β-Hydroxybutyrate aggravates LPS-induced inflammatory response in bovine endometrial epithelial cells by activating the oxidative stress/NF-κB signaling pathway

Article

Author: Yang, Wanghao ; Liu, Jijun ; Jin, Yaping ; Chen, Huatao ; Wang, Fengbo ; Wang, Aihua ; Gao, Dengke ; Zhang, Haisen ; Wang, Xuerong

Ketosis, a metabolic disorder characterized by elevated levels of ketone bodies in the blood or urine, is known to impair the health and productivity of dairy cows, leading to substantial economic losses in the dairy industry. When ketosis occurs in dairy cows, the levels of β-hydroxybutyrate (BHBA), an abundant form of ketone bodies, in the blood increase significantly. Elevated BHBA levels have been shown to negatively impact reproductive performance and increase the incidence of periparturient diseases in dairy cows, including mastitis and endometritis. However, the role of BHBA in the development of endometritis in dairy cows and its underlying mechanisms remain largely unclear. The present study was designed to investigate the specific role of BHBA in the development of endometritis using an inflammatory response model of the bovine endometrial epithelial cell line (BENDs). Escherichia coli lipopolysaccharide (LPS) treatment (1 μg/mL) significantly increased the expression levels of interleukin (IL)-6 and IL-1β, as well as the phosphorylation of p65 and IκB in BENDs. In addition, co-treatment with BHBA (2.4 mM) and LPS (1 μg/mL) significantly increased the expression levels of proinflammatory cytokines (IL-6, IL-1β, and IL-8), as well as the phosphorylation of p65 and IκB, compared to the LPS-only treatment group. Immunofluorescence staining showed that the addition of LPS altered the nuclear localization of p65, and co-treatment with BHBA and LPS further promoted the translocation of p65 to the nucleus. Additionally, the addition of BHBA significantly increased the levels of oxidation indicators (MDA), whereas the levels of antioxidative indicators, including heme oxygenase-1 (HO-1) and catalase (CAT), were markedly decreased in BENDs. As a representative antioxidant, N-acetylcysteine (NAC) treatment significantly reduced the phosphorylation of p65 and IκB in the BHBA and LPS co-treatment group. SC75741, an NF-κB signaling pathway inhibitor, significantly decreased the expression levels of proinflammatory cytokines (IL-6, IL-1β, IL-8, and CCL5) in the BHBA and LPS co-treatment group. In summary, the current study demonstrates that BHBA aggravates LPS-induced inflammatory response in BENDs through the activation of oxidative stress/NF-κB signaling pathway, unravelling the mechanism by which BHBA exacerbates the inflammatory response in the BENDs of dairy cattle. This study elucidates the role of ketosis and its key metabolite BHBA in the pathogenesis of endometritis in dairy cows, providing valuable insights for understanding this pathological process.

01 Dec 2024·Molecular Diversity

Repositioning of anti-infective compounds against monkeypox virus core cysteine proteinase: a molecular dynamics study

Article

Author: Alwarthan, Sara ; Alotaibi, Nouf ; Alshahrani, Fatimah S ; Sabour, Amal A ; Alsaleh, Abdulmonem A ; AlShehail, Bashayer M ; Rabaan, Ali A ; Garout, Mohammed ; Abduljabbar, Wesam A ; Mashraqi, Mutaib M ; Aljeldah, Mohammed ; Alshehri, Ahmad A ; Alfaraj, Amal H ; Alestad, Jeehan H ; Alissa, Mohammed

Monkeypox virus (MPXV) core cysteine proteinase (CCP) is one of the major drug targets used to examine the inhibitory action of chemical moieties. In this study, an in silico technique was applied to screen 1395 anti-infective compounds to find out the potential molecules against the MPXV-CCP. The top five hits were selected after screening and processed for exhaustive docking based on the docked score of ≤ -9.5 kcal/mol. Later, the top three hits based on the exhaustive-docking score and interaction profile were selected to perform MD simulations. The overall RMSD suggested that two compounds, SC75741 and ammonium glycyrrhizinate, showed a highly stable complex with a standard deviation of 0.18 and 0.23 nm, respectively. Later, the MM/GBSA binding free energies of complexes showed significant binding strength with ΔG_TOTAL from -21.59 to -15 kcal/mol. This report reported the potential inhibitory activity of SC75741 and ammonium glycyrrhizinate against MPXV-CCP by competitively inhibiting the binding of the native substrate.

01 Nov 2024·Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology

[IL-6 upregulates the expression of human placental MSC SPP1 through the NF-κB signaling pathway and promotes M2 macrophage polarization].

Article

Author: Pan, Lin ; Ye, Peng ; Zhu, Yongzhao ; Ma, Shuqin ; Tao, Jin ; Cai, Ruizhi ; Li, Li

Objective To investigate the molecular mechanism of IL-6 regulating the expression of secretory phosphoprotein 1 (SPP1) in human placental-derived mesenchymal stem cells (hfPMSCs) and influencing the polarization of macrophages. Methods hfPMSCs were prepared by enzymatic digestion and cultured in a defined, serum-free medium. The morphology of hfPMSCs was observed under a microscope, and the expression of surface markers CD14, CD34, CD45, CD73, CD90, CD105, and human leukocyte antigen DR (HLA-DR) was detected by flow cytometry. hfPMSCs were treated with IL-6 at the final dosage of 100 ng/mL for 24 hours. ELISA, Western blot, and real-time quantitative PCR were used to detect the expression of SPP1 at the protein and mRNA levels; after being treated with IL-6, hfPMSCs infected with SPP1 interference lentivirus were co-cultured with activated macrophage THP-1 cells induced by 100 ng/mL lipopolysaccharide (LPS) and 80 ng/mL phorbol 12-myristate 13-acetate (PMA), and flow cytometry was used to detect the proportion of CD11c and CD206 positive cells in THP-1 cells; hfPMSCs were treated with IL-6 and/or specific inhibitors of nuclear factor kappa B p65 (NF-κB p65), SC75741, and Western blot was used to detect the expression of genes in the NF-κB signaling pathway and SPP1. Results IL-6 significantly upregulates the expression of SPP1 in protein and mRNA levels in hfPMSCs; interference of SPP1 significantly downregulates the expression of SPP1 in hfPMSCs and significantly reduces the positive cell ratio of CD206 in co-cultured macrophages; IL-6 significantly upregulates the expression of p-p65 in hfPMSCs, activating the NF-κB signaling pathway; SC75741 significantly downregulates the expression of p-p65 and SPP1 in hfPMSCs treated with IL-6. Conclusion IL-6 upregulates the expression of SPP1 through the NF-κB signaling pathway in hfPMSCs, which enhances the capability to induce macrophages to polarize towards the M2 phenotype.

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Indication	Highest Phase	Country/Location	Organization	Date
Virus Diseases	Preclinical	Germany	4SC AG	31 Jul 2008

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