A thrombopoietic factor, termed thrombopoietin (TPO), was highly purified directly from the plasma of sublethally irradiated 1,100 rats by measuring the production of megakaryocytes from a highly enriched population of rat megakaryocyte progenitor cells (CFU-MK). The rat plasma TPO is a glycoprotein and strongly hydrophobic. The total activity and purification yields obtained were about 29% and 1.49 x 10(8), respectively. The amino acid sequences of the two peptide fragments prepared from the purified 19 kDa TPO were analyzed, and used for the cloning of rat and human TPO cDNAs. It was found that the 19 kDa TPO was truncated but comprised at least 163 amino acids. The sequence of human TPO cDNA revealed that the TPO was identical to the c-Mpl ligand. Both rat and human TPOs expressed in COS-1 cells exhibited significant activity toward the CFU-MK in vitro, and were active in stimulating platelet production in mice. These results indicate that a thrombopoietic factor originally found in the irradiated rat plasma is a ligand for the rat c-Mpl.
Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure. Here, we have shown that mast cells, key mediators of allergic and immune responses, are critically involved in AF pathogenesis in stressed mouse hearts. Pressure overload induced mast cell infiltration and fibrosis in the atrium and enhanced AF susceptibility following atrial burst stimulation. Both atrial fibrosis and AF inducibility were attenuated by stabilization of mast cells with cromolyn and by BM reconstitution from mast celldeficient WBB6F1-Kit W/W-v mice. When cocultured with cardiac myocytes or fibroblasts, BM-derived mouse mast cells increased platelet-derived growth factor A (PDGF-A) synthesis and promoted cell proliferation and collagen expression in cardiac fibroblasts. These changes were abolished by treatment with a neutralizing antibody specific for PDGF α-receptor (PDGFR-α). Consistent with these data, upregulation of atrial Pdgfa expression in pressure-overloaded hearts was suppressed by BM reconstitution from WBB6F1-Kit W/W-v mice. Furthermore, injection of the neutralizing PDGFR-α-specific antibody attenuated atrial fibrosis and AF inducibility in pressure-overloaded hearts, whereas administration of homodimer of PDGF-A (PDGF-AA) promoted atrial fibrosis and enhanced AF susceptibility in normal hearts. Our results suggest a crucial role for mast cells in AF and highlight a potential application of controlling the mast cell/PDGF-A axis to achieve upstream prevention of AF in stressed hearts.
Diabetes mellitus is a chronic disease that is characterized by hyperglycemia caused by insufficient insulin action. We have explored the edible ingredients from folk medicines in Japan that contain substances complementing insulin action, such as the induction of adipocyte differentiation and the enhancement of glucose uptake. We eventually found that the ethanol extract from a Japanese herb "Ashitaba", Angelica keiskei, contained two major chalcones of 4-hydroxyderricin (4-HD) and xanthoangelol that showed strong insulin-like activities via a pathway independent of the peroxisome proliferator-activated receptor-gamma activation. The 4-HD especially showed the preventive effects on the progression of diabetes in genetically diabetic KK-Ay mice.
High-fat diet (HFD)-induced alteration in the gut microbial composition, known as dysbiosis, is increasingly recognized as a major risk factor for various diseases, including colon cancer. This report describes a comprehensive investigation of the effect of agaro-oligosaccharides (AGO) on HFD-induced gut dysbiosis, including alterations in short-chain fatty acid contents and bile acid metabolism in mice. C57BL/6N mice were fed a control diet or HFD, with or without AGO. Terminal restriction fragment-length polymorphism (T-RFLP) analysis produced their fecal microbiota profiles. Profiles of cecal organic acids and serum bile acids were determined, respectively, using HPLC and liquid chromatography-tandem mass spectrometry systems. T-RFLP analyses showed that an HFD changed the gut microbiota significantly. Changes in the microbiota composition induced by an HFD were characterized by a decrease in the order Lactobacillales and by an increase in the Clostridium subcluster XIVa. These changes of the microbiota community generated by HFD treatment were suppressed by AGO supplementation. As supported by the data of the proportion of Lactobacillales order, the concentration of lactic acid increased in the HFD + AGO group. Data from the serum bile acid profile showed that the level of deoxycholic acid, a carcinogenic secondary bile acid produced by gut bacteria, was increased in HFD-receiving mice. The upregulation tended to be suppressed by AGO supplementation. Finally, results show that AGO supplementation suppressed the azoxymethane-induced generation of aberrant crypt foci in the colon derived from HFD-treated mice. Our results suggest that oral intake of AGO prevents HFD-induced gut dysbiosis, thereby inhibiting colon carcinogenesis.
. Here we defined the role of PDK1 in controlling cardiac homeostasis. Cardiac expression of PDK1 was significantly decreased in murine models of heart failure. Tamoxifeninducible and heart-specific disruption of Pdk1 in adult mice caused severe and lethal heart failure, which was associated with apoptotic death of cardiomyocytes and 1-adrenergic receptor (AR) downregulation. Overexpression of Bcl-2 protein prevented cardiomyocyte apoptosis and improved cardiac function. In addition, PDK1-deficient hearts showed enhanced activity of PI3-K␥, leading to robust 1-AR internalization by forming complex with -AR kinase 1 (ARK1). Interference of ARK1/PI3-K␥ complex formation by transgenic overexpression of phosphoinositide kinase domain normalized  1 -AR trafficking and improved cardiac function. Taken together, these results suggest that PDK1 plays a critical role in cardiac homeostasis in vivo by serving as a dual effector for cell survival and -adrenergic response.AGC kinase ͉ apoptosis ͉ heart failure ͉ receptor internalization H eart failure, a major cause of morbidity and mortality worldwide, is a clinical syndrome in which the heart is incapable of pumping blood at a rate commensurate with systemic demands (1). Injurious stresses from extrinsic or intrinsic origins trigger the complex intracellular signaling pathways in cardiomyocytes and thereby activate the compensatory mechanisms involving alterations in survival and growth signals, calcium handling, and energy production (2). Simultaneously, the sympathetic nervous, reninangiotensin-aldosterone, and cytokine systems are activated to cope with a decline in cardiac performance. Although these compensatory systems initially maintain cardiac function within a physiological range, prolonged activation of these systems paradoxically leads to cardiac damage and worsens clinical prognosis (2). Therefore, for the elucidation of the pathophysiology of heart failure, it is very important to dissect the inherent complexity of intracellular signaling pathways that coordinate the cellular homeostasis and neurohumoral responses in cardiomyocytes.The 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a member of the AGC serine/threonine kinase family that functions downstream of phosphoinositide 3-kinase (PI3-K) and activates several AGC kinases, including Akt, p70 ribosomal S6 kinase (p70S6K), and serum-and glucocorticoid-induced protein kinase 1 (SGK1), by phosphorylating these enzymes at their activation loops (3). The physiological functions of PDK1 have been investigated by targeted disruption of Pdk1 gene. Mouse embryos systemically deficient for Pdk1 were lethal during early embryogenesis, displaying multiple abnormalities that included lack of somites, forebrain, and neural crest-derived tissues (4). Alessi et al. (5) recently generated striated muscle-specific PDK1 conditional knockout mice (PDK1-MCKCre) by crossing mice harboring a ''floxed'' Pdk1 allele with transgenic mice expressing Cre recombinase under the control of the muscle creatine kinase (MC...
Type 1 angiotensin II (AT 1 ) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT 1 receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT 1 receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT 1 receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT 1 receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT 1 receptor and the stretch-induced activation of AT 1 receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr 113 and between the carboxyl group of olmesartan and Lys 199 and His 256 , were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT 1 -N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor. These results suggest that multivalent interactions between an inverse agonist and the AT 1 receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the Keywords: angiotensin II; cardiac hypertrophy; G protein-coupled receptor; inverse agonist; mechanical stress INTRODUCTIONThe type 1 angiotensin II (AT 1 ) receptor is a member of the G proteincoupled receptor (GPCR) family and mediates most of the actions that angiotensin II (AngII) exerts on the cardiovascular system. 1 AT 1 receptor blockers (ARBs) are non-peptide compounds that selectively bind to the AT 1 receptor and inhibit AngII-induced receptor activation. At present, several ARBs are clinically available as a highly effective and well-tolerated class of drugs for the management of hypertension. In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic proper-
Objectives: To examine trends in meal patterns and food choices across two generations of Japanese-American females born in the USA. Design: Cross-sectional cohort study. Setting: Gardena, a suburb of Los Angeles, California. Subjects: One-hundred and seventy-six Japanese-American females, participating in a morning exercise class from December 1998 to January 1999. Intervention: Eighty-eight Nisei (second generation) mothers and their Sansei (third generation) daughters completed a food frequency questionnaire, answering questions regarding meal patterns and consumption frequency of 51 food items. Results: The Sansei ate fewer meals per day compared with the Nisei. Mean frequencies of takeout foods and eating out were higher in the Sansei vs the Nisei. Mean intake of meats and eggs were similar between the two groups. However, mean consumption of traditional Japanese complement foods including ®sh, vegetables and legumes was lower in the Sansei vs the Nisei. Intake of more`Westernized' accessory foods, including salty snacks, regular soft drinks and alcoholic beverages, was higher in the Sansei vs the Nisei. Conclusion: Findings from this study indicate that meal patterns and food choices have changed in succeeding generations of Japanese-American females from traditional fare to a diet containing many complement and accessory foods that are higher in fat, sugar, sodium and calories. Health professionals should be advised to consider the whole diet in making nutrition recommendations to this population as well as providing information to this group on the nutritional bene®ts of many traditional foods.
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