Bombyx mori nucleopolyhedrovirus (BmNPV) is one of the primary pathogens of the silkworm. Cytochrome c (cytc) showed a significant response to BmNPV infection in our previous transcriptome study. However, little is known about the role of Bombyx mori cytc (Bmcytc) in resistance to BmNPV infection. In this study, the expression levels analysis of Bmcytc showed stable expression levels in selected tissues of the resistant strain AN following BmNPV infection, while there was downregulation in the susceptible strain p50, except in the malpighian tubule. To further study the role of Bmcytc in viral infection, Bmcytc was knocked down with siRNA in vitro, resulting in significant downregulation of selected downstream genes of the mitochondrial pathway, including Bmapaf, Bmcaspase-Nc, and Bmcaspase-1; this was also confirmed by overexpression of Bmcytc using the pIZT/V5-His-mCherry insect vector, except Bmcaspase-1. Moreover, knockdown of Bmcytc significantly promoted the infection process of BmNPV in vitro, while the infection was inhibited by overexpression of Bmcytc at the early stage and subsequently increased rapidly. Based on these results, we concluded that Bmcytc plays a vital role in BmNPV infection by regulating the mitochondrial apoptosis pathway. Our work provides valuable data for the clarification of the mechanism of silkworm resistance to BmNPV infection.
Opinion statement Immunotherapy is revolutionizing tumor treatment by activating the immune response to tumors. Among them, immunotherapy represented by immune checkpoint inhibitors is considered to be a milestone in tumor treatment. It has revolutionized the management of advanced malignant tumors by activating T cells, promoting cytotoxic signaling pathways, and killing tumor cells, effectively improving the overall survival of patients. However, resistance to immunotherapy and immune-related adverse events remain challenges for immunotherapy. It has been demonstrated in previous studies that modulating intestinal microbiota can enhance immunotherapy response and reduce complications. Currently, the more mature method for microbiota regulation is fecal microbiota transplantation, which involves transfering a donor’s microbiome to the recipient in the form of capsules or fecal microbiota suspension to restore the richness of the recipient’s intestinal microbiota. In terms of cancer immunotherapy, fecal microbiota transplantation in patients who fail to respond to immune checkpoint inhibitors is expected to produce better prognosis for patients.
Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/β-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo , compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl 4 -induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.
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