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关键词： Inflammation   Nanocarrier   Antioxidant enzyme   Anti-inflammatory cytokine   Kidney-targeting peptide  

摘要： Kidney disease has emerged as a significant public health concern, affecting approximately 10 % of adults worldwide. Especially, acute kidney injury (AKI) increases in-hospital morbidity and mortality. This study introduces a dual-therapeutic strategy combining interleukin-10 (IL-10), an anti-inflammatory cytokine, and catalase (CAT), a reactive oxygen species (ROS)-scavenging enzyme, for the treatment of inflammatory kidney injury. A kidney-targeting peptide-conjugated, Pluronic-based nanocarrier (K-NC) was developed to enable the co-delivery and sustained release of IL-10 and CAT. Compared to no-ligand conjugated NC, K-NC was selectively accumulated in the damaged kidneys while reducing liver accumulation. In vitro, CAT effectively reduced ROS levels in tubular epithelial cells, while IL-10 suppressed inflammatory cytokine expression and promoted M2 macrophage polarization. In vivo, co-delivery of IL-10 and CAT using K-NC resulted in significantly enhanced therapeutic effects on AKI compared to single delivery of IL-10 or CAT using K-NC (IL-10@K-NC or CAT@K-NC), or co-delivery of IL-10 and CAT using no-ligand conjugated NC (IL-10/CAT@NC) by showing reduced levels of serum creatinine and BUN, reduced reactive oxygen species, reduced pro-inflammatory cytokine expression, inhibited M1 macrophage polarization, and promoted M2 macrophage polarization in the kidney. This study not only presents a promising approach for the treatment of kidney inflammation but is also the first report demonstrating enhanced therapeutic effects through a combination of an antioxidant enzyme with an antiinflammatory cytokine.

关键词： Atypical antigen-presenting cells   MHC II   Professional antigen-presenting cells   Tumor immunotherapy  

摘要： Major Histocompatibility Complex class II (MHC II) molecules present tumor antigens to CD4 + T cells, playing a pivotal role in initiating anti-cancer immunity. Recent discoveries of MHC II expression on atypical antigenpresenting cells (APCs) have spurred interest in targeting MHC II for immunotherapy. Emerging therapies seek to enhance MHC II expression in tumors, particularly immunologically "cold" tumors with limited T-cell infiltration, to amplify CD4 + T cell-mediated anti-tumor responses. Clinical advances include MHC II-guided personalized vaccines, immune checkpoint blockade (ICB), and combination strategies showing promising efficacy. This review delineates MHC II-mediated immunoregulatory networks across professional and atypical APCs, explores their potential as biomarkers and therapeutic targets, and discusses predictive models of MHC IIantigen interactions to advance precision oncology. By elucidating the complexity of MHC II-driven immune regulation, this work aims to optimize immunotherapy design, address tumor heterogeneity, and foster tailored therapeutic approaches for diverse cancer types.

关键词： Anti-inflammatory alkaloids   SARS-CoV-2   respiratory infections   mechanistic action   drug   Human immunodeficiency virus (HIV)  

摘要： Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the deadliest viruses among respiratory viruses which resulted in COVID-19 pandemic. The virus gets transmitted by the nasal route and moves down to the trachea, bronchi, and then to the lungs. Once replicated inside the alveolar cells, the SARS-CoV-2 makes the membrane of the alveolar sac porous, which causes the leaking of plasma from surrounding blood vessels into the alveolar sac leading to its buildup. This process results in the production of pro-inflammatory cytokines like interleukin-1 beta (IL-1 beta) and Tumor necrosis factor-alpha (TNF-alpha) by the helper T-cells at the site of the infection, causing difficulty in breathing. Plant-based alkaloids can be promising to treat viral infections. Plants have contributed to drug development against viruses like Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and viruses that cause respiratory diseases in humans. Plant alkaloids, either in the form of extract, infusion, or powder, have shown potential in treating viral diseases mainly by targeting the replication of viruses. Alkaloids like Tetrandrine, Oxymatrine, and Berberine have been shown to have a positive role in mediating pro-inflammatory cytokines like IL-1. These alkaloids thus inactivate the nuclear factor kappa-B (NF-kB) pathway, inhibiting the expression of its targeted genes, IL-1 beta and TNF-alpha. This inactivation of NF-kB results in reduced levels of IL-1 and TNF-alpha, and consequently reduced inflammation, decreasing the stress on the immune cells and increasing the ability of the patient to fight the infection. Despite vaccine development for SARS-CoV-2, the virus is continuously evolving into new varieties, posing a threat to humans and it is necessary to develop effective drug discovery programs. Natural products can pave the way in this regard. This review can contribute towards safer drug development against SARS-CoV-2, combati

关键词： Osteoarthritis   Interlukin-33   Inflammation   Metformin   Single nucleotide polymorphism  

摘要： Background: Osteoarthritis (OA) is among the common chronic health conditions which impacts many aspects of an individual's life from physical function to mental health. Inflammation, in the joint as well as system inflammation is among the many mechanisms hypothesized to be involved in OA. IL-33 which belongs to the IL-1 family, is considered as an alarmin in OA. IL-33 binds to a group of receptors to stimulate signaling among which is the ST2L receptor that induced the activation of NF kappa b, thus, working as a booster of the inflammatory cascade. Many polymorphisms have been identified on the IL-33 gene which are assumed to be associated with inflammatory diseases. Methods: In the current double-blind placebo-controlled clinical trial study, patients diagnosed with knee OA were randomly divided into two groups: one group received metformin and the other received a placebo for 16 consecutive weeks (starting at 0.5 g/day, increasing to 1 g/day at week two, and increasing to 1.5 g/day for the remaining 14 weeks). Besides the evaluation of the clinical response to metformin using the Knee Injury and OA Outcome Score (KOOS) questionnaire, the serum levels of IL-33 was measured using enzyme-linked immunosorbent assay (ELISA) kits before (time 0) and after treatment (month 4). Genetic polymorphism of rs1929992 was assessed using in extracted DNAs using PCR-RFLP method. Results: Serum levels of IL-33 were significantly higher in OA patients compered to healthy individuals (P<0.001). Mutant allele (G allele) of the rs1929992 was significantly associated with OA (P=0.028;OR=1.9;95%CI: 1.02-3.6). AG+GG genotypes were also associated with OA (P=0.004;OR=3.8, 95%CI: 1.5-9.5). Metformin did not affect IL-33 levels (P>0.05). Variants of rs1929992 were not associated with response to metformin (P>0.05). Conclusion: Our findings support the role of polymorphisms of IL-33 gene and circulating levels of IL-33 in OA. Drugs targeting IL-33 signaling pathway may propose beneficial e

关键词： Interleukin-11   Randall's plaque   Ectopic calcification   TGF-beta 1   Renal fibroblasts   Renal epithelial cells  

摘要： Randall's plaque (RP) is one of the key causes of calcium oxalate (CaOx) kidney stones formation and recurrence characterized by osteogenic differentiation and fibrosis in renal papilla area. Previous studies have found that IL-11 could promote the osteogenesis of fibroblasts and function as a pro-fibrotic cytokine. Moreover, IL-11 expression is increased in RP tissues. This study aims to explore the role and underlying mechanism of IL-11 in the regulation of RP formation. IL-11 levels were significantly upregulated in RP tissues, urine, and serum of CaOx kidney stones patients. IL-11 could promote the ectopic calcification of renal fibroblasts via activating ERK1/2 and JNK signaling pathways. In co-culture system, CaOx crystals could induce a TGF-(31/IL-11 positive feedback loop between renal epithelial cells and fibroblasts, consequently enhance the ectopic calcification of renal fibroblasts. In vivo, anti-IL-11 neutralizing antibodies significantly inhibited hyperoxaluria-induced osteogenic differentiation, fibrosis, and CaOx crystal depositions in the kidney. Our findings highlight a critical role of IL-11 in RP formation and emphasize the TGF-(31/IL-11 positive feedback loop in renal fibroblast calcification, providing new insights into the pathogenesis of RP from the perspective of intercellular communication.

关键词： Cardiotrophin-like cytokine factor 1   IL12   Th1 cells   IL12R beta 2   Cytokine-receptor interaction   Proteolysis  

摘要： Cardiotrophin-like cytokine factor 1 (CLCF1) is a cytokine of the IL6/IL12 family with immune-modulating functions, mainly on B cells and myeloid cells. CLCF1 also plays a crucial role in the embryonic development of motor neurons, such that Clcf1-knock out mice are not viable. In order to further study the immune activities of CLCF1, we used a mouse model with a knock-out of Clcf1 in hematopoietic cells under the Vav promoter. While characterizing this model, we observed that CD4+ T cells from Clcf1-/- mice produced more IFN gamma than those from Clcf1+/+ mice when activated in the presence of IL12. We also observed that CLCF1 induces a downregulation of IL12R beta 2 expression levels. We further demonstrated that CLCF1 interacts with IL12R beta 2 and promotes its degradation through the proteasome in a manner independent of ubiquitination. Altogether, these results suggest that CLCF1 can act as a negative regulator of IL12 activity, a role which could be exploited therapeutically to dampen the inflammatory response driven by Th1 cells. Our observations may also hint at a new role for CLCF1 as a mediator of protein degradation.

关键词： Allergic asthma   Luteolin   Type 2 inflammation   IL-33/ST pathway   M2 macrophage  

摘要： Allergic asthma is a prevalent non-infectious inflammatory disease characterized by type 2 inflammation. Although multiple treatment options are available, their efficacy is often limited due to the heterogeneous nature of asthma. Luteolin (LUT), a naturally occurring flavonoid, has demonstrated therapeutic potential in various inflammatory conditions. The aim of this research is to investigate the underlying pathogenesis mechanisms of allergic asthma and to evaluate the therapeutic effects of LUT on allergic asthma via IL-33/ST2 signaling pathway. We established a murine model of allergic asthma by sensitizing and challenging BALB/c mice with ovalbumin (OVA), followed by treatment with LUT. The effects of LUT in allergic asthma mice were evaluated via the following techniques: pathological staining, Immunohistochemical staining (IHC), enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). Additionally, we also used IL-33 to stimulate RAW264.7 cells. Assays in vitro including cell counting Kit-8 (CCK-8), RT-qPCR and WB were performed to investigate potential mechanisms of LUT on IL-33/ST2 pathway activation and M2 macrophages polarization. LUT was verified to have crucial effects on ameliorating asthmatic mice lung function as evidenced by down-regulated airway resistance by 23 % and 48 % (p < 0.05 vs. OVA/saline group);regulating airway type 2 inflammation via decrease the content of type 2 inflammatory cytokines (IL-4, IL-5, and IL-13) by 17 %-78 % (**p < 0.01;*p < 0.001 vs. OVA/saline group);decreasing airway inflammatory cells infiltration by 54 % and 65 % (*p < 0.001 vs. OVA/saline group);inhibiting mucus secretion by 75 % and 89 % (*p < 0.001 vs. OVA/saline group). Mechanistic research revealed that LUT can treat asthma via IL-33/ST2-GSK3 beta-M2 macrophages polarization pathway, thereby regulating airway inflammation, remodeling, and immune responses in allergic asthma. Collectively, these

关键词： Endometrial cancer   Interleukin-6   KIAA1429   Ferroptosis  

摘要： Endometrial cancer (EC) exhibits significant resistance to ferroptosis. Interleukin (IL)-6 is a pleiotropic cytokine that is a regulator of the expression of various oncogenes and tumour suppressor genes. Notably, N6methyladenosine (m6A) modification has been demonstrated to play a significant role in tumour occurrence and development. However, IL-6 regulatory role in ferroptosis during carcinogenesis and whether it affects m6A modification in EC remain unclear. The present study aimed to investigate the effect of IL-6 on m6A modification in EC. The degree of ferroptosis of EC in vitro and in vivo was evaluated using a cell proliferation assay, western blotting, total reactive oxygen species (ROS) detection, a lipid peroxidation assay, and a subcutaneous xenograft tumour model. The regulation of downstream molecules by KIAA1429 was confirmed using dot blot, RNA and methylated RNA immunoprecipitation (RIP), a RNA stability assay, and fluorescence in situ hybridisation (FISH). IL-6 upregulated overall m6A levels in EC cells, with the KIAA1429 expression upregulation being the most significant. Functionally, IL-6 inhibited EC cell ferroptosis and promoted proliferation. The downregulation of KIAA1429 triggered ferroptosis, subsequently suppressing the proliferation of EC cells in vitro and tumour growth in vivo. Mechanistically, IL-6 activated KIAA1429 expression through the JAK1/STAT3 pathway. KIAA1429 regulated DDIT3 expression and promoted its degradation through m6A modification. IL-6 is crucial in EC cell ferroptosis resistance. Overall, the IL-6/KIAA1429/DDIT3 axis is a novel pathway that promotes EC progression and provides novel directions for targeted EC therapy.

关键词： Sepsis-associated encephalopathy   IL-1 alpha/IL-1 beta   Endothelial cell   BBB disruption  

摘要： Sepsis-Associated Encephalopathy (SAE), a disorder affecting the central nervous system (CNS), is highly prevalent, occurring in approximately 70 % of sepsis patients in intensive care units (ICU). Although numerous studies have highlighted the critical role of IL-1 beta in the pathogenesis of SAE, the specific downstream mechanisms remain poorly understood. Moreover, the Phase III clinical trial of IL-1R1 antagonists for SAE therapy ended in failure. In this study, we found that IL-1R1, the receptor for IL-1 beta, is exclusively and highly expressed on CNS endothelial cells during early sepsis. Specifically inhibiting IL-1R1 expression in endothelial cells during the early stage of sepsis can significantly suppress the onset of SAE. Mechanistically, elevated levels of LPS, IL-1 alpha, or IL-1 beta in the serum during sepsis induce IL-1R1 expression on endothelial cells, leading to the activation of IL-1 beta signaling. Activation of the IL-1 beta/IL-1R1 signaling pathway in endothelial cells triggers the expression of adhesion molecules, pro-inflammatory cytokines, and chemokines, which in turn exacerbate neuroinflammation and contribute to cognitive impairments. This research not only elucidates the pathogenic mechanisms underlying SAE but also introduces an advanced approach for targeted gene intervention in CNS endothelial cells, potentially offering a new strategy for the treatment of SAE and other neurodegenerative disease induced by systemic inflammation.

关键词： Pterostilbene   Lipid nanoparticles   Ultrasound   Ovarian cancer  

摘要： The current investigation explores a novel combinational approach for ovarian cancer treatment by formulating Pterostilbene-loaded solid lipid nanoparticles (PT-SLNPs) and enhancing their therapeutic efficiency using ultrasound stimulation. The formulated PT-SLNPs displays favorable physicochemical properties, with a mean particle size of 133.46 +/- 24.21 nm, a low polydispersity index (0.14 +/- 0.02), and high entrapment efficiency (87.76 +/- 0.5 %). The uniqueness of this work is attributed to the synergistic application of PT-SLNPs and ultrasound (US), which significantly enhanced the cytotoxic effect against human ovarian cancer cell A2780. Further, flowcytometry method confirmed a considerable increase in apoptosis in cells treated with PT-SLNPs + US combination. Mechanistically, exposure of cancer cells to PT-SLNPs + US downregulated the key tumor associated pro-survival and proliferative pathways by suppressing IL-6 expression and inhibiting STAT3 phosphorylation. These findings highlight the innovative potential of US assisted PT-SLNPs as a promising, less toxic alternative to conventional chemotherapy and radiotherapy in ovarian cancer treatment.