Background: Type 2 diabetes mellitus (T2DM) induces endothelial dysfunction and inflammation, which are the main factors for atherosclerosis and cardiovascular disease. The present study aimed to compare the effects of rosuvastatin monotherapy and rosuvastatin/ezetimibe combination therapy on lipid profile, insulin sensitivity, and vascular inflammatory response in patients with T2DM. Methods: A total of 101 patients with T2DM and dyslipidemia were randomized to either rosuvastatin monotherapy (5 mg/day, n=47) or rosuvastatin/ezetimibe combination therapy (5 mg/10 mg/day, n=45) and treated for 12 weeks. Serum lipids, glucose, insulin, soluble intercellular adhesion molecule-1 (sICAM-1), and peroxiredoxin 4 (PRDX4) levels were determined before and after 12 weeks of treatment. Results: The reduction in low density lipoprotein cholesterol (LDL-C) by more than 50% from baseline after treatment was more in the combination therapy group. The serum sICAM-1 levels increased significantly in both groups, but there was no difference between the two groups. The significant changes in homeostasis model assessment of insulin resistance (HOMA-IR) and PRDX4 were confirmed only in the subgroup in which LDL-C was reduced by 50% or more in the combination therapy group. However, after adjusting for diabetes mellitus duration and hypertension, the changes in HOMA-IR and PRDX4 were not significant between the two groups. Conclusion Although rosuvastatin/ezetimibe combination therapy had a greater LDL-C reduction effect than rosuvastatin monotherapy, it had no additional effects on insulin sensitivity and vascular inflammatory response. Further studies are needed on the effect of long-term treatment with ezetimibe on insulin sensitivity and vascular inflammatory response.

Drug-induced liver injury (DILI) is considered to be a significant cause of drug wastage. Tomitigate clinical DILI risks, assessing drugs using human liver models is crucial since animal studies may fall short due to species-specific liver pathway variations. Cell-based preclinical hepatotoxicity testing is often pertinent. In the present study, cells from a human liver cancer line (HepG2 and HepaRG) were cultured in both formats of 2D and 3D spheroids to explore their responses to drugs. Liver-specific marker expressions across cell lines and culture formats were also examined to assess disparities in DILI marker expressions. After treating each cell with the drugs, cytotoxicity and liver injury markers aspartate aminotransferase and alanine aminotransferase were increased. In addition, liver specific markers albumin and urea decreased in a drug concentration-dependent manner. These findings were consistent with drug sensitivity. Additionally, mRNA expression levels of cytochrome P450 enzymes (CYPs) involved in hepatocellular drug metabolism were compared following treatment with enzyme inducers. CYP1A2 and CYP2C9 were not epxressed in HepG2 cells. HepaRG cells exhibited significantly increased expression of CYP1A2, 2C9, and 3A4 post-treatment. No-tably, enzyme expression was notably higher in 3D cultures than in 2D cultures. Collectively, these findings suggest that HepaRG cells and 3D cultures hold promise for evaluating DILI during early-stage drug development.

Background: Citric acid (CA) and sodium hypochlorite (NaOCl) have been used to disinfect animals to protect them against avian influenza and foot-and-mouth disease. Objectives: We performed a good laboratory practice (GLP)-compliant animal toxicity study to assess the acute toxic effects of CA and NaOCl aerosol exposure in Sprague-Dawley rats. Methods: Groups of five rats per sex were exposed for 4 h to four concentrations of the two chemicals, i.e., 0.00, 0.22, 0.67, and 2.00 mg/L, using a nose-only exposure. After a single exposure to the chemicals, clinical signs, body weight, and mortality was observed during the observation period. On day 15, an autopsy, and then gross findings, and histopathological analysis were performed. Results: After exposure to CA and NaOCl, body weight loss was observed but recovered.Two males died in the CA 2.00 mg/L group and, two males and one female died in the 2.00 mg/L NaOCl group. In the gross findings and histopathological analysis, discoloration of the lungs was observed in the CA exposed group and inflammatory lesions with discoloration of the lungs were observed in the NaOCl exposed group. These results suggest that the lethal concentration 50 (LC50) of CA is 1.73390 mg/L for males and > 1.70 mg/L for females. For NaOCl, the LC50 was 2.22222 mg/L for males and 2.39456 mg/L for females. Conclusions The Globally Harmonized System is category 4 for both CA and NaOCl. In this study, the LC50 results were obtained through a GLP-based acute inhalation toxicity assessment. These results provide useful data to reset safety standards for CA and NaOCl use.

Background: Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy. To define the altered pathway in GDM placenta, we investigated the transcriptomic profiles from human placenta between GDM and controls. Methods: Clinical parameters and postpartum complications were reviewed in all participants.Differentially expressed canonical pathways were analyzed between the GDM and control groups based on transcriptomic analysis. CD4 + T, CD8 + T, and senescent T cell subsets were determined by flow cytometry based on staining for specific intracellular cytokines. Results: Gene ontology analysis revealed that the placenta of GDM revealed upregulation of diverse mitochondria or DNA replication related pathways and downregulation of T-cell immunity related pathways. The maternal placenta of the GDM group had a higher proportion of CD4 + T and CD8 + T cells than the control group. Interestingly, senescent CD4 + T cells tended to increase and CD8 + T cells were significantly increased in GDM compared to controls, along with increased programmed cell death-1 (CD274 + ) expression. Programmed death-ligand 1 expression in syncytotrophoblasts was also significantly increased in patients with GDM. Conclusion This study demonstrated increased proinflammatory T cells, senescent T cells and immune-check point molecules in GDM placentas, suggesting that changes in senescent T cells and immune-escape signaling might be related to the pathophysiology of GDM.

Stem cell-based products (SCPs) are an emerging field of veterinary medicine that focuses on the regeneration, repair, or replacement of damaged tissues or organs. However, there are some issues in applying the traditional regulatory guideline for the approval of SCPs as veterinary medicinal products. This article describes the positions of Korea, US, and EU regarding SCPs, and compares the regulatory guidelines of each country for their safety evaluation. Although there are some differences in the regulatory guidelines, similar considerations in identifying the quality of SCPs and their safety has adopted. Overall, these guidelines need to be harmonized among countries.

Background: Although previous in vivo studies explored urinary microRNA (miRNA), there is no agreement on nephrotoxicity-specific miRNA biomarkers. Objectives: In this study, we assessed whether urinary miRNAs could be employed as biomarkers for nephrotoxicity. Methods: For this, literature-based candidate miRNAs were identified by reviewing the previous studies. Female Sprague-Dawley rats received subcutaneous injections of a single dose or repeated doses (3 consecutive days) of gentamicin (GEN; 137 or 412 mg/kg). The expression of miRNAs was analyzed by real-time reverse transcription-polymerase chain reaction in 16 h pooled urine from GEN-treated rats. Results: GEN-induced acute kidney injury was confirmed by the presence of tubular necrosis.We identified let-7g-5p, miR-21-3p, 26b-3p, 192-5p, and 378a-3p significantly upregulated in the urine of GEN-treated rats with the appearance of the necrosis in proximal tubules.Specifically, miR-26-3p, 192-5p, and 378a-3p with highly expressed levels in urine of rats with GEN-induced acute tubular injury were considered to have sensitivities comparable to clinical biomarkers, such as blood urea nitrogen, serum creatinine, and urinary kidney injury molecule protein. Conclusions These results indicated the potential involvement of urinary miRNAs in chemical-induced nephrotoxicity, suggesting that certain miRNAs could serve as biomarkers for acute nephrotoxicity.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 not yet has established its treatment, but convalescent plasma has been expected to increase survival rates as in the case with other emerging viral infections. We describe two cases of COVID-19 treated with convalescent plasma infusion. Both patients presented severe pneumonia with acute respiratory distress syndrome and showed a favorable outcome after the use of convalescent plasma in addition to systemic corticosteroid. To our knowledge, this is the first report of the use of convalescent plasma therapy for COVID-19 in Korea.

In vitro prediction of hepatotoxicity can enhance the performance of non-clinical animal testing for identifying chemical hazards. In this study, we assessed high-content analysis (HCA) using multi-parameter cell-based assays as an in vitro hepatotoxicity testing model using various hepatotoxicants and human hepatocytes such as HepG2 cells and human primary hepatocytes (hPHs). Both hepatocyte types were exposed separately to multiple doses of ten hepatotoxicants associated with liver injury whose mechanisms of action have been described. HCA data were obtained using fluorescence probes for nuclear size (Hoechst), mitochondrial membrane potential (TMRM), cytosolic free calcium (Fluo-4AM), and lipid peroxidation (BODIPY). Cellular alterations were observed in response to all hepatotoxicants tested. The most sensitive parameter was TMRM, with high sensitivity at a low dose, next was BODIPY, followed by Fluo-4AM. HCA data from HepG2 cells and hPHs were generally concordant, although some inconsistencies were noted. Both hepatocyte types showed mild or severe mitochondrial impairment and lipid peroxidation in response to several hepatotoxicants. The results demonstrate that the application of HCA to in vitro hepatotoxicity testing enables more efficient hazard identification, and further, they suggest that certain parameters could serve as sensitive endpoints for predicting the hepatotoxic potential of chemical compounds.
Animals ; Calcium ; Cytosol ; Fluorescence ; Hep G2 Cells ; Hepatocytes ; Humans ; In Vitro Techniques ; Lipid Peroxidation ; Liver ; Membrane Potential, Mitochondrial

With the increased use of cell therapy in the veterinary sector, there is a growing demand for the development of cell-based medicinal products and the determination of their safety. Currently, the Korean Animal and Plant Quarantine Agency has established a guideline for evaluating the safety of cell-based medicinal products for animal use. The guideline includes items related to definition, classification, management, manufacturing procedure and quality control (standard and test method), stability testing, toxicity testing, pharmacological testing, and performance of clinical trials. In addition, testing protocols related to safety assessment of animal cell-based products such as chromosome karyotyping, tumorigenicity testing, confirmatory testing of biodistribution and kinetics, and target animal safety testing are described in detail. Moreover, because cell-based medicinal products are novel therapies, deviations from traditional designs may be justified in order to obtain relevant safety information on the treatment. Additionally, this guideline can be amended on the basis of new scientific findings.
Animals ; Carcinogenicity Tests ; Cell- and Tissue-Based Therapy ; Classification ; Karyotyping ; Kinetics ; Plants ; Quality Control ; Quarantine ; Toxicity Tests

Acetylcholinesterase (AChE) activity level can be used as a diagnostic marker for anticholinesterase pesticide poisoning. In this study, we aimed to establish a baseline level of normal brain AChE activity in wild birds. AChE activity was measured in the brains of 87dead wild birds (26 species). The level of AChE activity ranged from 6.40 to 15.9 µmol/min/g of brain tissue in normal wild birds. However, the brain tissue AChE activity level in wild birds exposed to organophosphate (OP) pesticide was 48.0%–96.3% of that in the normal birds. These results may serve as reference values to facilitate routine diagnosis and monitoring of OP-poisoned wild birds.
Acetylcholinesterase ; Birds ; Brain ; Diagnosis ; Organophosphates ; Poisoning ; Reference Values