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https://www.readbyqxmd.com/read/28915228/analysis-of-the-genes-involved-in-mendelian-forms-of-low-renin-hypertension-in-chinese-early-onset-hypertensive-patients
#1
Kai Liu, Fang Qin, Xiaolu Sun, Yang Zhang, Jizheng Wang, Yajie Wu, Wenjun Ma, Wei Wang, Xueyi Wu, Ying Qin, Huimin Zhang, Xianliang Zhou, Haiying Wu, Rutai Hui, Yubao Zou, Xiongjing Jiang, Lei Song
BACKGROUND: The study aimed to analyze genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. METHODS: A panel of nine genes, namely SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3, nuclear receptor subfamily 3, group C (NR3C)1, NR3C2, and HSD11B2 were screened by targeted resequencing in 260 Chinese early-onset hypertensive patients. Additionally, exon 13 of both SCNN1B and SCNN1G was sequenced in an independent cohort of 506 Chinese early-onset hypertensive patients...
September 14, 2017: Journal of Hypertension
https://www.readbyqxmd.com/read/28819369/in-vitro-cytotoxic-activities-of-the-oral-platinum-iv-prodrug-oxoplatin-and-hsp90-inhibitor-ganetespib-against-a-panel-of-gastric-cancer-cell-lines
#2
Lukas Klameth, Barbara Rath, Gerhard Hamilton
Gastric cancer exhibits a poor prognosis and is the third most common cause of cancer death worldwide. Chemotherapy of metastatic gastric cancer is based on combinations of platinum drugs and fluoropyrimidines, with added agents. Oxoplatin is a stable oral platinum(IV) prodrug which is converted to a highly active tetrachlorido(IV) complex under acidic conditions. In the present work, we studied the cytotoxic effects of oxoplatin against a panel of four gastric cancer cell lines in vitro. Furthermore, the role of HSP90 in chemoresistance of these lines was investigated using the specific inhibitor ganetespib...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28771350/optimization-of-allosteric-with-no-lysine-wnk-kinase-inhibitors-and-efficacy-in-rodent-hypertension-models
#3
Ken Yamada, Julian Levell, Taeyong Yoon, Darcy Kohls, David Yowe, Dean F Rigel, Hidetomo Imase, Jun Yuan, Kayo Yasoshima, Keith DiPetrillo, Lauren Monovich, Lingfei Xu, Meicheng Zhu, Mitsunori Kato, Monish Jain, Neeraja Idamakanti, Paul Taslimi, Toshio Kawanami, Upendra A Argikar, Vidya Kunjathoor, Xiaoling Xie, Yukiko I Yagi, Yuki Iwaki, Zachary Robinson, Hyi-Man Park
The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies...
August 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28770829/wnk1-is-required-for-proliferation-induced-by-hypotonic-challenge-in-rat-vascular-smooth-muscle-cells
#4
Ya-Juan Zhang, Hua-Qing Zheng, Bao-Yi Chen, Lu Sun, Ming-Ming Ma, Guan-Lei Wang, Yong-Yuan Guan
Hypotonic challenge evoked vascular cell proliferation through activation of volume-regulated Cl(-) channel (VRCC), leading to a decrease in the intracellular Cl(-) concentration ([Cl(-)]i). We hypothesize that the decrease in [Cl(-)]i may activate one or several Cl(-)-sensitive kinases, resulting in a subsequent signaling cascade. In this study we demonstrated that WNK1, a Cl(-)-sensitive kinase, was involved in VRCC-induced proliferative signaling pathway in A10 vascular smooth muscle cells in vitro. A10 cells were exposed to a hypotonic challenge (225 mosmol·kg(-1)·H20), which caused significantly increase in WNK1 phosphorylation without altering WNK1 protein expression...
August 3, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28743496/wnk4-is-indispensable-for-the-pathogenesis-of-pseudohypoaldosteronism-type-ii-caused-by-mutant-klhl3
#5
Koichiro Susa, Eisei Sohara, Daiei Takahashi, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida
WNK-OSR1/SPAK-NCC signaling cascade is important for regulating salt balance and blood pressure. Activation of WNK-OSR1/SPAK-NaCl cotransporter (NCC) cascade increases sodium reabsorption in the kidney, leading to pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. It has been previously demonstrated that the amount of phosphorylated and total NCC markedly decreased in WNK4(-/-) mice, indicating that WNK4 plays a major role for activation of OSR1/SPAK-NCC signaling...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28679620/integrated-single-cell-genetic-and-transcriptional-analysis-suggests-novel-drivers-of-chronic-lymphocytic-leukemia
#6
Lili Wang, Jean Fan, Joshua M Francis, George Georghiou, Sarah Hergert, Shuqiang Li, Rutendo Gambe, Chensheng W Zhou, Chunxiao Yang, Sheng Xiao, Paola Dal Cin, Michaela Bowden, Dylan Kotliar, Sachet A Shukla, Jennifer R Brown, Donna Neuberg, Dario R Alessi, Cheng-Zhong Zhang, Peter V Kharchenko, Kenneth J Livak, Catherine J Wu
Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype-phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways...
August 2017: Genome Research
https://www.readbyqxmd.com/read/28672809/montelukast-induces-apoptosis-inducing-factor-mediated-cell-death-of-lung-cancer-cells
#7
Ming-Ju Tsai, Wei-An Chang, Pei-Hsun Tsai, Cheng-Ying Wu, Ya-Wen Ho, Meng-Chi Yen, Yi-Shiuan Lin, Po-Lin Kuo, Ya-Ling Hsu
Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0...
June 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28596815/next-generation-sequencing-traces-human-induced-pluripotent-stem-cell-lines-clonally-generated-from-heterogeneous-cancer-tissue
#8
Tetsuya Ishikawa
AIM: To investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS: Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19...
May 26, 2017: World Journal of Stem Cells
https://www.readbyqxmd.com/read/28522431/wnk1-and-p38-mapk-distribution-in-ionocytes-and-accessory-cells-of-euryhaline-teleost-fish-implies-ionoregulatory-function
#9
W S Marshall, R R F Cozzi, M Spieker
Ionocytes of euryhaline teleost fish secrete NaCl, under regulation by serine and threonine kinases, including with-no-lysine kinase (WNK1) and p38 mitogen-activated protein kinase (MAPK). Mummichogs (Fundulus heteroclitus L.) were acclimated to freshwater (FW), full strength seawater (SW) and hypersaline conditions (2SW). Immunocytochemistry of ionocytes in opercular epithelia of fish acclimated to SW and 2SW revealed that WNK1-anti-pT58 phosphoantibody localized strongly to accessory cells and was present in the cytosol of ionocytes, close to cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane and the sodium potassium 2 chloride cotransporter (NKCC) in the basolateral membrane...
July 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28511177/familial-hyperkalemia-and-hypertension-fhht-and-klhl3-description-of-a-family-with-a-new-recessive-mutation-s553l-compared-to-a-family-with-a-dominant-mutation-q309r-with-analysis-of-urinary-sodium-chloride-cotransporter
#10
Orit Kliuk-Ben Bassat, Vered Carmon, Aaron Hanukoglu, Liat Ganon, Eias Massalha, Eliezer J Holtzman, Zvi Farfel, Haim Mayan
BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described...
2017: Nephron
https://www.readbyqxmd.com/read/28489665/the-nogo-receptor-inhibits-proliferation-migration-and-axonal-extension-by-transcriptionally-regulating-wnk1-in-pc12-cells
#11
Tao Yang, Kai Zhao, Haifeng Shu, Xin Chen, Jingmin Cheng, Song Li, Ziyi Zhao, Yongqin Kuang, Sixun Yu
Neuronal regeneration and axonal regrowth mechanisms in the injured mammalian central nervous system are largely unknown. As part of a major pathway for inhibiting axonal regeneration, activated neuronal glycosylphosphatidylinositol-anchored Nogo receptor (NgR) interacts with LINGO-1 and p75NTR to form a complex at the cell surface. However, it was found in our previous report that upregulation of NgR stimulated by injury plays a key role in neuronal regeneration in the neonatal cortex freeze-lesion model, but its downstream signalling remains elusive...
June 14, 2017: Neuroreport
https://www.readbyqxmd.com/read/28422281/wnk1-hsn2-founder-mutation-in-patients-with-hereditary-sensory-and-autonomic-neuropathy-a-japanese-cohort-study
#12
Jun-Hui Yuan, Akihiro Hashiguchi, Akiko Yoshimura, Norio Sakai, Masanori P Takahashi, Takehiro Ueda, Akira Taniguchi, Sayaka Okamoto, Nobuo Kanazawa, Yuki Yamamoto, Kazumasa Saigoh, Susumu Kusunoki, Masahiro Ando, Yu Hiramatsu, Yuji Okamoto, Hiroshi Takashima
The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in five patients. This mutation was homozygous in four cases and of a compound heterozygous genotype in one case...
April 19, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28414128/impaired-degradation-of-medullary-wnk4-in-the-kidneys-of-klhl2-knockout-mice
#13
Yuri Kasagi, Daiei Takahashi, Tomomi Aida, Hidenori Nishida, Naohiro Nomura, Moko Zeniya, Takayasu Mori, Emi Sasaki, Fumiaki Ando, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), and Cullin3 (CUL3) genes were identified as being responsible for hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Normally, the KLHL3/CUL3 ubiquitin ligase complex degrades WNKs. In PHAII, the loss of interaction between KLHL3 and WNK4 increases levels of WNKs because of impaired ubiquitination, leading to abnormal over-activation of the WNK-OSR1/SPAK-NCC cascade in the kidney's distal convoluted tubules (DCT)...
May 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28401010/downregulation-of-acsm3-promotes-metastasis-and-predicts-poor-prognosis-in-hepatocellular-carcinoma
#14
Hao-Yu Ruan, Chen Yang, Xue-Mei Tao, Jia He, Ting Wang, Hui Wang, Cun Wang, Guang-Zhi Jin, Hao-Jie Jin, Wen-Xin Qin
Understanding mechanisms of cancer metastasis is crucial for reduction of cancer mortality. Acyl-CoA medium-chain synthetase 3 (ACSM3) is an acyl-CoA synthetase which takes part in the first step of fatty acid metabolism. However, the expression, clinical significance and biological function of ACSM3 remain unknown in hepatocellular carcinoma (HCC). In this study, the expression and prognostic relevance of ACSM3 were investigated by tissue microarray and HCC clinical samples. Migration and invasion assays were carried out for functional analysis in vitro and a xenograft model was used to analyze the effects of ACSM3 on cancer metastasis in vivo...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28389565/akt3-kinase-suppresses-pinocytosis-of-low-density-lipoprotein-by-macrophages-via-a-novel-wnk-sgk1-cdc42-protein-pathway
#15
Liang Ding, Lifang Zhang, Michael Kim, Tatiana Byzova, Eugene Podrez
Fluid-phase pinocytosis of LDL by macrophages is regarded as a novel promising target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. The mechanisms of regulation of fluid-phase pinocytosis in macrophages and, specifically, the role of Akt kinases are poorly understood. We have found previously that increased lipoprotein uptake via the receptor-independent process in Akt3 kinase-deficient macrophages contributes to increased atherosclerosis in Akt3(-/-) mice. The mechanism by which Akt3 deficiency promotes lipoprotein uptake in macrophages is unknown...
June 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28289184/renal-tubular-ubiquitin-protein-ligase-nedd4-2-is-required-for-renal-adaptation-during-long-term-potassium-depletion
#16
Lama Al-Qusairi, Denis Basquin, Ankita Roy, Renuga Devi Rajaram, Marc P Maillard, Arohan R Subramanya, Olivier Staub
Adaptation of the organism to potassium (K(+)) deficiency requires precise coordination among organs involved in K(+) homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K(+) retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na(+)/Cl(-) cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K(+) restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout (Nedd4L(Pax8/LC1) ) mice exhibited severe hypokalemia and urinary K(+) wasting...
August 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28282258/wnk1-is-an-unexpected-autophagy-inhibitor
#17
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
Autophagy is a cellular degradation pathway that is essential to maintain cellular physiology, and deregulation of autophagy leads to multiple diseases in humans. In a recent study, we discovered that the protein kinase WNK1 (WNK lysine deficient protein kinase 1) is an inhibitor of autophagy. The loss of WNK1 increases both basal and starvation-induced autophagy. In addition, the depletion of WNK1 increases the activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, which is required to induce autophagy...
May 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28237360/involvement-of-wnk1-mediated-potassium-channels-in-the-sexual-dimorphism-of-blood-pressure
#18
Guofeng Yu, Mengting Cheng, Wei Wang, Rong Zhao, Zhen Liu
Potassium homeostasis plays an essential role in the control of blood pressure. It is unknown, however, whether potassium balance is involved in the gender-associated blood pressure differences. We therefore investigated the possible mechanism of sexual dimorphism in blood pressure regulation by measuring the blood pressure, plasma potassium, renal actions of potassium channels and upstream regulator in male and female mice. Here we found that female mice exhibited lower blood pressure and higher plasma K(+) level as compared to male littermates...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28236964/wnk-kinases-in-development-and-disease
#19
REVIEW
Aylin R Rodan, Andreas Jenny
WNK (With-No-Lysine (K)) kinases are serine-threonine kinases characterized by an atypical placement of a catalytic lysine within the kinase domain. Mutations in human WNK1 or WNK4 cause an autosomal dominant syndrome of hypertension and hyperkalemia, reflecting the fact that WNK kinases are critical regulators of renal ion transport processes. Here, the role of WNKs in the regulation of ion transport processes in vertebrate and invertebrate renal function, cellular and organismal osmoregulation, and cell migration and cerebral edema will be reviewed, along with emerging literature demonstrating roles for WNKs in cardiovascular and neural development, Wnt signaling, and cancer...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28222034/three-cases-of-gordon-syndrome-with-dominant-klhl3-mutations
#20
Ji Soo Park, Eujin Park, Hye Sun Hyun, Yo Han Ahn, Hee Gyung Kang, Il-Soo Ha, Hae Il Cheong
BACKGROUND: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. CASE PRESENTATION: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases...
March 1, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
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