Protein Tyrosine Phosphatase Receptors N and N2 Control Pituitary Melanotroph Development and POMC Expression.

The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, 2 members of protein tyrosine phosphatase receptors void of enzymatic activity, and whose function and mechanism of action have not been elucidated. To explore the role(s) of Ptprn and Ptprn2 on the hypothalamic-pituitary-adrenal axis, we used mice in which both genes were knocked out (DKO). The focus in this study was on corticotrophs and melanotrophs from the anterior and intermediate lobes of the pituitary gland, respectively. In both sexes, DKO caused an increase in the expression of the corticotroph/melanotroph genes Pomc and Tbx19 and the melanotroph-specific gene Pax7. We also found in vivo and in vitro increased synthesis and release of beta-endorphin, alpha-melanocyte-stimulating hormone, and ACTH in DKO mice, which was associated with increased serum corticosterone levels and adrenal mass. DKO also increased the expression of other melanotroph-specific genes, but not corticotroph-specific genes. The dopaminergic pathway in the hypothalamus and dopaminergic receptors in melanotrophs were not affected in DKO mice. However, hyperplasia of the intermediate lobe was observed in DKO females and males, accompanied by increased proopiomelanocortin immunoreactivity per cell. These results indicate that protein tyrosine phosphatase receptor type N contributes to hypothalamic-pituitary-adrenal function by being involved in processes governing postnatal melanotroph development and Pomc expression.

Angelica acutiloba Exerts Antihypertensive Effect and Improves Insulin Resistance in Spontaneously Hypertensive Rats Fed with a High-Fat Diet.

INTRODUCTION: Angelica acutiloba is one of the crude drugs used in Chinese herbal medicine, and its intake is expected to improve metabolic syndrome-associated disorders. Here, we examined the effects of A. acutiloba extract (AAE) on hypertension and insulin resistance induced by the treatment of high-fat diet (HFD) to spontaneously hypertensive rats (SHRs). Then, we investigated the mechanisms associated with the effects of AAE. METHODS: AAE was administered to HFD-fed SHRs. Systolic blood pressure (SBP), sympathetic nerve activity, hypothalamic angiotensin-converting enzyme (ACE) activity, blood glucose level, plasma insulin concentration, visceral fat mass, and gene expression of tumor necrosis factor-alpha (TNF-α) in the visceral fat were evaluated. RESULTS: AAE reduced the increases in SBP and hypothalamic ACE activity observed in the HFD-fed SHRs, whereas the suppressive effect on sympathetic nerve activity was slight. Environmental stress-induced pressure and sympathetic overactivity were suppressed by the treatment of AAE. It also decreased the increase in the blood glucose level, plasma insulin concentration, homeostasis model assessment for the insulin resistance, and TNF-α gene expression in the visceral fat, but not the increase in the visceral fat mass. CONCLUSION: AAE has an antihypertensive effect, suppresses stress-induced hypertension, and improves insulin resistance in HFD-fed SHRs. The suppression of brain ACE activity, sympathetic nerve activity, and inflammation are partly involved in the effects of AAE.

Induction of autophagy has protective roles in imatinib-induced cardiotoxicity.

Cardiotoxicity is one of the severe adverse effects of chemotherapeutic agents. Imatinib was previously reported to induce cardiotoxicity. Autophagy is an intracellular bulk protein and organelle degradation process, but its roles in cardiac diseases are unclear. We examined whether imatinib induces cardiomyocyte autophagy, and the role of autophagy in imatinib-induced cardiotoxicity using in vitro and in vivo experiments. In in vitro experiments, neonatal rat cardiomyocytes were treated with imatinib (1, 5, or 10 µM; 6 h). Myocyte autophagy was assessed by microtubule-associated protein light chain (LC) 3-II, beclin 1, mature cathepsin D, and acridine orange-stained mature autolysosome expression. Imatinib increased their expression, suggesting that it induced autophagy. Consequently, imatinib altered the production of mitochondria-derived reactive oxygen species (ROS) and loss of mitochondrial membrane potential, which were assessed by the fluorescent indicator MitoSOX and JC-1, respectively, leading to cardiomyocyte apoptosis. 3-methyl-adenine (3MA), an autophagic inhibitor, exacerbated imatinib-induced apoptosis by 30 %. In in vivo experiments, C57BL/6 mice were treated with imatinib (50 and 200 mg/kg/day) for 5 weeks in the presence or absence of 3MA. Echocardiographic measurement revealed that imatinib (200 mg) caused dilatation of the left ventricle (LV) and reduced LV fractional shortening. Apoptosis and LC3-II expression in cardiac tissue were increased by imatinib. Co-treatment with 3MA and imatinib further impaired imatinib-induced cardiac apoptosis and LV dysfunction. This study suggests that imatinib induces cardiomyocyte apoptosis, leading to cardiac dysfunction. Imatinib increases cardiomyocyte autophagy as a consequence of apoptosis and autophagy has a pro-survival role in imatinib-induced cardiac impairment.

Febuxostat Attenuates the Progression of Periodontitis in Rats.

INTRODUCTION: Periodontitis is a lifestyle-related disease that is characterized by chronic inflammation in gingival tissue. Febuxostat, a xanthine oxidase inhibitor, exerts anti-inflammatory and antioxidant effects. OBJECTIVE: The present study investigated the effects of febuxostat on periodontitis in a rat model. METHODS: Male Wistar rats were divided into 3 groups: control, periodontitis, and febuxostat-treated periodontitis groups. Periodontitis was induced by placing a ligature wire around the 2nd maxillary molar and the administration of febuxostat (5 mg/kg/day) was then initiated. After 4 weeks, alveolar bone loss was assessed by micro-computed tomography and methylene blue staining. The expression of osteoprotegerin (OPG), a bone resorption inhibitor, was detected by quantitative RT-PCR and immunological staining, and the number of osteoclasts in gingival tissue was assessed by tartrate-resistant acid phosphatase staining. The mRNA and protein expression levels of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß), in gingival tissue were measured using quantitative RT-PCR and immunological staining. Oxidative stress in gingival tissue was evaluated by the expression of 4-hydroxy-2-nonenal (4-HNE), and 8-hydroxy-2-deoxyguanosine (8-OHdG). To clarify the systemic effects of periodontitis, blood pressure and glucose tolerance were examined. RESULTS: In rats with periodontitis, alveolar bone resorption was associated with reductions in OPG and increases in osteoclast numbers. The gingival expression of TNF-α, IL-1ß, 4-HNE, and 8-OHdG was up-regulated in rats with periodontitis. Febuxostat significantly reduced alveolar bone loss, proinflammatory cytokine levels, and oxidative stress. It also attenuated periodontitis-induced glucose intolerance and blood pressure elevations. CONCLUSION: Febuxostat prevented the progression of periodontitis and associated systemic effects by inhibiting proinflammatory mediators and oxidative stress.

Antihypertensive and Renoprotective Effects of Dietary Flaxseed and its Mechanism of Action in Deoxycorticosterone Acetate-Salt Hypertensive Rats.

BACKGROUND/AIMS: Flaxseed contains alpha-linolenic acid (ALA), lignans, and dietary fiber, and its intake lowers blood pressure in hypertensive patients. Here, we examined the effects of flaxseed powder, which includes all flaxseed components, flaxseed oil, composed mainly of ALA, flaxseed lignan, and flaxseed fiber, on hypertension and renal damage induced by deoxycorticosterone acetate (DOCA)-salt. Then, we investigated the mechanisms of action associated with the effects of flaxseed. METHODS: Flaxseed powder, oil, lignan, or fiber was administered to DOCA-salt rats. Systolic blood pressure (SBP), urinary protein excretion, renal angiotensin converting enzyme (ACE) activity, sympathetic nerve activity, and gene expression of inflammatory mediators in the kidney and hypothalamus were measured. RESULTS: Flaxseed powder and oil reduced the increases in SBP and urinary protein excretion induced by DOCA-salt treatment, whereas lignan and fiber had no effects. Flaxseed oil suppressed the increase in renal ACE activity, sympathetic nerve activity, and gene expression of renal and hypothalamic inflammatory mediators. CONCLUSION: Flaxseed has antihypertensive and renoprotective effects in DOCA-salt rats. These effects are likely principally exerted by ALA. Furthermore, the suppression of renal ACE activity, sympathetic nerve activity, and inflammation is partly involved in the effects of flaxseed.