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Justine I Blum, Kaiser M Bijli, Tamara C Murphy, Jennifer M Kleinhenz, C Michael Hart
BACKGROUND: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the expression of its downstream target pyruvate dehydrogenase kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant phenotype in pulmonary vascular cells. Activation of the nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) proliferation...
July 2016: American Journal of the Medical Sciences
Shan-Qing Zheng, Xiao-Bing Huang, Ti-Kun Xing, Ai-Jun Ding, Gui-Sheng Wu, Huai-Rong Luo
Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague...
July 4, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
S Drozdovska, B Gavenauskas, T Drevytska, V Nosar, V Nagibin, I Mankovska, V Dosenko
Molecular mechanisms of adaptation to exercise despite a large number of studies remain unclear. One of the crucial factors in this process is hypoxia inducible factor (HIF) that regulates transcription of many target genes encoding proteins that are implicated in molecular adaptation to hypoxia. Experiments were conducted on 24 adult male Fisher rats. Real-time PCR analysis was performed for quantitative evaluation of Hif3α, Igf1, Glut-4 and Pdk-1 in m. gastrocnemius, m. soleus, in lung and heart tissues...
June 2016: Biology of Sport
Anthony S Malamas, Erlei Jin, Maneesh Gujrati, Zheng-Rong Lu
Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model...
July 5, 2016: Molecular Pharmaceutics
Julijana Stanimirovic, Milan Obradovic, Aleksandra Jovanovic, Emina Sudar-Milovanovic, Sonja Zafirovic, Samantha J Pitt, Alan J Stewart, Esma R Isenovic
Men and women differ substantially with regard to the severity of insulin resistance (IR) but the underlying mechanism(s) of how this occurs is poorly characterized. We investigated whether a high fat (HF) diet resulted in sex-specific differences in nitrite/nitrate production and lipid metabolism and whether these variances may contribute to altered obesity-induced IR. Male and female Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. The level of plasma nitrite/nitrate, as well as free fatty acid (FFA), in both plasma and liver lysates were assessed...
April 1, 2016: Nitric Oxide: Biology and Chemistry
O O Linnik, T I Drevytska, O O Gonchar, S A Chornyy, O M Kovalyov, I M Mankovska
It was studied the effect of doxorubicin on the HIF system and the pro-antioxidant balance of neonatal cardiomyocytes as well as the possibility of the oxidative stress correcting using curcumin. It has been revealed that the expression of mRNA HIF-1α using doxorubicin at a dose of 0.5 μM was 2.9 ± 0.8 cu, so it decreased by 20% compared to control--3.6 ± 0.7 cu (P < 0.05). The level of expression of the HIF target gene PDK-1 also significantly decreased (4 times). During the incubation with doxorubicin, the number of live cells decreased by 50...
2015: Fiziolohichnyĭ Zhurnal
Fa-Cai Li, Robin B Gasser, James B Lok, Pasi K Korhonen, Li He, Wen-Da Di, Fang-Yuan Yin, Rui Zhou, Yan-Qin Zhou, Jun-Long Zhao, Min Hu
BACKGROUND: Phosphoinositide-dependent protein kinase-1 (PDK-1), which functions downstream of phosphoinositide 3-kinase (AGE-1) and activates protein kinases of the AGC family, plays critical roles in regulating biology processes, such as metabolism, growth, development and survival. In the free-living nematode Caenorhabditis elegans, PDK-1 is a key component of the insulin-like signalling pathway, regulating the entry into and exit from dauer (arrested development). Although it is proposed that similar molecular mechanisms control the transition from the free-living to the parasitic stages of nematodes, nothing is known about PDK-1 in Haemonchus contortus, a socioeconomically important gastric nematode of ruminants...
2016: Parasites & Vectors
Bing-Qing Xu, Ping Yang, Yu-Qing Zhang
BACKGROUND: Diabetes mellitus is a serious disease affecting about 5% of people worldwide. Although several studies have indicated hypoglycemic activities of Gynura divaricata (GD), the mechanisms by which GD improves the symptoms of diabetes remain unclear. OBJECTIVE: The aim of this study was to investigate the potential hypoglycemic effects of GD. DESIGN: The leaves and stems of GD were prepared and lyophilized into a powder, which was added to the diet of mice with type 2 diabetes induced by a high-fat diet in combination with streptozotocin for 4 weeks...
2015: Food & Nutrition Research
Li-li Tang, Yuan-bo Wu, Chuan-qin Fang, Ping Qu, Zong-liang Gao
BACKGROUND: Microglia microvesicles (MVs) has shown to have significant biological functions under normal conditions. A diversity of miRNAs is involved in neuronal development, survival, function, and plasticity, but the exact functional role of NDRG2 and secreted miR-375 in MVs in neuron damage is poorly understood. We investigated the effect of NDRG2 and secreted miR-375 in MVs shed from M1 microglia on neuron damage. METHODS: Expression of Nos2, Arg-1, miR-375, syntaxin-1A, NDRG2 and Pdk 1 were evaluated using RT-PCR or western blotting...
January 15, 2016: Biochemical and Biophysical Research Communications
Boh-Ram Kim, Seung-Hoon Lee, Mi-Sun Park, Seung-Hee Seo, Young-Min Park, Young-Joo Kwon, Seung-Bae Rho
Myristoylated alanine-rich C kinase substrate-like 1 (MARCKSL1) plays a pivotal role in the regulation of apoptosis and has been shown to maintain antitumor and metastasis-suppressive properties. In the present study, we examined the effects of MARCKSL1 as a novel anti-angiogenic agent on the inhibition of angiogenesis-mediated cell migration. MARCKSL1 also reduced vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) proliferation, as well as capillary-like tubular structure formation in vitro...
February 2016: Oncology Reports
Charles C King, Marygorret Obonyo
BACKGROUND: Helicobacter pylori (H. pylori) infection affects cell survival signaling pathways including cell apoptosis and proliferation, which are considered risk factors for the development of gastric cancer when unregulated. In the present study, we investigated the effect of H. pylori infection on the phosphorylation state of 3-phosphoinositide-dependent kinase-1 (PDK-1), a master kinase that regulates phosphorylation of Akt (also known as protein kinase B, PKB) and cell survival...
October 21, 2015: BMC Microbiology
Shinkyo Yoon, Jong Gwang Kim, An Na Seo, Soo Yeun Park, Hye Jin Kim, Jun Seok Park, Gyu Seog Choi, Ji Yun Jeong, Do Youn Jun, Ghil Suk Yoon, Byung Woog Kang
PURPOSE: Recently, enzymes of the serine synthetic pathway (SSP) have been suggested as key player in the metabolic adaptation of oncogenesis. We assessed the expression of enzymes of the SSP in colonic tumor tissue (TT) and paired normal tissue (pNT) and the prognostic implications. METHODS: From 2006 to 2010, we included 486 patients with colon cancer who underwent curative surgery at Kyungpook National University Hospital. Phosphoglycerate dehydrogenase (PHGDH), pyruvate dehydrogenase kinase (PDK) 1, PDK2, pyruvate kinase M2 (PKM2), and phosphoserine aminotransferase (PSAT) expression were investigated by immunohistochemical staining (IHC) in TT and pNT...
2015: Oncology
Seth A Wescott, Elizabeth A Ronan, X Z Shawn Xu
Insulin signaling has been suggested to modulate nicotine dependence, but the underlying genetic evidence has been lacking. Here, we used the nematode, Caenorhabditis elegans, to investigate whether genetic alterations in the insulin signaling pathway affect behavioral responses to nicotine. For this, we challenged drug-naive C. elegans with an acute dose of nicotine (100 μmol/l) while recording changes in their locomotion speed. Although nicotine treatment stimulated locomotion speed in wild-type C. elegans, the same treatment reduced locomotion speed in mutants defective in insulin signaling...
February 2016: Behavioural Pharmacology
Venkata Naga Srikanth Garikipati, Prasanna Krishnamurthy, Suresh Kumar Verma, Mohsin Khan, Tatiana Abramova, Alexander R Mackie, Gangjian Qin, Cynthia Benedict, Emily Nickoloff, Jennifer Johnson, Ehre Gao, Douglas W Losordo, Steven R Houser, Walter J Koch, Raj Kishore
Poor survival and function of transplanted cells in ischemic and inflamed myocardium likely compromises the functional benefit of stem cell-based therapies. We have earlier reported that co-administration of interleukin (IL)-10 and BMPAC enhances cell survival and improves left ventricular (LV) functions after acute myocardial infarction (MI) in mice. We hypothesized that IL-10 regulates microRNA-375 (miR-375) signaling in BMPACs to enhance their survival and function in ischemic myocardium after MI and attenuates left ventricular dysfunction after MI...
December 2015: Stem Cells
Cheng-Wei Wu, Ryan A Bell, Kenneth B Storey
BACKGROUND: The insulin signaling pathway functions as a major regulator of many metabolic and cellular functions, and has been shown to be reversibly suppressed in many species during hibernation. This study characterized the regulation of PTEN phosphatase, a negative regulator of the insulin receptor network, over the torpor-arousal cycle of hibernation in the skeletal muscle of Ictidomys tridecemlineatus. METHODS: Western blotting and RT-PCR were used to analyze post-translational and transcriptional regulations of PTEN respectively...
November 2015: Biochimica et Biophysica Acta
Helena Pópulo, Regina Caldas, José Manuel Lopes, Joana Pardal, Valdemar Máximo, Paula Soares
OBJECTIVE: We aimed to verify if there is evidence to consider dichloroacetate (DCA), which inhibits the pyruvate dehydrogenase kinase (PDK) and reverts the metabolic shift of cancer cells from glycolysis to oxidative phosphorylation, as a promising drug for therapy of cutaneous melanoma (CM) patients. RESEARCH DESIGN AND METHODS: We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumors express the DCA targets, if this expression correlates with the activation of important signaling cascades for melanomagenesis and also with the prognosis of melanoma patients...
June 2015: Expert Opinion on Therapeutic Targets
Zhuang Zhuonan, Guo Sen, Ji Zhipeng, Zhuang Maoyou, Yin Linglan, Wang Gangping, Jin Cheng, Meng Zhongliang, Jessie Tian, Zhang Peijian, Xu Kesen
BACKGROUND: Ischemia and reperfusion (I/R) injury is one of the main lesions after liver transplantation. This study aims to detect hypoxia-induced HIF-1α protects transplanted liver against I/R injury by promoting glucose metabolism to decrease mitochondrial injury and apoptosis on rat model. METHODS: The rats were given a treatment of 90 min non-lethal hypoxic preconditioning to induce and increase the HIF-1α expression. The autologous orthotopic liver transplantation model was used to imitate liver I/R injury...
October 2015: Clinics and Research in Hepatology and Gastroenterology
Irene Cuadrado-Berrocal, María V Gómez-Gaviro, Yolanda Benito, Alicia Barrio, Javier Bermejo, María Eugenia Fernández-Santos, Pedro L Sánchez, Manuel Desco, Francisco Fernández-Avilés, María Fernández-Velasco, Lisardo Boscá, Beatriz de Las Heras
Therapeutic approaches to protect the heart from ischemia/reperfusion (I/R) injury are an area of intense research, as myocardial infarction is a major cause of mortality and morbidity. Diterpenes are bioactive natural products with great therapeutic potential. In the present study, we have investigated the in vivo cardioprotective effects of a labdane diterpene (DT1) against cardiac I/R injury and the molecular mechanisms involved. DT1 attenuates post-ischemic injury via an AKT-dependent activation of HIF-1α, survival pathways and inhibition of NF-κB signaling...
February 15, 2015: Biochemical Pharmacology
Nazila Tehrani, John Del Rosario, Moises Dominguez, Robert Kalb, Itzhak Mano
During ischemic stroke, malfunction of excitatory amino acid transporters and reduced synaptic clearance causes accumulation of Glutamate (Glu) and excessive stimulation of postsynaptic neurons, which can lead to their degeneration by excitotoxicity. The balance between cell death-promoting (neurotoxic) and survival-promoting (neuroprotective) signaling cascades determines the fate of neurons exposed to the excitotoxic insult. The evolutionary conserved Insulin/IGF Signaling (IIS) cascade can participate in this balance, as it controls cell stress resistance in nematodes and mammals...
2014: PloS One
Shingo Shimada, Moto Fukai, Kenji Wakayama, Takahisa Ishikawa, Nozomi Kobayashi, Taichi Kimura, Kenichiro Yamashita, Toshiya Kamiyama, Tsuyoshi Shimamura, Akinobu Taketomi, Satoru Todo
BACKGROUND AND PURPOSE: Hydrogen sulfide (H2S) ameliorates hepatic ischemia and reperfusion injury (IRI), but the precise mechanism remains elusive. We investigated whether sodium hydrogen sulfide (NaHS), a soluble derivative of H2S, would ameliorate hepatic IRI, and if so, via what mechanism. METHODS: Mice were subjected to partial warm ischemia for 75 min followed by reperfusion. Either NaHS or saline was administered intravenously 10 min before reperfusion...
July 2015: Surgery Today
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