ABSTRACT
Smallpox, caused by the variola virus belonging to the genus Orthopoxvirus, is an acute contagious disease that killed 300 million people in the 20th century. Since it was declared to be eradicated and the national immunization program against it was stopped, the variola virus has become a prospective bio-weapon. It is necessary to develop a safe vaccine that protects people from terrorism using this biological weapon and that can be administered to immunocompromised people. Our previous study reported on the development of an attenuated smallpox vaccine (KVAC103). This study evaluated cellular and humoral immune responses to various doses, frequencies, and routes of administration of the KVAC103 strain, compared to CJ-50300 vaccine, and its protective ability against the wild-type vaccinia virus Western Reserve (VACV-WR) strain was evaluated. The binding and neutralizing-antibody titers increased in a concentration-dependent manner in the second inoculation, which increased the neutralizing-antibody titer compared to those after the single injection. In contrast, the T-cell immune response (interferon-gamma positive cells) increased after the second inoculation compared to that of CJ-50300 after the first inoculation. Neutralizing-antibody titers and antigen-specific IgG levels were comparable in all groups administered KVAC103 intramuscularly, subcutaneously, and intradermally. In a protective immunity test using the VACV-WR strain, all mice vaccinated with CJ-50300 or KVAC103 showed 100% survival. KVAC103 could be a potent smallpox vaccine that efficiently induces humoral and cellular immune responses to protect mice against the VACV-WR strain.
Subject(s)
Smallpox Vaccine , Smallpox , Variola virus , Animals , Mice , Humans , Smallpox/prevention & control , Vaccines, Attenuated , Prospective Studies , Vaccinia virus/genetics , Immunity, Cellular , Antigens, Viral , Antibodies, Viral , Mice, Inbred BALB CABSTRACT
Preservation of the pancreatic ß-cell population is required for the development of therapies for diabetes, which is caused by a decrease in ß-cells. Here, we demonstrate the antidiabetic effects of substance P (SP) in type 1 diabetes (T1D) mice induced with streptozotocin. SP enhanced the compensatory proliferation of ß-cells in order to restore ß-cells in response to acute injury induced by a single high-dose of streptozotocin. However, SP affected neither the basal proliferation of ß-cells nor their apoptosis. In vitro studies by using the INS-1 pancreatic ß-cell line showed that SP mediated the increase in the proliferation of ß-cells via the activation of Akt. Chronic systemic treatment with SP restored the mass of ß-cells and inhibited insulitis in T1D mice induced with multiple low-doses of streptozotocin. Therefore, systemic treatment with SP may be a promising therapeutic strategy for treating diabetes in patients with loss of functional ß-cells.
Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Insulin-Secreting Cells/drug effects , Pancreatitis/prevention & control , Substance P/pharmacology , Acute Disease , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Injections, Intraperitoneal , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Pancreatitis/chemically induced , Pancreatitis/pathology , Streptozocin/administration & dosage , Structure-Activity RelationshipABSTRACT
The activity of the ubiquitin proteasome system (UPS) is downregulated in aggregation diseases such as Alzheimer's disease (AD). In this study, we investigated the therapeutic potential of the Agouti-related peptide (AgRP), which is secreted by human mesenchymal stem cells (MSCs), in terms of its effect on the regulation of proteasome activity in AD. When SH-SY5Y human neuroblastoma cells were co-cultured with MSCs isolated from human Wharton's Jelly (WJ-MSC), their proteasome activity was significantly upregulated. Further analysis of the conditioned media after co-culture allowed us to identify significant concentrations of a neuropeptide, called AgRP. The stereotactic delivery of either WJ-MSCs or AgRP into the hippocampi of C57BL6/J and 5XFAD mice induced a significant increase of proteasome activity and suppressed the accumulation of ubiquitin-conjugated proteins. Collectively, these findings suggest strong therapeutic potential for WJ-MSCs and AgRP to enhance proteasome activity, thereby potentially reducing abnormal protein aggregation and delaying the clinical progression of various neurodegenerative diseases.
Subject(s)
Agouti-Related Protein/metabolism , Alzheimer Disease/pathology , Mesenchymal Stem Cells/metabolism , Proteasome Endopeptidase Complex/metabolism , Up-Regulation , Animals , Biological Therapy , Cell Line , Coculture Techniques , Culture Media, Conditioned , Disease Models, Animal , Humans , Mice , Models, Biological , Treatment OutcomeABSTRACT
The rescue of glucose tolerance and insulinsensitivity in peripheral tissues, including adipose tissue, is essential in therapeutic strategies for diabetes. The present study demonstrated that substance P (SP) increases the accumulation of lipids in 3T3L1 cells during their differentiation into adipocytes in response to a high concentration of glucose. SP reciprocally regulated the activities of AMPactivated protein kinase (AMPK) and Akt: SP enhanced the activation of AMPK, although the activity of Akt was downregulated. Notably, SP induced an increase in the expression level of glucose transporter 4 in the 3T3L1 adipocytes. Therefore, it is possible that SP leads to an increase in glucose uptake and the accumulation of lipids in adipocytes, and may contribute towards the rescue of insulinsensitivity in diabetes.
