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摘要： Long-acting controlled drug release formulations are highly desired for potentiating efficacy and reducing administration frequency. Here we present a kinetically controllable long-term interleukin-2 (IL-2) release platform by the fusion and boundary elimination of calcium carbonate and calcium phosphate amorphous phases. Unlike mixtures, a group of hybrid biominerals with the chemical formula Ca(CO3)(x)(PO4)(2(1-x)/3) (CaCPs, 0 < x < 1) was fabricated under high pressure (2 GPa), and the CaCPs showed crystallization-driven release behaviors to optimize the in vivo fate of IL-2. Ca(CO3)(1/2)(PO4)(1/3) dynamically remodeled immunosuppressive tumor microenvironments, preferentially activated cytotoxic and memory T cells by improving IL-2 redistribution and achieved weeks-long IL-2 retention in tumors with high tolerance and biosafety. In a melanoma model in female mice, Ca(CO3)(1/2)(PO4)(1/3) revealed superior antitumor effects to inhibit local tumor recurrence, hinder the growth of distant untreated tumors and maintain long-term T cell responses against the rechallenged metastatic tumors.

关键词： Th1 cell responses   complement   complosome   C5aR2   prostaglandin   prostacyclin   IL-1β   Crohn’s disease   rheumatoid arthritis   cryopyrin-associated periodic fever syndrome   CAPS  

摘要： T helper 1 (Th1) cell initiation pathways are well characterized;however, those regulating their contraction are less understood. Here, we define a CD4+ T cell-autonomous pathway in which complement C5 orchestrated a shift from prostaglandin E2 (PGE2) dominance to enhanced prostacyclin (PGI2) production via activation of C5a receptor 2 (C5aR2). This pivot in lipid mediators induced autocrine signaling through the PGI2 receptor and expression of the interleukin-1 (IL-1) decoy IL-1 receptor type 2 (IL-1R2), which sequestered Th1 cell-driving intrinsic IL-1 beta, facilitating Th1 cell contraction. Disruption of this C5aR2-PGI2-R axis was a hallmark of pathologically persistent Th1 cell activity in inflammatory conditions, including cryopyrin-associated periodic syndromes (CAPS), Crohn's disease, and rheumatoid arthritis. Rebalancing this axis through selective PGE2 synthase inhibition rectified the hyperactive Th1 cell phenotype in vitro in T cells from individuals with CAPS. Therefore, complement is a key controller of prostanoid metabolism, and the latter is an intrinsic-and potentially druggable-checkpoint for the cessation of Th1 cell effector responses.

摘要： Although multiple single-cell RNA sequencing (scRNA-seq) based studies have explored rheumatoid arthritis (RA), most have focused on synovial tissue, limiting the ability to perform paired pre- and post-treatment comparisons and to elucidate dynamic changes. Moreover, the single-cell impact of TNF-alpha and JAK inhibitors on RA remains poorly understood, hindering effects toward precision medicine for RA. Here, we present a comprehensive scRNA-seq analysis of synovial fluid samples of RA patients treated with tofacitinib or adalimumab, both pre- and post-treatment. Following stringent quality control, we analyzed 100,387 high-quality cells, providing an in-depth characterization of cell composition, molecular signaling pathways, and functional properties. This rich dataset offers a valuable resource to address diverse research questions, from uncovering the mechanisms of action of TNF-alpha and JAK inhibitors, to identifying novel therapeutic targets for RA, and advancing our understanding of the pathogenesis of inflammatory diseases.

关键词： PIEZO1   Psoriasis   IL-17   NF-kB   Inflammation   Keratinocyte   Th17 cells  

摘要： Background Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and an altered immune response. PIEZO1, a mechanically activated ion channel, has been implicated in various cellular processes, but its role in psoriasis pathogenesis remains unclear. Methods We examined PIEZO1 expression in skin samples from psoriatic patients and healthy individuals using western blot, immunohistochemistry, and mRNA expression analyses. Subsequently, we employed PIEZO1 knock-out (KO) mice to establish imiquimod (IMQ)-induced psoriasiform models for in vivo experiments. Additionally, we conducted in vitro experiments with PIEZO1-silenced human keratinocytes (HaCaT cells) to investigate the impact on keratinocyte function and the expression of inflammatory cytokines. Results PIEZO1 expression was significantly upregulated in the basal layer of psoriatic lesions compared to healthy controls. In vivo, PIEZO1 KO mice showed attenuated psoriasis-like symptoms, reduced keratinocyte proliferation, inflammatory cell infiltration, and less Th17 cells compared to wild-type mice. Loss of PIEZO1 in vitro inhibited keratinocyte proliferation and migration, while inducing apoptosis. Transcriptome sequencing and subsequent analyses revealed that PIEZO1 knockdown modulates the NF-kB signaling pathway and associated inflammatory genes. The in vitro activation of NF-kB signaling was diminished by PIEZO1 silencing in keratinocytes, resulting in decreased inflammatory cytokine and chemokine expression. Furthermore, PIEZO1 facilitated keratinocyte-mediated CD4 + T cell differentiation into Th17 cells, a key pathogenic factor in psoriasis. Conclusion This study highlights the critical role of PIEZO1 in psoriatic skin inflammation and suggests that PIEZO1 may serve as a novel therapeutic target for psoriasis treatment. Our findings reveal that PIEZO1 modulates keratinocyte proliferation, immune cell infiltration, and T cell differentiation through the NF-kB sig

关键词： Multiple myeloma   IL-17   Immunotherapy   MM progression   Adjuvant therapy   Bone marrow microenvironment  

摘要： Multiple myeloma (MM), a plasma cell malignancy, despite the progress in treatment, is still a challenge for both clinicians and affected patients. Modern treatment regimens including monoclonal antibodies, bispecific antibodies, CAR-T cell therapy as well as new generations of immunomodulatory drugs and proteasome inhibitors significantly improved clinical outcomes. Nonetheless, there is still a room for improvement and novel therapeutic strategies. IL-17-related signaling is a relatively undiscovered area in MM research. It was established that IL-17 is the growth factor for plasma cells including their malignant counterparts, is associated with myelomagenesis and disease progression. Furthermore, IL-17 axis can be pharmacologically targeted by monoclonal antibodies currently being used in different indications. In this narrative review we summarized the role of IL-17 axis in MM. Specifically, we focused on the role of IL-17 in MM development and progression with a particular emphasis upon clinical implications. Moreover, we have briefly summarized the potential role of therapeutic interference with IL-17-related singling and have outlined future research directions.

关键词： Crohn's disease   Omvoh   Skyrizi   Stelara   Tremfya   adverse effects   dosage   drug interactions   efficacy   guselkumab   lactation   mirikizumab   pregnancy   risankizumab   safety   ustekinumab  

关键词： anti-inflammatory   diabetes   electrostatic complexation   Il-1Ra   interleukin-1   nanoparticles   protein delivery  

摘要： Diabetes is a prevalent and potentially serious endocrine disorder characterized by elevated blood glucose levels and beta-cell destruction. Interleukin-1 receptor antagonist (IL-1Ra), a competitive inhibitor of the IL-1 receptor, downregulates inflammatory pathways contributing to beta-cell destruction. However, its short half-life (4-6 h) and rapid clearance hinder its clinical effectiveness. In this study, a dual-polymeric system comprising cationic and lipid-based polymers is developed for IL-1Ra delivery. IL-1Ra nanocomplexes (IL-1Ra NCs) are formed through electrostatic interactions, confirmed by SDS-PAGE, TEM, and particle size analysis (167.57 +/- 1.08 nm for IL-1Ra NCs vs 153.21 +/- 1.85 nm for blank NCs) with zeta potentials of +8.66 +/- 0.46 mV versus +24.03 +/- 1.1 mV. In vitro, IL-1Ra NCs demonstrate anti-inflammatory activity against IL-1 beta-induced inflammation in cells. In vivo pharmacokinetic studies show significant improvements in Cmax, AUC, half-life (t1/2), and mean residence time (MRT) for IL-1Ra NCs compared to free IL-1Ra, suggesting reduced dosing frequency and enhanced patient compliance. Mice treated with IL-1Ra NCs exhibit a significant reduction in fasting blood glucose levels (232.25 +/- 23.64 mg dL-1 vs 367.88 +/- 21.83 mg dL-1 in the diabetic control). Furthermore, IL-1Ra NCs preserve beta-cell integrity and exhibit an improved anti-inflammatory response as assessed by H&E and IHC analysis.

关键词： computational protein design   human leukocyte antigen   peptide antigen   cell receptor   HLA  

摘要： Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC- I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC- I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC- I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC- I complex limits data quality. Here, we demonstrate that a designed MHC- I protein, SMART A*02:01, enables facile solution mapping of MHC- I:TCR interactions at scale. Our approach can be combined with computational modeling and structure- guided engineering to aid the development of TCR- based therapeutics.

关键词： IL-5   IL-9   allergic asthma   polymorphism   sensitivity  

摘要： BackgroundThe purpose of this research is to examine whether or not there is a connection between polymorphisms in the IL-5 and IL-9 genes and the prevalence of allergic asthma in Iraqi *** investigate the variants in the genes rs2069812T/C (IL-5) and rs1859430 C/T (IL-9) and their association with the likelihood of developing allergic *** hundred forty, one hundred twenty without asthma and one hundred twentywith the condition, made up the healthy subjects. We determined the levels of IL-5 and IL-9 using the enzyme-linked immunosorbent assay (ELISA) after separating sera from peripheral blood. Additionally, the allele-specific PCR method was used to identify the polymorphism distribution of rs2069812 (IL-5) and rs1859430 (IL-9).ResultsStudy participants with allergic asthma had significantly higher levels of interleukin (IL)-9 and interleukin (IL)-5 than those in the healthy subjects: 2 and 2.39 ± 0.18 pg/ml, compared to 1.004 ± 0.04 pg/ml and 2.21 ± 0.16 pg/ml, respectively, with a significance level of P < 0.05. In terms of age, gender, and place of residence, there was no statistically significant difference between the ill group and the healthy control group. The patients' group had 66 cases of the heterozygous genotype TG compared to 58 cases in the control group. Thus, the TG genotype was associated with an increased risk of allergic asthma illness (etiologic fraction: 0.2963) and an odds ratio of 2.4074 (95% CI: 1.2462-4.6505). The patients' group also had a higher frequency of the homozygous genotype GG (65 cases vs. 54 cases in the control group). The odds ratio for allergic asthma illness was 1.0578 (95% CI: 0.6386-1.7522), and the etiologic fraction was 0.0299, indicating that genotype GG was a risk *** findings provide more evidence that interleukin-5 and interleukin-9 play critical roles in allergic asthma, particularly in eosinophilic inflammation. Consequently, it is important to target them in order