Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0.71% w/v), in the drinking water. Treatment with the HDACi decreased steatosis and the expression of lipogenic genes in the livers of CS rats. The enrichment of GR at the promoters of the lipogenic genes, such as acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and sterol regulatory element binding protein 1c (Srebp1c), was markedly decreased by VPA. Pan-HDACi and an HDAC class I-specific inhibitor, but not an HDAC class II a-specific inhibitor, attenuated dexamethasone (DEX)-induced lipogenesis in HepG2 cells. The transcriptional activity of Fasn was decreased by pretreatment with VPA. In addition, pretreatment with VPA decreased DEX-induced binding of GR to the glucocorticoid response element (GRE). Treatment with VPA increased the acetylation of GR in ACTH-infused rats and DEX-induced HepG2 cells. Taken together, these results indicate that HDAC inhibition attenuates hepatic steatosis hrough GR acetylation in experimental CS.
Acetyl-CoA Carboxylase ; Acetylation ; Adrenocorticotropic Hormone ; Animals ; Cushing Syndrome* ; Dexamethasone ; Drinking Water ; Hep G2 Cells ; Histone Deacetylase Inhibitors ; Histone Deacetylases* ; Histones* ; Hydrocortisone ; Infusions, Subcutaneous ; Lipogenesis ; Liver ; Rats* ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; Response Elements ; Sterol Regulatory Element Binding Protein 1 ; Valproic Acid

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.
Animals ; Blood Pressure ; Body Weight ; Cardiomegaly* ; Chemistry ; Cholesterol ; Connective Tissue Growth Factor ; Desoxycorticosterone ; Desoxycorticosterone Acetate ; Drinking Water ; Eosine Yellowish-(YS) ; Fibronectins ; Fibrosis* ; Glucose ; Heart ; Hematoxylin ; Histone Deacetylase Inhibitors* ; Histone Deacetylases* ; Histones* ; Hypertension ; Methods ; Potassium ; Rats* ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Relaxation ; Sodium ; Triglycerides

Due to the global public health crisis caused by the coronavirus disease 2019 (COVID-19) pandemic, the importance of vaccine development has increased. In particular, a rapid supply of vaccines and prompt deployment of vaccination programs are essential to prevent and overcome the spread of COVID-19. As a part of the vaccine regulations, national lot release is regulated by the responsible authorities, and this process involves the assessment of the lot before a vaccine is marketed. A lot can be released for use when both summary protocol (SP) review and quality control testing are complete. Accelerated lot release is required to distribute COVID-19 vaccines in a timely manner. In order to expedite the process by simultaneously undertaking the verification of quality assessment and application for approval, it is necessary to prepare the test methods before marketing authorization. With the prolonged pandemic and controversies regarding the effectiveness of the COVID-19 vaccine against new variants, public interest for the development of a new vaccine are increasing. Domestic developers have raised the need to establish standard guidance on the requirements for developing COVID-19 vaccine. This paper presents considerations for quality control in the manufacturing process, test items, and SP content of viral vector vaccines.