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关键词： Acetylation   Aryl hydrocarbon receptor   ITE   MMP-9   TNF-alpha  

摘要： Matrix metalloproteinase 9 (MMP-9) plays a key role in the pathogenesis of inflammatory diseases and is upregulated by TNF-alpha. ITE (2-[1'H-indole-3'-carbonyl]-thiazole-4-carboxylic acid methyl ester) functions as an endogenous ligand for the aryl hydrocarbon receptor and is involved in inflammation. It is still uncertain whether ITE could affect TNF-alpha-induced MMP-9 expression in monocytic cells. In this study, we explored the effect of ITE on TNF-alpha-induced MMP-9 expression and the underlying mechanisms involved. Our results show that pretreatment of THP-1 monocytic cells with ITE significantly blocked TNF-alpha-induced MMP-9 expression at both the mRNA and protein secretion levels. Similar results were seen in primary human monocytes. The inhibition of MMP-9 by ITE occurs independently of TNFR1/2 modulation and apoptotic processes. RNA transcription data revealed that ITE suppresses the genes associated with inflammatory pathways. Mechanistically, histone modification profiling identified H3K9 acetylation as an epigenetic regulatory mark of TNF-alpha-induced MMP-9 expression. ChIP-qPCR data revealed that ITE pretreatment decreased TNF-alpha-triggered transcriptionally permissive acetylation marks at H3K9 in the MMP-9 promoter. Pharmacological inhibition of histone acetylation mimics the action of ITE in suppressing TNF-alpha-induced MMP-9 gene expression. Conversely, the acetylation induced by trichostatin A effectively reverses the inhibitory action of ITE. Moreover, increased TNF-alpha-induced binding of NF-kappa B or AP-1 at the MMP-9 promoter region was inhibited by ITE, resulting in suppression of MMP-9 gene expression. In conclusion, our study demonstrates that ITE reduces the TNF-alpha-induced MMP-9 expression via the H3K9 acetylation/NF-kappa B/AP-1 axis, highlighting a potential mechanism for mitigating MMP-9-related inflammatory disorders.

关键词： Solid-phase extraction   Ionic liquid-modified carbon nanotubes   Aflatoxin B   HPLC-fluorescence detection  

摘要： Edible oils are prone to contamination by aflatoxin B-1 (AFB(1)), posing significant food safety risks. In this study, a series of imidazolium ionic liquids (ILs) with varying alkyl chain lengths (C-2, C-4, C-6, C-8) were covalently grafted onto multi-walled carbon nanotubes (MWCNTs) via a free-radical method to develop IL@MWCNT adsorbents (EMIM@MWCNT, BMIM@MWCNT, HMIM@MWCNT, OMIM@MWCNT) for solid-phase extraction (SPE) of AFB(1), followed by HPLC-fluorescence detection. Comprehensive characterization revealed that chain length critically influenced material properties: SEM and BET analysis demonstrated that HMIM@MWCNT (C-6) exhibited the highest specific surface area (101.6 m(2)/g) and optimal pore diameter (35.64 nm), while contact angle measurements and dispersion tests in non-polar solvents highlighted its superior hydrophobicity and oil-matrix compatibility. FTIR and XPS confirmed covalent IL grafting and the presence of oxygenated groups (hydroxyl, epoxy), which facilitated pi-pi stacking, hydrogen bonding, and electrostatic interactions with AFB(1). Adsorption studies indicated that HMIM@MWCNT achieved the fastest kinetics (equilibrium within 20 min) and highest capacity (45.2 mg/g), following pseudo-second-order kinetics and Freundlich isotherm models. The C-6 chain length balanced hydrophobicity and steric effects, enhancing AFB(1) affinity compared to shorter chains (C-2, C-4) and mitigating aggregation observed with longer chains (C-8). The optimized SPE-HPLC method demonstrated a wide linear range (0.5 mu g/L-500 mu g/L, R-2 = 0.9997), ultra-low detection limit (0.1 mu g/L), and satisfactory recoveries (88.0-104%) in spiked corn oil with RSD <= 6.0%. The adsorbent retained >98% efficiency over five cycles, underscoring its reusability. This work elucidates the role of IL alkyl chain length in tailoring adsorbent properties for efficient AFB(1) extraction, offering a robust strategy for mycotoxin monitoring in lipid-rich matrices.

关键词： IL-6   MyD88   NF-KB   TLR3   TNF   TRIF   cytokine   inflammation   macrophage  

摘要： Toll-like receptor 3 (TLR3) initiates antiviral and inflammatory responses exclusively through the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β). In contrast, MyD88 (myeloid differentiation primary response 88), a central adaptor for most other TLRs, is traditionally considered dispensable for TLR3 signaling. Here, we demonstrate that MyD88 directly contributes to TLR3-mediated NF-κB activation and cytokine production in macrophages. Bone marrow-derived macrophages (BMDMs) from MyD88 deficient mice exhibited significantly attenuated NF-κB activation in response to the TLR3 agonist polyinosinic-polycytidylic acid (poly(I:C)) compared to wild-type cells, as evidenced by the reduced phosphorylation of NF-κB p65 and IκBα, as well as IκBα degradation. Consistently, pro-inflammatory cytokine production, including IL-6, TNF-α, and IFN-β, was attenuated in MyD88-deficient BMDMs in vitro following stimulation by poly(I:C) or poly(A:U), another TLR3 agonist. Blood concentrations of IL-6, TNF-α, and IFN-β were significantly reduced in both TRIF-deficient mice and MyD88-deficient mice challenged by the i.p. injection of poly(I:C). Mechanistic analyses revealed that MyD88 physically associates with activated TLR3 upon poly(I:C) stimulation, and that TLR3 engagement triggered MyD88 oligomerization, which was absent in TLR3 or TRIF deficient macrophages. Our findings highlight a previously unrecognized dual-adaptor mechanism for TLR3, wherein MyD88 recruitment amplifies NF-κB signaling dynamics by bridging TLR3 to the canonical NF-κB activation cascade and robust cytokine induction. This study expands the paradigm of TLR3 signaling by establishing MyD88 as a direct contributor to TLR3-driven innate immune responses, offering new insight into cross-talk between MyD88-dependent and -independent pathways.

关键词： HLA-G   14 bp insertion/deletion variant   3142G > C variant   Rheumatoid arthritis   Soluble HLA-G  

摘要： Background Genetic predisposition is an important and fundamental determinant of susceptibility to rheumatoid arthritis (RA), a chronic autoimmune disease with joint deformity and disability. HLA-G plays an important role in the modulation of autoimmune disorders and inflammatory processes. The HLA-G + 3142G > C and 14 bp insertion/deletion variants have a controversial impact on pathogenesis of RA in various populations globally. The present study aimed to evaluate the possible association of HLA-G + 3142 G > C and 14-bp insertion/deletion variants with RA and to compare the concentration of soluble HLA-G in serum of RA patients and healthy controls. Methodology Two thirty RA patients and two fifty healthy controls fulfilling the ACR-EULAR/2010 criteria were included in this study. Genotyping of HLA-G + 3142G > C and 14 bp insertion/deletion variants was performed using PCR-RFLP and PCR-SSP methods, respectively. The concentration of soluble HLA-G was quantified using sHLA-G sandwich ELISA kit. Chi-squared test and unpaired t-test were employed for the analysis of categorical and continuous data, respectively, using SPSS 27.0. Bonferroni corrected p value < 0.05 was considered as statistically significant. Results Significant difference in the genotype frequencies of HLA-G + 3142G > C variant was observed between RA patients and controls under codominant (GG versus GC: p = 0.009, OR = 1.817), dominant (GG versus GC + CC, p = 0.033, OR = 1.618) and over dominant (GG + CC versus GC: p = 0.002, OR = 1.847) inheritance models. Further, sHLA-G level was significantly reduced in RA patients as compared to controls (21.37 +/- 10.53 ng/ml versus 29.83 +/- 14.97 ng/ml, p < 0.001). Conclusion The findings of this study reveal an association between + 3142G > C variant of HLA-G gene and increased risk of RA in Indian Bengali population. Further, decreased sHLA-G concentration in RA patients in contrast to healthy controls indicates the dysregulation of immunoregulatory mechan

摘要： Binding in cis-configuration to the PD-1 receptor (PD-1) and IL-2 receptor (IL-2R) has been shown to lead to differentiation of CD8 T cells to better effectors, which is anticipated to drive efficacy of the immune-targeted cytokine eciskafusp alfa, or PD1-IL2v. Here we present a geometrically driven mathematical formulation informed by in vitro and early clinical data which enables prediction of doses at which cis-binding is at its highest, and explains observed differences in concentration-time profiles for patients who had recent exposure to other anti-PD-1 molecules compared with those who had not. Furthermore, binding in cis-configuration is expected to follow a "bell-shaped" relationship with drug concentration such that high concentrations may lead to reduced benefit/risk ratio compared with concentrations around the peak of the bell-shape. Model simulations identify patient cohorts for whom the upper limit of the pharmacological dosing range may be defined by either undesirable off-tumor target engagement or a decrease in on-tumor cis-binding.

关键词： Traumatic brain injury   amygdala   anxiety   pyroptosis   IL-18 binding protein  

摘要： Primary Objective: This study investigates the effect and underlying mechanisms of IL-18 binding protein (IL-18BP) on anxiety-like behaviors in rats following traumatic brain injury (TBI). Methods and Procedures: Thirty-six Sprague-Dawley rats were divided into three groups: sham, TBI, and TBI+IL-18BP. Anxiety-like behaviors were evaluated using the open field and elevated plus maze tests. Immunofluorescence staining was performed to assess the number of neurons, activated astrocytes, and the proportion of astrocytes positive for NLRP3 and IL-18. IL-18 levels in serum and cerebrospinal fluid (CSF) were quantified via ELISA. Western blot analysis was conducted to measure the expression of NLRP3, cleaved caspase-1 (cl-caspase-1), and N-GSDMD in the amygdala. Main Outcomes and Results: Thirty days post-TBI, both the TBI and TBI+IL-18BP groups exhibited increased anxiety-like behaviors, elevated IL-18 levels in serum and CSF, greater activation of astrocytes in the amygdala, a higher percentage of NLRP3 and IL-18-positive astrocytes, and upregulated expression of pyroptosis-related proteins compared to the sham group (p < 0.05). However, the TBI+IL-18BP group showed significant reductions in these parameters compared to the TBI group (p < 0.05). Conclusions: IL-18BP appears to mitigate anxiety-like behaviors in TBI rats, likely through a mechanism that involves reducing astrocyte apoptosis.

关键词： eosinophilic myocarditis   eosinophilic granulomatosis with polyangiitis   hypereosinophilic syndrome   IL-5 blockade   mepolizumab   benralizumab   Charcot–Leyden crystals   case report   literature review  

摘要： Background/Objectives: Eosinophilic myocarditis (EM) is a rare, life-threatening inflammatory cardiomyopathy driven by eosinophil cytotoxicity and extracellular trap formation. Interleukin-5 (IL-5) inhibition may disrupt this pathogenic cascade. We reviewed contemporary evidence on IL-5 blockade in EM and contextualized it with an illustrative case. Methods: We searched PubMed through May 2025 for reports of EM treated with mepolizumab or benralizumab. Inclusion criteria were consistent with prior cohorts: acute cardiac symptoms with biomarker elevation plus abnormalities on transthoracic echocardiography and/or cardiac magnetic resonance imaging (CMR), along with documented IL-5-targeted therapy. We extracted clinical, imaging, biopsy, treatment-timing, and outcome data and included one institutional case. Results: Twenty-one episodes were analyzed (median age, 45 years; 10 men). Underlying conditions included eosinophilic granulomatosis with polyangiitis (10 cases; 48%), hypereosinophilic syndrome (5 cases; 24%), drug reaction with eosinophilia and systemic symptoms (DRESS, 3 cases; 14%), and eosinophilic asthma (3 cases; 14%). Treatments involved mepolizumab in 17 cases (81%) and benralizumab in 4 (19%); 4 patients received “early-start” therapy within 14 days of EM diagnosis. Among the 11 episodes with reported left ventricular ejection fraction (LVEF) at baseline and follow-up, the median baseline LVEF was 40% (range, 30–62), with 10 of 11 (91%) <50%. On follow-up, all 11 patients improved: 4 normalized (≥50%) and 7 improved to 40–49%. CMR (n = 18) demonstrated late gadolinium enhancement in 14 cases (78%), edema in 9 (50%), and intracardiac thrombus in 4 (22%). Endomyocardial biopsy confirmed eosinophilic infiltration in 13 of 15 cases (87%). Outcomes included one death (fulminant DRESS), one recovery following veno-arterial extracorporeal membrane oxygenation, and one successful heart transplantation. Illustrative case: A 24-year-old man on a steroid taper re