Hypoglycemic, hypolipidemic and antioxidant effects of iridoid glycosides extracted from: Corni fructus: Possible involvement of the PI3K-Akt/PKB signaling pathway

Iridoid glycosides (CIG) are the major component of Corni fructus. In this work, we researched the antioxidative, hypoglycemic and lowering blood lipids effects of CIG on diabetic mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Furthermore, to investigate the molecular mechanism of action, the phosphorylation and protein expression of phosphoinositide 3-kinase (PI3K) and its downstream proteins, such as insulin receptor (INSR), protein kinase B (Akt/PKB) and glucose transporter 4 (GLUT4) have been detected. The results showed that CIG significantly improved oral glucose tolerance in diabetic mice. Biochemical indices also revealed that CIG had a positive effect on lipid metabolism and oxidative stress. In addition, CIG can significantly enhance the expression level of the PI3K-Akt/PKB pathway related proteins in skeletal muscle, which is the key pathway of insulin metabolism. These findings show that CIG can improve the hyperglycemia and hyperlipidemia of HFD-STZ-induced diabetic mice through the PI3K-Akt/PKB signaling pathway, and CIG might be a potential medicine or functional food for type 2 diabetes mellitus remedies. © 2018 The Royal Society of Chemistry

Strategi Kampanye Calon Legislatif Partai Kebangkitan Bangsa (Pkb) Dapil Satu Kabupaten Minahasa Utara Tahun 2014

Sepanjang sejarah, Indonesia telah menyelenggarakan 11 kali pemilihan umum (Pemilu), yaitu pada tahun 1955, 1971, 1977, 1982, 1987, 1992, 1997, 1999, 2004, 2009 dan 2014. Menjelang pemilu 2014, dinamika politik di Indonesia semakin hari semakin tinggi, mengingat jadwal pemilihan umum 2014 tinggal sesaat lagi. Tidak hanya calon Presiden dan Wakil Presiden yang turut meramaikan pesta politik tersebut, tetapi juga para calon legislative (Caleg). Sebagai partai senior PKB terdiri dari berbagai golongan dan diharapkan bersinergi dalam membesarkan PKB. Caleg PKB juga senantiasa menggunkan citra dirinya dalam dunia poltik sendiri melalui Visi dan Misi agar masyarakat mau dan turut memberikan dukungan suara terhadap PKB. Dengan menggunakan strategi pendekatan yaitu, menggunakan media luar ruang dapat mempermudah strategi pengenalan diri caleg PKB agar lebih dikenal masyarakat dan caleg PKB juga mengkomunikasikan diri mereka melalui orang-orang atau kelompok yang berpengaruh sehingga PKB dapat memperoleh dukungan yang maksimal dan dapat mencapai tujuan partai yaitu menambah satu kuota kursi di DPRD Kabupaten Minahasa Utara karena selama dua periode PKB menduduki kursi DPRD, PKB hanya menduduki satu kursi saja. Karena perolehan suara yang di peroleh PKB dalam pemilu tahun 2014 belum mampu menambah satu kursi di DPRD Minahasa utara untuk dapil satu. Dengan menggunakan analisis SWOT yaitu kekuatan (strenght), kelemahan (weakness), peluang (opportunities) bahkan ancaman (threats) dalam menjalankan strategi kampanye pemenangan politiknya. Hal tersebut membuat penulis tertarik untuk meneliti “strategi kampanye calon legislatif partai kebangkitan bangsa (PKB) dapil satu kabupaten minahasa utara tahun 2014”. Penelitian ini menggunakan metode kualitatif dengan subyek penelitiannya adalah timsukses kampanye, tokoh masyarakat, dan tokoh pemuda, sedangkan obyek penelitiannya adalah rancangan strategi kampanye calon legislatif partai kebangkitan bangsa (PKB). Informan penelitian dipilih secara purposive. Hasil penelitian menunjukan bahwa strategi kampanye calon legislatif partai kebangkitan bangsa (PKB) dapil satu kabupaten minahasa utara tahun 2014 belum bisa mencapai target partai, yaitu menambah satu kuota kursi di kabupaten minahasa utara untuk PKB

Insulin-stimulated phosphorylation of endothelial nitric oxide synthase at serine-615 contributes to nitric oxide synthesis

Insulin stimulates endothelial NO (nitric oxide) synthesis via PKB (protein kinase B)/Akt-mediated phosphorylation and activation of eNOS (endothelial NO synthase) at Ser-1177. In previous studies, we have demonstrated that stimulation of eNOS phosphorylation at Ser-1177 may be required, yet is not sufficient for insulin-stimulated NO synthesis. We therefore investigated the role of phosphorylation of eNOS at alternative sites to Ser-1177 as candidate parallel mechanisms contributing to insulin-stimulated NO synthesis. Stimulation of human aortic endothelial cells with insulin rapidly stimulated phosphorylation of both Ser-615 and Ser-1177 on eNOS, whereas phosphorylation of Ser-114, Thr-495 and Ser-633 was unaffected. Insulin-stimulated Ser-615 phosphorylation was abrogated by incubation with the PI3K (phosphoinositide 3-kinase) inhibitor wortmannin, infection with adenoviruses expressing a dominant-negative mutant PKB/Akt or pre-incubation with TNFα (tumour necrosis factor α), but was unaffected by high culture glucose concentrations. Mutation of Ser-615 to alanine reduced insulin-stimulated NO synthesis, whereas mutation of Ser-615 to aspartic acid increased NO production by NOS in which Ser-1177 had been mutated to an aspartic acid residue. We propose that the rapid PKB-mediated stimulation of phosphorylation of Ser-615 contributes to insulin-stimulated NO synthesis

Nowcasting Quarterly GDP Dynamics in the Euro Area – The Role of Sentiment Indicators

The paper compares the most closely watched sentiment indicators with respect to their ability to nowcast quarterly GDP dynamics in the Euro Area and its biggest economies. We analyse cross-correlations and out-of-sample forecast errors generated from equations estimated by rolling regressions in fixed-length window. The results show that models employing PMI Composite perform best in the cases of the Euro Area, Germany, France and Italy, whilst Spanish GDP dynamics is best nowcasted using ESI-based models. PMI-based models generate the most accurate nowcasts at the beginning of the quarter, as well as during periods of high volatility of GDP growth ratesW artykule porównane zostały zdolności najpilniej obserwowanych wskaźników obrazujących nastroje gospodarcze do bieżącego prognozowania kwartalnej dynamiki PKB w strefie euro i jej największych państwach członkowskich. Analizowane są korelacje krzyżowe oraz błędy prognoz poza próbę, wygenerowane z równań szacowanych w oparciu o regresję kroczącą w oknie stałej długości. Wyniki wskazują, że modele wykorzystujące wskaźnik PMI Composite dają na ogół najlepsze wyniki w strefie euro, Niemczech, Francji i Włoszech, podczas gdy bieżąca dynamika hiszpańskiego PKB jest najprecyzyjniej prognozowana przez modele oparte na wskaźniku ESI. Modele oparte na PMI generują relatywnie najlepsze prognozy na początku kwartału, a także w okresach wysokiej zmienności stóp wzrostu PKB

Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20–37 kg/m2). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min−1.m−2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR

Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation

The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1- IRS-1/2 signaling, BiP/CHOP/IRE1, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of 4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser501/503 and S6K1 Thr389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser473 phosphorylation was higher from 3– 6 days, and this was associated with increased TSC2 Thr939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr1462, was unchanged at 6 days. In agreement with the phosphorylation of Thr1345, SA led to activation of AMPK1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1 levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1. m

11 beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle

OBJECTIVE: Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity. \ud RESEARCH DESIGN AND METHODS: Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action. \ud RESULTS: Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer$^{307}$ insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer$^{307}$ IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer$^{307}$ IRS1 decreased and pThr$^{308}$ Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.\ud CONCLUSIONS: Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer$^{307}$ IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer$^{307}$ IRS1, increases pThr$^{308}$ Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action

ASPEK PERJANJIAN KERJA BERSAMA (PKB)DALAM HUBUNGAN KERJA

Perjanjian Kerja Bersama (PKB) merupakan hal yang sangat penting keberadaannya dalam suatu hubungan kerja terutama untuk mempertegas hak-hak dan kewajiban-kewajiban dari pengusaha, organisasi/serikat pekerja maupun pekerja perorangan. PKB merupakan suatu perjanjian obligator antara serikat pekerja dan pengusaha. Sebagai suatu perjanjian obligator, maka masing- masing pihak terikat pada yang telah diperjanjikan dalam PKB tersebut. Dari sudut perlindungan hukum, PKB berfungsi sebagai sarana yang memberikan perlindungan hukum pada pekerja dan pengusaha. Masing-masing pihak dapat memenuhi kepentingannya dengan baik sehingga dapat tercipta suatu hubungan kerja yang harmonis antara pekerja dan pengusaha