ABSTRACT
The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , Humans , Mice , Animals , Hepatitis B virus/physiology , Hepatitis B Surface Antigens , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Interferon-alpha/pharmacology , Interferon-alpha/therapeutic use , Leukocytes, Mononuclear/metabolism , Recombinant Proteins/pharmacology , Polyethylene Glycols/pharmacology , DNA, Viral , Treatment OutcomeABSTRACT
The destruction of proteins via the ubiquitin-proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival and are promising anticancer agents. Oprozomib (OPZ), an oral second-generation proteasome inhibitor, has been shown to inhibit the growth of several cancers in preclinical and clinical trials, including multiple myeloma and head and neck cancers, but its effects on lung cancer has not yet been determined. In this study, we evaluated the inhibitory effects of OPZ on lung cancer cell lines in vitro. The results showed that OPZ significantly suppressed cell proliferation and strongly induced apoptosis in both tested lung cancer cells independent of p53 expression. OPZ was able to cause obvious caspase 3 and PARP cleavages and stabilize p53 and its transcriptional targets p21, PUMA, and Noxa. Moreover, OPZ was capable of sensitizing lung cancer cells to the conventional chemotherapeutic drug cisplatin. Our study provides preclinical data and sheds light on the potential applications of proteasome inhibitor OPZ in lung cancer treatment.
Subject(s)
Antineoplastic Agents/pharmacology , Lung Neoplasms/drug therapy , Oligopeptides/pharmacology , Proteasome Inhibitors/pharmacology , Administration, Oral , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Lung Neoplasms/metabolism , Oligopeptides/administration & dosage , Proteasome Inhibitors/administration & dosage , Tumor Suppressor Protein p53/metabolismABSTRACT
The hypoglycemic and anti-diabetic effect of Rehmannia glutinosa oligosaccharide (ROS) in glucose-induced hyperglycemic and alloxan-induced diabetic rats and its mechanism was investigated in this paper. It was found that pretreatment of ROS in normal rats with 100 mg/kg for 3 days, i.p., induced a partial prevention of hyperglycemia caused by glucose (2g/kg, i.p.), while when hyperglycemia was induced in adrenalectomized (ADX) rats, the preventive effect of ROS on hyperglycemia was lost. In alloxan-induced diabetic rats, ROS (100 mg/kg for 15 days, i.p.) showed a significant decrease in blood glucose level and hepatic glucose-6-phosphatase activity with an increase in hepatic glycogen content. Furthermore, ROS raised plasma insulin level and lowered plasma corticosterone level in alloxan-induced diabetic rats. The results indicated that oligosaccharide of Rehmannia glutinosa Libosch. exerted a significant hypoglycemic effect in normal and alloxan-induced diabetic rats. The regulatory mechanism of ROS on glucose metabolism was adrenal dependent and had a close relation with the neuroendocrine system.