BIOCONJUGATE CHEMISTRY
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2024
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IF 4
Shu Li,Shibo Song,Xiaojing Liu,Xingjiao Zhang,Xueya Liang,Xin Chang,Daijun Zhou,Jianting Han,Yaoyan Nie,Chen Guo,Xiaojun Yao,Min Chang,Yali Peng
Aberrant canonical NF-κB signaling has been implicated in diseases, such as autoimmune disorders and cancer. Direct disruption of the interaction of NEMO and IKKα/β has been developed as a novel way to inhibit the overactivation of NF-κB. Peptides are a potential solution for disrupting protein–protein interactions (PPIs); however, they typically suffer from poor stability in vivo and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine SNAr chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling in vitro and in vivo, and presented positive metabolic stability, anti-inflammatory effects, and low cytotoxicity. Importantly, our results also revealed that cyclic peptides had huge potential in acute lung injury (ALI) treatment, and confirmed the role of the decafluorobiphenyl-based cyclization strategy in enhancing the biological activity of peptide NEMO–IKKα/β inhibitors. Moreover, it provided a promising method for the development of peptide-PPI inhibitors.
研究领域:
药理学
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分子生物学
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炎症研究
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药物开发
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肽化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Liwei Xue,Xiaosheng Jin,Tingting Ji,Rongzhou Li,Xiaoju Zhuge,Fang Xu,Zijiao Quan,Haibin Tong,Weilai Yu
Objectives Luteolin, known for its multifaceted therapeutic properties against inflammatory diseases, holds potential for addressing the unmet need for effective treatments in ulcerative colitis (UC), a prevalent subtype of inflammatory bowel disease (IBD). This study aimed to comprehensively assess luteolin's therapeutic efficacy in a dextran sulfate sodium (DSS)-induced colitis mouse model, shedding light on its anti-UC mechanisms. Methods Our investigation encompassed in vivo assessments of luteolin's therapeutic potential against DSS-induced colitis through rigorous histopathological examination and biochemical analyses. Furthermore, we scrutinized luteolin's anti-inflammatory prowess in vitro using lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary peritoneal macrophages. Additionally, we quantitatively evaluated the impact of luteolin on C–C motif chemokine ligand 2 (CCL2)-induced macrophage migration employing Transwell and Zigmond chambers. Furthermore, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and molecular docking were employed to identify potential therapeutic targets of luteolin and investigate their binding sites and interaction patterns. Results Luteolin demonstrated therapeutic potential against DSS-induced colitis by ameliorating colitis symptoms, restoring intestinal barrier integrity, and inhibiting proinflammatory cytokine production in the colonic tissues. Moreover, luteolin demonstrated robust anti-inflammatory activity in vitro , in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary peritoneal macrophages. Notably, luteolin suppressed the phosphorylation of IKKα/β, IκBα, and p65, along with preventing IκBα degradation in LPS-treated RAW264.7 cells and peritoneal macrophages. Furthermore, luteolin impaired the migratory behavior of RAW264.7 cells and peritoneal macrophages, as evidenced by reduced migration distance and velocity of luteolin-treated macrophages. Mechanistically, luteolin was found to antagonize IKKα/β, subsequently inhibiting IKKα/β phosphorylation and the activation of NF-κB signaling. Conclusion Luteolin emerges as a promising lead compound for the clinical therapy of colitis by virtue of its ability to ameliorate DSS-induced colitis, antagonize IKKα/β, suppress NF-κB signaling, and impede macrophage activation and migration.
研究领域:
药理学
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免疫学
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胃肠病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INFECTION GENETICS AND EVOLUTION
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2021
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IF 3.342
M.A. Abo-Kadoum,Mohammed Assad,Moure UAE,Stech A.E. Nzaou,Zhen Gong,Asmaa Moaaz,Samson Teweldebrhan,Adel Eltoukhy,Ai Xuefeng,Yu Chen,Jianping Xie
Mycobacterium tuberculosis (Mtb) survival and virulence largely reside on its ability to manipulate the host immune response . We have previously shown that M. tuberculosis Raf kinase inhibitor protein (RKIP) Rv2140c regulates diverse phosphorylation events in M. smegmatis . However, its role during infection is unknown. In this report, we show that Rv2140c can mimic the mammalian RKIP function. Rv2140c inhibit the activation of extracellular signal-regulated kinase (ERK) and nuclear factor κB (NF-κB) via decreasing the phosphorylation capacity of upstream mediators MEK1, ERK1/2, and IKKα/β, thus leading to a reduction in pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. This effect can be reversed by RKIP inhibitor locostatin. Furthermore Rv2140c mediates apoptosis associated with activation of caspases cascades. This modulation enhances the intracellular survival of M. smegmatis within macrophage. We propose that Rv2140c is a multifunctional virulence factor and a promising novel anti-Tuberculosis drug target.
研究领域:
微生物学
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免疫学
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传染病学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
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2019
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IF 3.197
Yanbei Tu,Kai Wang,Jian-Bo Wan,Chengwei He
Glycine tabacina (Labill.) Benth, a renowned Chinese medicinal herb, has been used for treatment of rheumatoid arthritis (RA) and joint infection. This study aimed to investigate inhibitory effect of its ethanol extract (GTE) on RA-associated inflammation. Nine isoflavonoids of twelve ones which were found in G. tabacina roots were identified by UHPLC-DAD-MS/MS. GTE treatment suppressed lipopolysaccharide-stimulated overproduction of nitric oxide, TNF-α and IL-6, and iNOS expression in macrophages. GTE blocked the activation of NF-κB and MAPK pathways, as indicated by reduced levels of phosphorylation of IKKα/β, IκBα, p38, ERK and JNK, and the suppressed nuclear translocation of NF-κB p65. Additionally, GTE administration decreased swelling of arthritic paw and serum TNF-α and IL-1β levels in collagen-induced arthritis (CIA) mice. These results demonstrated that GTE exhibited strong anti-inflammatory and anti-arthritic activities through suppressing NF-κB and MAPK pathways activation in activated macrophages and CIA mice, suggesting the potential applications of this species in RA prevention and treatment as functional food or therapeutic agent.
研究领域:
药理学
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免疫学
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炎症研究
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风湿病学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）