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Ying Huang, Fang Liu, Fang Zhang, Pingsheng Liu, Tao Xu, Wenjun Ding
Numerous studies have demonstrated that vanadium compounds are able to improve lipemia and triglyceridemia in both humans and animals. However, the molecular mechanism remains elusive. The present study was conducted to investigate the anti-hyperlipidemic effect of vanadium(IV) complex with 4-chlorodipicolinic acid (VOdipic-Cl)-induced autophagy on hepatic lipid accumulation. To explore the possible underlying mechanisms, primary rat hepatocytes, human hepatoma cell line HepG2, and liver tissue from C57BL/6 mice fed a high-fat diet (HFD) were used...
March 14, 2018: Journal of Inorganic Biochemistry
(no author information available yet)
MEF2C activity in acute myeloid leukemia is dependent upon salt-inducible kinase (SIK) signaling.
March 16, 2018: Cancer Discovery
Chia-Sheng Yen, Cheuk-Sing Choy, Wei-Jan Huang, Shiu-Wen Huang, Pin-Ye Lai, Meng-Chieh Yu, Ching Shiue, Ya-Fen Hsu, Ming-Jen Hsu
Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. However, the precise mechanisms underlying hydroxamate derivative-induced cancer cell death remain incomplete understood. In this study, we explored the anti-tumor mechanisms of a novel aliphatic hydroxamate-based compound, WMJ-J-09, in FaDu head and neck squamous cell carcinoma (HNSCC) cells. WMJ-J-09 induced G2/M cell cycle arrest and apoptosis in FaDu cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, transcription factor p63 phosphorylation, as well as modulation of p21 and survivin...
2018: Frontiers in Pharmacology
Qian Chen, Mengyang Liu, Haiyang Yu, Jian Li, Sijian Wang, Yi Zhang, Feng Qiu, Tao Wang
Scutellaria baicalensis has been reported to improve the lipid metabolism of high-fat diet-induced liver dysfunction, but direct evidence is rare. This study aimed to explore the effects and mechanisms of S. baicalensis and its major constituent baicalin on hepatic lipotoxicity. KK-Ay mice and orotic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) rats were used to evaluate lipid metabolism regulatory effects. Sodium oleate-induced triglyceride-accumulated HepG2 cells were used for the mechanism study, pretreated with or without compound C or STO-609 or transfected with liver kinase B1 (LKB1) siRNA...
March 14, 2018: Journal of Natural Medicines
Lars Kullmann, Michael P Krahn
The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer...
March 15, 2018: Oncogene
Yusuke Tarumoto, Bin Lu, Tim D D Somerville, Yu-Han Huang, Joseph P Milazzo, Xiaoli S Wu, Olaf Klingbeil, Osama El Demerdash, Junwei Shi, Christopher R Vakoc
The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF...
February 28, 2018: Molecular Cell
Peng Liu, Tingting Feng, Xuan Zuo, Xiao Wang, Jinque Luo, Ni Li, Xiaowan Han, Ningyu Zhu, Suowen Xu, Yanni Xu, Zheng Gen Jin, Shuyi Si
Sirtuin 1 (SIRT1) is an NAD+ -dependent protein deacetylase that plays a critical role in controlling energy metabolism, stress response and aging. Hence, enhancing SIRT1 activity could be a potential therapeutic strategy to treat metabolic diseases such as diabetes. However, pharmacological activators for SIRT1 are scarce to date. In this study, using the optimized high throughput screening, we identified E6155, a piperazine 1, 4- diamide compound, as a new small molecular activator of SIRT1. We further found that E6155 significantly upregulated glucose uptake in cultured mouse liver cells and skeletal muscle cells through increasing SIRT1 deacetylase activity...
March 7, 2018: Biochemical and Biophysical Research Communications
Dongdong Wu, Honggang Wang, Tieshan Teng, Shaofeng Duan, Ailing Ji, Yanzhang Li
Hydrogen sulfide (H2 S) has been considered the third gaseous signaling molecule that plays important roles in a wide range of physiological and pathological conditions. However, there has been some controversy on the role of H2 S in autophagy. Recent studies indicate that a number of signaling pathways are involved in the pro-autophagy effect of H2 S, such as PI3 K/Akt/mTOR, AMPK/mTOR, LKB1/STRAD/MO25, and miR-30c signaling pathways. On the other hand, there are many signaling pathways that play important roles in the anti-autophagy effect of H2 S, including SR-A, PI3 K/SGK1/GSK3β, PI3 K/AKT/mTOR, Nrf2-ROS-AMPK, AMPK/mTOR, and JNK1 signaling pathways...
March 4, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Loredana Mauro, Giuseppina Daniela Naimo, Luca Gelsomino, Rocco Malivindi, Leonardo Bruno, Michele Pellegrino, Roberta Tarallo, Domenico Memoli, Alessandro Weisz, Maria Luisa Panno, Sebastiano Andò
Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-α (ERα)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active...
March 7, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Stefanie Klinger, Gerhard Breves
BACKGROUND: Beneficial effects of Resveratrol (RSV) have been demonstrated, including effects on transporters and channels. However, little is known about how RSV influences intestinal transport. The aim of this study was to further characterize the effects of RSV on intestinal transport and the respective mechanisms. METHODS: Porcine jejunum and ileum were incubated with RSV (300 µM, 30 min) in Ussing chambers (functional studies) and tissue bathes (detection of protein expression, phosphorylation, association with detergent resistant membranes (DRMs))...
March 3, 2018: Nutrients
Eun-Bin Kwon, Myung-Ji Kang, Soo-Yeon Kim, Yong-Moon Lee, Mi-Kyeong Lee, Heung Joo Yuk, Hyung Won Ryu, Su Ui Lee, Sei-Ryang Oh, Dong-Oh Moon, Hyun-Sun Lee, Mun-Ock Kim
Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
Soma Behera, Bandish Kapadia, Vasundhara Kain, Neeraja P Alamuru-Yellapragada, Vachana Murunikkara, Sireesh T Kumar, Phanithi Prakash Babu, Sriram Seshadri, Prasad Shivarudraiah, Jagadheshan Hiriyan, Narmadha Reddy Gangula, Subbareddy Maddika, Parimal Misra, Kishore V L Parsa
Nutritional abundance associated with chronic inflammation and dyslipidemia impairs the functioning of endoplasmic reticulum (ER) thereby hampering cellular responses to insulin. PHLPP1 was identified as a phosphatase which inactivates Akt, the master regulator of insulin mediated glucose homeostasis. Given the suggestive role of PHLPP1 phosphatase in terminating insulin signalling pathways, deeper insights into its functional role in inducing insulin resistance are warranted. Here, we show that PHLPP1 expression is enhanced in skeletal muscle of insulin resistant rodents which also displayed ER stress, an important mediator of insulin resistance...
February 27, 2018: Biochimica et Biophysica Acta
Peng Wang, Lizhu Jiang, Nian Zhou, Hao Zhou, Huzhe Liu, Wenrui Zhao, Hanxiang Zhang, Xiang Zhang, Zhenming Hu
Resveratrol is known to improve functional recovery after spinal cord injury, but the exact mechanism involved is yet unclear. The aim of this study was to clarify whether resveratrol can exert neuroprotective effects via activating neuronal autophagic flux, in view of the underlying role of the autophagic flux mediated by resveratrol on neuronal apoptosis after spinal cord injury, and identify the role of the liver kinase B1(LKB1)/adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/ p70 ribosomal protein S6 kinase (p70s6k) signal pathway in the autophagic flux mediated by resveratrol...
February 2, 2018: Oncotarget
Chun-Fang, Bo-Bo Zhang, Lin-Han, Cai-Feng Gao, Min-Wang
d-Fagomine, an analogue of 1-deoxynojirimycin (DNJ), has been shown to have hypoglycemic activity. This study is aimed at investigating if d-fagomine could attenuate high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and elucidate the underlying mechanism. Our results showed that d-fagomine reduced intracellular reactive oxygen species (ROS) production and malondialdehyde (MDA) levels. It also reversed the decrease of superoxide dismutases (SOD) and glutathione reductase (GR) activity, suggesting an inhibitory effect of d-fagomine on oxidative damage in HUVECs...
February 28, 2018: Journal of Agricultural and Food Chemistry
Ningbo Xu, Yixin Zhang, Desislava Met Doycheva, Yan Ding, Yiting Zhang, Jiping Tang, Hongbo Guo, John H Zhang
Adiponectin is an important adipocyte-derived plasma protein that has beneficial effects on cardio- and cerebrovascular diseases. A low level of plasma Adiponectin is associated with increased mortality post ischemic stroke; however, little is known about the causal role of Adiponectin as well as its molecular mechanisms in neonatal hypoxia ischemia (HI). In the present study, ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. Recombinant human Adiponectin (rh-Adiponectin) was administered intranasally 1 h post HI...
February 24, 2018: Neuropharmacology
Jui-Shu Chang, Hung-Jen Lin, Jeng-Shyan Deng, Wen-Tzu Wu, Shyh-Shyun Huang, Guan-Jhong Huang
Velvet antler ( Cervus elaphus ) is a typical traditional animal medicine. It is considered to have various pharmacological effects including stimulation of the immune system, increase in the physical strength, and enhancement of sexual function. This paper aims to investigate the aqueous extract of velvet antler (AVA) in the mouse models of LPS-induced ALI. Inhibition of NO, TNF- α , IL-1 β , IL-6, and IL-10 productions contributes to the attenuation of LPS-induced lung inflammation by AVA. A 5-day pretreatment of AVA prevented histological alterations and enhanced antioxidant enzyme activity in lung tissues...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
Ebony M Flowers, Jessica Sudderth, Lauren Zacharias, Glenda Mernaugh, Roy Zent, Ralph J DeBerardinis, Thomas J Carroll
Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth...
February 26, 2018: Nature Communications
Diana Moreira, Jérôme Estaquier, Anabela Cordeiro-da-Silva, Ricardo Silvestre
The study of host AMP-activated protein kinase (AMPK) activation during Leishmania infection imposes distinct types of techniques to measure protein expression and activation, as well as to quantify, at transcription and translational levels, its downstream targets. The investigation of host AMPK protein modulation during Leishmania infection should primarily be assessed during in vitro infections using as a host murine bone marrow-derived macrophages (BMMos). The infection outcome is assessed measuring the percentage of infected cells in the context of BMMos...
2018: Methods in Molecular Biology
Chen-Song Zhang, Mengqi Li, Yue Zong, Sheng-Cai Lin
Recent studies have revealed how AMPK is activated inside the cell and animal tissues: in response to low glucose, AXIN tethers LKB1, by virtue of their constitutive association, to AMPK located on the surface of late endosome/lysosome. Importantly, the lysosomal v-ATPase (vacuolar ATPase)-Ragulator complex, when primed by glucose starvation or concanamycin A, facilitates AXIN/LKB1 to interact with AMPK. Here, we describe the experimental procedures of the assays for detecting the translocation of AXIN/LKB1 or the assembly of the AXIN-based AMPK-activating complexes on the late endosome/lysosome...
2018: Methods in Molecular Biology
Cheng-Chung Wu, De-Wei Wu, Ying-Yu Lin, Po-Lin Lin, Huei Lee
BACKGROUND: Hepatitis B virus X (HBx) protein plays critical roles in hepatitis B virus (HBV)-associated hepatocellular tumorigenesis through different molecular mechanisms, including inactivation of p53, a key transcription factor of liver kinase B1 (LKB1). We hypothesized that p53 inactivation by HBx protein could decrease LKB1 expression, thereby promoting tumor progression and poor outcomes in patients with HBV-associated hepatocellular carcinoma. METHODS: Manipulation strategies for HBx protein and/or p53 were used to verify that loss of LKB1 could promote colony formation and invasiveness in HepG2 and Hep3B cells...
February 20, 2018: Surgery
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