Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

BACKGROUND AND OBJECTIVES: Recent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes. METHODS: Cardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects. RESULTS: Mice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor. CONCLUSIONS: SGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.

Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

BACKGROUND AND OBJECTIVES@#Recent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes.@*METHODS@#Cardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects.@*RESULTS@#Mice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor.@*CONCLUSIONS@#SGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.

Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3

BACKGROUND: Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated. METHODS: Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells. RESULTS: Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3. CONCLUSION: PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

Clinical validation of the 2017 international consensus guidelines on intraductal papillary mucinous neoplasm of the pancreas

PURPOSE: The 2017 international consensus guidelines (ICG) for intraductal papillary mucinous neoplasm (IPMN) of the pancreas were recently released. Important changes included the addition of worrisome features such as elevated serum CA 19-9 and rapid cyst growth (>5 mm over 2 years). We aimed to clinically validate the 2017 ICG and compare the diagnostic performance between the 2017 and 2012 ICG. METHODS: This was a retrospective cohort study. During January 2000–January 2017, patients who underwent complete surgical resection and had pathologic confirmation of branch-duct or mixed-type IPMN were included. To evaluate diagnostic performance, the areas under the receiver operating curves (AUCs) were evaluated. RESULTS: A total of 448 patients were included. The presence of mural nodule (hazard ratio [HR], 9.12; 95% confidence interval [CI], 4.60–18.09; P = 0.001), main pancreatic duct dilatation (>5 mm) (HR, 5.32; 95% CI, 2.67–10.60; P = 0.001), thickened cystic wall (HR, 3.40; 95% CI, 1.51–7.63; P = 0.003), and elevated CA 19-9 level (>37 unit/mL) (HR, 5.25; 95% CI, 2.05–13.42; P = 0.001) were significantly associated with malignant IPMN. Malignant lesions showed a cyst growth rate >5 mm over 2 years more frequently than benign lesions (60.9% vs. 29.7%, P = 0.012). The AUC was higher for the 2017 ICG than the 2012 ICG (0.784 vs. 0.746). CONCLUSION: The new 2017 ICG for IPMN is clinically valid, with a superior diagnostic performance to the 2012 ICG. The inclusion of elevated serum CA 19-9 level and cyst growth rate to the 2017 ICG is appropriate.

Oculogyric Crisis Due to Metronidazole Toxic Encephalopathy

Oculogyric crisis is an acute dystonia involving ocular muscles characterized by sustained conjugate upward or lateral deviation of the eyes. Metronidazole is a commonly used antimicrobial agent in treatment of anaerobic infections. However, its long-term use can cause toxic encephalopathy particularly in patients with hepatic dysfunction. Here, we describe a case of oculogyric crisis as a presenting manifestation of metronidazole-induced encephalopathy.

Inhibition of Serotonin Synthesis Induces Negative Hepatic Lipid Balance

BACKGROUND: Hepatic steatosis is caused by metabolic stress associated with a positive lipid balance, such as insulin resistance and obesity. Previously we have shown the anti-obesity effects of inhibiting serotonin synthesis, which eventually improved insulin sensitivity and hepatic steatosis. However, it is not clear whether serotonin has direct effect on hepatic lipid accumulation. Here, we showed the possibility of direct action of serotonin on hepatic steatosis. METHODS: Mice were treated with para-chlorophenylalanine (PCPA) or LP-533401 to inhibit serotonin synthesis and fed with high fat diet (HFD) or high carbohydrate diet (HCD) to induce hepatic steatosis. Hepatic triglyceride content and gene expression profiles were analyzed. RESULTS: Pharmacological and genetic inhibition of serotonin synthesis reduced HFD-induced hepatic lipid accumulation. Furthermore, short-term PCPA treatment prevented HCD-induced hepatic steatosis without affecting glucose tolerance and browning of subcutaneous adipose tissue. Gene expression analysis revealed that the expressions of genes involved in de novo lipogenesis and triacylglycerol synthesis were downregulated by short-term PCPA treatment as well as long-term PCPA treatment. CONCLUSION: Short-term inhibition of serotonin synthesis prevented hepatic lipid accumulation without affecting systemic insulin sensitivity and energy expenditure, suggesting the direct steatogenic effect of serotonin in liver.

Osteogenic Differentiation of Bone Marrow Stem Cell in Poly(Lactic-co-Glycolic Acid) Scaffold Loaded Various Ratio of Hydroxyapatite

BACKGROUND AND OBJECTIVES: Hydroxyapatite has biocompatibility and bioactivity and similar to bone of in human body. The purpose of this study is to evaluate osteogenic differentiation of bone marrow stem cell (BMSC) in PLGA Scaffold added various ratio of hydroxyapatite (HAp). METHODS AND RESULTS: PLGA and PLGA/HAp scaffold were prepared using solvent casting/salt-leaching method. BMSC was seeded on the PLGA and PLGA/HAp scaffold and the samples were cultured in 37degrees C incubator with 5% CO2 for 28 days. Alkaline phosphatase (ALP) was carried out to evaluate alkaline phosphatase activity at 1, 3, 7, 10 and 14 days. Alizarin Red S stating was performed to identify calcium in scaffold at 1, 7, 14, 21 and 28 days. Compressive strength was measured to evaluate mechanical property of scaffold. To confirm cell viability, MTT was carried out at 1, 3, 7, 14 and 28 days. RT-PCR was performed to verify specific marker expression of osteoblast and stem cell at 7, 14, 21 and 28 days. CONCLUSIONS: Osteogenic differentiation of BMSC was confirmed through ALP, RT-PCR, and alizarin red S staining in this study. These results suggest that HAp helps osteogenic differentiation of BMSC.

The Study of Voice in Postmenopausal Syndrome / 대한이비인후과학회지

OBJECTIVES: We intended to evaluate the relationship between voice and the menopause, so we observed vocal symptoms and voice parameters in patients of postmenopausal syndrome compared with those in premenopausal women. MATERIALS AND METHODS: Forty postmenopausal and twenty premenopausal women were included in this study. Each woman was asked to describe their subjective vocal symptoms and phonate a vowel /a/ sound for 3 seconds. The voices were recorded and analyzed by the Multi-Dimensional Voice Program and a Laryngograph. A statistical analysis of voice parameters was done by a paired-t-test. RESULTS: Vocal symptoms detected in the menopausal women were lowered pitch, voice fatigue, recurrent hoarseness, and loss of high tone. Jitter in postmenopausal group was significantly increased compared with the premenopausal group, but the fundamental frequency, shimmer, the Harmonics-to-noise ratio and the closing quotient showed no significant differences. There were no significant changes of voice parameters between menopausal patients with and without vocal symptoms. CONCLUSION: The change of voice may be objectively identified in postmenopausal women. In treating the postmenopausal symptoms, it may be required to take voice changes into consideration.