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关键词： Cytokine   Immunotherapy   Immune Checkpoint Inhibitor   Tumor microenvironment - TME   T cell  

摘要： Background Combining interleukin-2 (IL-2) agonism with programmed cell death protein 1 (PD-1) checkpoint inhibition has shown synergistic potential in reinvigorating antitumor T cell responses. However, integrating these two mechanisms within a single molecule has been challenging due to competing requirements for PD-1 engagement and IL-2 receptor signaling. ANV600 is a novel bispecific antibody-cytokine fusion protein that targets a non-blocking epitope on PD-1, enabling cis-targeted IL-2R beta gamma agonism while preserving combinability with therapeutic PD-1 inhibitors. This design allows for selective expansion of tumor antigen-specific T cells while avoiding the systemic toxicity and regulatory T cell (Treg) expansion associated with conventional IL-2 *** The PD-1-targeting antibody used in ANV600 was generated by immunization of humanized mice and selected for its ability to bind PD-1 without blocking the binding epitope of PD-1 checkpoint blocking agents. ANV600 was evaluated in multiple syngeneic tumor models using human PD-1 transgenic mice. Tumor-infiltrating lymphocytes were analyzed to assess the selectivity of ANV600 for PD-1+ T cell subsets. Combination studies with pembrolizumab and nivolumab were performed to assess synergy with checkpoint *** ANV600 significantly inhibited tumor growth as monotherapy across multiple models, including the immune checkpoint-resistant B16F10 melanoma. By targeting PD-1, ANV600 selectively expanded tumor antigen-specific CD8+T cells, particularly progenitor exhausted (Tpex) and cytotoxic exhausted (Tcex) subsets, while sparing Tregs and NK cells. Combination with pembrolizumab and nivolumab resulted in additive effects, consistent with the complementary roles of PD-1 blockade in expanding Tpex cells and IL-2R beta gamma signaling in reprogramming Tcex cells. ANV600's efficacy was dependent on CD8+T cells and primarily driven by tumor-resident T cells, as it remained effective despite blocked

关键词： In silico ADMET/Tox   Pro-inflammatory cytokine   Obesity   Pancreatic lipase   Corchorus olitorius L   Polyphenol  

摘要： This study aimed to evaluate the antioxidant, anti-inflammatory, and anti-obesity effects of bioactive compounds derived from Corchorus olitorius L., using a combined in vitro, in vivo, and in silico approach. The in vitro phase involved polyphenol extraction and antioxidant activity assays. The in vivo phase used a high-fat diet (HFD)-induced obesity model in Wistar rats divided into four groups: standard diet (STD), high-fat diet (HFD), STD with C. olitorius extract (STD + C. olitorius), and HFD with C. olitorius extract (HFD + C. olitorius). Rats received a daily oral administration of C. olitorius extract (100 mg/kg) throughout a 9-week treatment period. Plasma biochemical parameters and adipose tissue histology were assessed. The in silico phase involved molecular docking of previously identified and synthesized C. olitorius compounds against obesity- and inflammation-related targets (TNF-alpha, IL-6, PL), followed by ADMET predictions and analog design via bioisosteric replacement. C. olitorius treatment reduced body weight gain, visceral fat accumulation, and lipid parameters in HFD-fed rats. Histological analysis showed decreased fibrosis and inflammatory cell infiltration in adipose tissue, supporting its anti-inflammatory and anti-fibrotic effects. Molecular docking revealed that key compounds-particularly L7 (methyl-1,4,5-tri-O-caffeoylquinic acid) and L2 (3,5-dicaffeoylquinic acid)-demonstrated strong binding affinities to proinflammatory cytokines and pancreatic lipase. Analog compounds designed via bioisosteric modification retained favorable biological activity. ADME analysis indicated that the principal compounds possess favorable oral absorption properties and align with drug-likeness criteria. Compared to orlistat, these natural compounds offer a safer profile with reduced toxicity risks. This study highlights the multi-target therapeutic potential of C. olitorius derived compounds-particularly L7 and its analogs-as promising candidates for natural

关键词： Acetylcholine receptor antibody   Biomarker   Disease activity   Interleukin   Myasthenia gravis  

摘要： Background: IL-10 and IL-12 family cytokines play important roles in various immunological diseases. This study identified a relationship between IL-10 and IL-12 family cytokines and the pathogenesis of myasthenia gravis (MG). Methods: We measured IL-10 and IL-12 family cytokines levels in 25 treatment-naive MG patients with acetylcholine receptor (AChR) antibodies and 28 controls and examined their relationships with clinical parameters. Results: Serum levels of IL-10, IL-12p40, IL-12p70, IL-20, IL-22, IL-26, IL-28A, IL-29, and IL-35 were significantly higher in MG group than in control group. Among these, IL-20, IL-26, IL-28A, and IL-29 levels decreased after immunotherapy. AChR antibody titers were negatively correlated with levels of IL-12p40, IL-22, and IL-26. Scores on the MG activities of daily living (MG-ADL) scale were negatively correlated with IL-20 levels. Conclusion: Serum levels of IL-10 and IL-12 family cytokines were elevated in MG. In particular, IL-12p40, IL-20, IL-22, and IL-26 levels might be potential disease biomarkers in MG patients.

关键词： Crystal violet dye   Simulation modeling   Adsorption mechanism   Textile effluent decolourisation   BMIM-PF6 (IL): CuO and ZnO nanomaterials  

摘要： In the present investigation, bare and 1-butyl-3-methylimidazoliums hexa-fluorophosphate (BMIM-PF6) ionic liquid (IL) based novel mesoporous nanomaterials of CuO and ZnO were fabricated via one-pot straightforward microwave irradiation approach and utilised for the adsorption of crystal violet (CV) dye from the synthetic solutions. The Fabricated bare CuO, CuO-IL, bare ZnO, and ZnO-IL nanomaterials (NMs) were fully characterised for associated physio-chemical properties via UV-Vis, powdered XRD, BET, FT-IR, TGA, FE-SEM/EDX, TEM, and ZetaSizer. Fabricated CuO-IL and ZnO-IL NMs exhibit smaller polycrystalline sizes and functionalisation with imidazole ring-based groups, which enhances colloidal dispersibility. The BET surface areas of CuO-IL and ZnO-IL NMs were recorded to be 29.409 m(2)/g and 63.516 m(2)/g, respectively, significantly improved than the bare CuO and ZnO NMs. It was established that the adsorption of CV dye was found to be pH-dependent, and maximum removal was achieved at 30mg/25 mL NMs dose at 60 min (at 30 degrees C) for all four NMs separately. Also, the dye adsorption was observed to be endothermic for both bare and BMIM-PF6 (hydrophobic and nonwater soluble) modified CuO-IL and ZnO-IL NMs. Langmuir and Temkin isotherms well explained dye adsorption onto each nanomaterial, and the adsorption rate followed pseudo second order kinetic. Achieved q(max) for CV dye using CuO-IL and ZnO-IL NMs were found to be 69.93 and 78.13 mg/g, respectively, attributed to the incorporation of imidazole aromatic ring from BMIM-PF6, significantly higher than the bare CuO and ZnO NMs (61.72 and 70.92 mg/g). Recyclability study of ZnO-IL and CuO-IL NMs up to four cycles approved their excellent removal capacity with >= 88.68 % (CuO-IL) and >= 91.22 % (ZnO-IL) recoverability. BMIM-PF6 based NMs are more efficient for removing CV dye than bare NMs, and feasibility approves their excellent decolourisation efficacy from real textile effluent.

关键词： Staphylococcus aureus   Biofilm   Coagulase   Fe3O4@Dex-QT   Quercetin  

摘要： The research investigated the effects of that magnetic nanoparticles coated with the plant-based flavonoid quercetin have on the growth of Staphylococcus aureus. The synthesis of magnetic nanoparticles proceeded through co-precipitation and further involved quercetin coating using a dextran stabilizer. A combined product of these materials received the chemical name Fe3O4@Dex-QT. The study included multiple analytical tests such as FTIR (Fourier Transform Infrared Spectroscopy), FE-SEM (Field Emission Scanning Electron Microscopy), EDS (Energy-Dispersive X-Ray Spectroscopy) and XRD (X-ray diffraction) together with cellular and molecular assays. Biofilm detection experiments showed that 95% of studied microorganisms had moderate-to-strong biofilm formation abilities. The examined strains that formed biofilms exhibited complete biofilm inhibition at a minimum concentration of 512 mu g/mL. Post-treatment with Fe3O4@Dex-QT nanoparticles, the Coa and Hla genes were expressed at 30 and 20% levels respectively, as determined through RT-PCR analysis. The research uncovered that Fe3O4@Dex-QT nanoparticles demonstrate successful antibacterial properties against S. aureus strains, making them viable for substituting conventional antibiotics.

关键词： hnRNP A1   原核表达   表达纯化   抗体制备  

摘要： 目的：本研究旨在通过PCR、双酶切等方法构建重组表达质粒，通过设置IPTG浓度、表达时间和表达温度的单因素实验，优化hnRNP A1蛋白在BL21感受态细胞中的表达条件，获得高浓度、高质量的纯化蛋白，并制备高效价hnRNP A1多克隆抗体。方法：利用生物信息学软件分析hnRNP A1的理化性质及结构，构建pET-28a-hnRNP A1重组质粒并转化至感受态BL21细胞，优化表达条件后通过镍柱纯化获得hnRNP A1蛋白，利用Western Blot鉴定其特异性。用纯化蛋白免疫C57BL/6小鼠，制备hnRNP A1多克隆抗体，并利用间接ELISA测定抗体的效价。结果：在IPTG浓度0.4 mmol/L、诱导温度42℃、诱导时间8 h的条件下，hnRNP A1表达量最高，纯化后蛋白浓度达2.0563 μg/μL，Western Blot验证为目标蛋白，间接ELISA检测抗体效价为1:409 600。结论：成功分析了hnRNP A1的理化性质，高效表达了hnRNP A1蛋白，并制备出高效价的鼠源多克隆抗体，为后续研究提供了重要工具。

关键词： macrophages   inflammation   tumor necrosis factor   interferon gamma   immune checkpoint inhibition   rheumatoid arthritis  

摘要： IL-1 beta-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. IL-1 beta+ macrophages express genes cooperatively induced by PGE2 and TNF signaling, but mechanisms that induce these cells are not known. We used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-gamma, as occurs in RA synovial macrophages. We identified a TNF + PGE2 (TP) induced gene expression signature that is enriched in IL1 beta+ RA and ICI-arthritis monocytic subsets, and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. ICI-arthritis myeloid cells mapped primarily onto four previously defined RA synovial monocytic clusters, and TP genes were expressed in a manner suggestive of a new functional monocyte subset. TP signature genes are distinct from canonical inflammatory NF-kappa B target genes such as TNF, IL6 and IL12B and are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-kappa B activity. Unexpectedly, IFN-gamma suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such as TNF and T cell chemokines like CXCL10. The opposing cross-regulation of PGE2 and IFN signaling in vitro was reflected in vivo in mutually exclusive expression of TP and IFN signatures in different cell clusters in RA and ICI-arthritis monocytes. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-gamma and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis.

关键词： T regulatory cells   interleukin-2   autoimmunity   experimental autoimmune encephalomyelitis  

摘要： Experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin basic protein (MBP) is a self-limiting disease model of multiple sclerosis. CD4+CD25+Foxp3+T cells play a role in limiting autoimmune disease but treatment with antigen na & iuml;ve CD4+CD25+ cells does not reduce EAE. This study examined if in vitro activation by MBP and rIL-2 induced CD4+CD25+Foxp3+ cells that could inhibit EAE. Culture of CD4+CD8-CD25+cells from na & iuml;ve rats with MBP and rIL-2 induced activated Treg that reduced the severity of clinical EAE and infiltration of CD8+T cells and macrophage into brain stem. CD4+CD25+T cells activated by an irrelevant autoantigen and rIL-2 did not suppress EAE. Resting CD4+CD25+T cells activated by autoantigen and rIL-2 have mRNA for Infgr, Il12rb2, Il5 but not Tbet, Gata3, Ilr5ra or Ifng. These changes in mRNA expression are the markers of Ts1 cells. A proportion of CD4+CD8-CD25+ cells activated by MBP/rIL-2 were induced to express CD8 alpha, CD8(3 and CD62L. Depletion of CD4+CD8 alpha+CD25+ cells removed the capacity of MBP and rIL-2 activated CD4+CD25+T cells to suppress EAE. This study demonstrated that in vitro activation of CD4+CD8-CD25+ cells by MBP/rIL-2 induced relevant antigen-specific Treg within days, which expressed CD8 alpha, CD8(3 and CD62L with a Ts1 phenotype and that had greater potency than freshly isolated antigen naive CD4+CD25+Treg in suppressing clinical severity of EAE and immune inflammation in CNS. These findings may guide development of antigen-specific Treg for therapy.

关键词： Cytokine   Immunotherapy   Solid tumor  

摘要： Background The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical *** In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo *** The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor alpha (IL-18R alpha) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) *** We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy.

关键词： erlotinib   familial adenomatous polyposis (FAP)   MHC   sulindac   tumor immunomodulation  

摘要： A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-gamma signaling as a key pathway. In this study, we combine intermittent low-dose ERL +/- SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL +/- SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 x 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL +/- SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 x 2 increases tumor-associated Cd4(+) T cells by similar to 2.6-fold (p < 0.05), with no apparent effect on Cd8(+) T cells. The treatment also increases tumor-associated Cd68(+) cells (p < 0.05) and decreases Foxp3(+) (p < 0.01) and Arg1(+) (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-gamma signaling may benefit FAP patients at drug doses below the clinical standard of care.