Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats.

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic had brought disastrous consequences throughout the entire world. While several manufactured vaccines have been approved for emergency use, continuous efforts to generate novel vaccines are needed. In this study, we developed SARS-CoV-2 virus-like particles (VLPs) containing the full length of spike (S) glycoprotein (S full), S1, or S2 together with the influenza matrix protein 1 (M1) as a core protein. Successfully constructed VLPs expressing the S full, S1, and S2 via Sf9 cell transfections were confirmed and characterized by Western blot and transmission electron microscopy (TEM). VLP immunization in mice induced higher levels of spike protein-specific IgG and its subclasses compared to naïve control, with IgG2a being the most predominant subclass. S full and S1 immune sera elicited virus-neutralizing activities, but these were not strong enough to fully inhibit receptor–ligand binding of the SARS-CoV-2. Neutralizing activities were not observed from the S2 VLP immune sera. Overall, our findings revealed that S full or S1 containing VLPs can be developed into effective vaccines.

Respiratory syncytial virus (RSV) infection affects the lives of neonates throughout the globe, causing a high rate of mortality upon hospital admission. Yet, therapeutic options to deal with this pulmonary pathogen are currently limited. Helminth therapy has been well received for its immunomodulatory role in hosts, which are crucial for mitigating a multitude of diseases. Therefore, in this study, we used the helminth Trichinella spiralis and assessed its capabilities for modulating RSV infection as well as the inflammatory response induced by it in mice. Our results revealed that RSV-specific antibody responses were enhanced by pre-existing T. spiralis infection, which also limited pulmonary viral replication. Diminished lung inflammation, indicated by reduced pro-inflammatory cytokines and inflammatory cell influx was confirmed, as well as through histopathological assessment. We observed that inflammation-associated nuclear factor kappa-light-chain enhancement of activated B cells (NF-κB) and its phosphorylated forms were down-regulated, whereas antioxidant-associated nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression was upregulated in mice co-infected with T. spiralis and RSV. Upregulated Nrf2 expression contributed to increased antioxidant enzyme expression, particularly NQO1 which relieved the host of oxidative stress-induced pulmonary inflammation caused by RSV infection. These findings indicate that T. spiralis can mitigate RSV-induced inflammation by upregulating the expression of antioxidant enzymes.

Diabetes mellitus (DM) is a chronic disease manifested by hyperglycemia and dyslipidemia. Histone deacetylase (HDAC) inhibitors have been emerged as new pharmacological approaches in the control of DM. However, the roles for HDAC inhibition in controlling DM are still elusive. We hypothesized that HDAC inhibition ameliorates hyperglycemia through down-regulation of gluconeogenesis in type II diabetic rats. Male normoglycemic Long-Evans-Tokushima-Otsuka (LETO) and hyperglycemic Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in drinking water for 20 weeks during which the levels of blood glucose were analyzed at 13 and 19 weeks. Blood chemistry such as glycated hemoglobin HbA1c, triglyceride and cholesterol were analyzed. The expression of gluconeogenic genes such as glucose 6-phosphatase, phosphoenolpyruvate carboxykinase, fructose-1,6-biphosphatase and pyruvate carboxylase was measured by quantitative real-time polymerase chain reaction. Acetylation of forkhead box protein O1 (FOXO1), which is a master transcription factor for gluconeogenic genes, was determined by western blot with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-FOXO1 antibody. The levels of blood glucose, HbA1c, triglyceride and cholesterol as well as body weight, were greater in OLETF rats than those in LETO rats. VPA administration attenuated weight gain, blood glucose, HbA1c, triglyceride and cholesterol, as well as the expression of gluconeogenic genes in OLETF rats but not in LETO rats. VPA increased acetylation of FOXO1, decreasing its transcription activity for gluconeogenic genes. These results suggest that HDAC inhibition ameliorates hyperglycemia through down-regulation of gluconeogenesis in type II diabetic rats.