent years, researchers have investigated the potential anti-arthritic properties of bee and wasp venoms. Studies have shown that both bee and wasp venom can improve swelling, pain, and inflammation caused by arthritis. The difference is that bee venom reduces arthritis damage to bone and cartilage by inhibiting the IRAK2/TAK1/NF-κB signaling pathway, NF-κB signaling pathway, and JAK/STAT signaling pathway, as well as decreasing osteoclastogenesis by inhibiting the RANKL/RANK signaling pathway. Wasp venom, on the other hand, regulates synovial cell apoptosis via the Bax/Bcl-2 signaling pathway, inhibits the JAK/STAT signaling pathway to reduce inflammation production, and also ameliorates joint inflammation by regulating redox balance and iron death in synovial cells. This review provides a detailed overview of the various types of arthritis and their current therapeutic approaches; additionally, it comprehensively analyzes the therapeutic properties of bee venom, wasp venom, or venom components used as anti-arthritic drugs and explores their mechanisms of action in anti-arthritic therapy. Full article