Recently, inflammatory bowel disease （IBD） has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesi...Recently, inflammatory bowel disease （IBD） has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase （SPAK） is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases （such as p38, JNK, NKCC1, PKCS, WNK and MLCK）, and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport. This review examines the involvement of Ste20-1ike kinases and downstream mitogen-activated protein kinases （MAPKs） pathways in the pathogenesis and control of intestinal inflammation. The primary focus will be on the molecular features of intestinal inflammation, with an emphasis on the interaction between SPAK and other molecules, and the effect of these interactions on homeostatic maintenance, cell volume regulation and increased cell permeability in intestinal inflammation.展开更多
The association of polymorphisms in exon 1 of the WNK1 gene with essential hypertension in the minority groups of Hani and Yi of China was investigated in the case-control study.The sequence of 1257 bp containing the ...The association of polymorphisms in exon 1 of the WNK1 gene with essential hypertension in the minority groups of Hani and Yi of China was investigated in the case-control study.The sequence of 1257 bp containing the WNK1 gene exon 1 was determined in 1307 individuals（649 essential hypertension subjects and 658 controls）to identify SNPs in Hani and Yi minority groups.Four of eleven previously known SNPs （rs3168640,rs11885,rs11554421 and rs34880640）were identified.The SNP analysis indicated that SNPs rs11885 and rs11554421 were significantly associated with hypertension in both Hani and Yi populations,and rs34880640 was significantly associated with hypertension in Hani but not in Yi population,adjusted for covariates.Haplotype analysis indicated that the haplotype H1 significantly decreased the risk of hypertension in both populations.These results suggested that WNK1 polymorphisms were involved in the predisposition of essential hypertension in Hani and Yi populations and its effects showed a clear population specificity.This finding supported the importance of population specificity in determining the genetic factors associated with diseases and thus disease treatment.展开更多
Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the i...Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.展开更多
Hypertension is the largest risk factor for cardiovascular disease,the leading cause of mortality worldwide.As blood pressure regulation is influenced by multiple physiological systems,hypertension cannot be attribute...Hypertension is the largest risk factor for cardiovascular disease,the leading cause of mortality worldwide.As blood pressure regulation is influenced by multiple physiological systems,hypertension cannot be attributed to a single identifiable etiology.Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling,particularly the distal convoluted tubule(DCT)-native,thiazide-sensitive Na-Cl cotransporter(NCC).Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon’s and Gitelman syndromes respectively.Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC.In particular,NCC activity is controlled by phosphorylation/dephosphorylation,and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination.Studies have even found parvalbumin to be an unexpected regulator of the NCC.In recent years,there have been considerable advances in our understanding of NCC control mechanisms,particularly via the pathway containing the with-no-lysine[K](WNK)and its downstream target kinases,SPS/Ste20-related proline-alanine-rich kinase(SPAK)and oxidative stress responsive 1(OSR1),which has led to the discovery of novel inhibitory molecules.This review summarizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeutic targets for treating hypertension.展开更多
文摘Recently, inflammatory bowel disease （IBD） has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase （SPAK） is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases （such as p38, JNK, NKCC1, PKCS, WNK and MLCK）, and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport. This review examines the involvement of Ste20-1ike kinases and downstream mitogen-activated protein kinases （MAPKs） pathways in the pathogenesis and control of intestinal inflammation. The primary focus will be on the molecular features of intestinal inflammation, with an emphasis on the interaction between SPAK and other molecules, and the effect of these interactions on homeostatic maintenance, cell volume regulation and increased cell permeability in intestinal inflammation.
基金financially supported by the National Nature Science Foundation of China (Nos. U0932603 and 3091112048)the Natural Science Foundation of Yunnan Province (No. 2009CC001).
文摘The association of polymorphisms in exon 1 of the WNK1 gene with essential hypertension in the minority groups of Hani and Yi of China was investigated in the case-control study.The sequence of 1257 bp containing the WNK1 gene exon 1 was determined in 1307 individuals（649 essential hypertension subjects and 658 controls）to identify SNPs in Hani and Yi minority groups.Four of eleven previously known SNPs （rs3168640,rs11885,rs11554421 and rs34880640）were identified.The SNP analysis indicated that SNPs rs11885 and rs11554421 were significantly associated with hypertension in both Hani and Yi populations,and rs34880640 was significantly associated with hypertension in Hani but not in Yi population,adjusted for covariates.Haplotype analysis indicated that the haplotype H1 significantly decreased the risk of hypertension in both populations.These results suggested that WNK1 polymorphisms were involved in the predisposition of essential hypertension in Hani and Yi populations and its effects showed a clear population specificity.This finding supported the importance of population specificity in determining the genetic factors associated with diseases and thus disease treatment.
基金supported by the Chongqing Academician Program(No.cstc2019yszx-jcyjx0008 to Y.W.)The Subject of Health Commission of Hubei Province,China(No.WJ2021M222 to X.-M.W.).
文摘Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.
基金supported by the University of Exeter Medical School(UK)NIH Grants R01 NS109358(USA)。
文摘Hypertension is the largest risk factor for cardiovascular disease,the leading cause of mortality worldwide.As blood pressure regulation is influenced by multiple physiological systems,hypertension cannot be attributed to a single identifiable etiology.Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling,particularly the distal convoluted tubule(DCT)-native,thiazide-sensitive Na-Cl cotransporter(NCC).Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon’s and Gitelman syndromes respectively.Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC.In particular,NCC activity is controlled by phosphorylation/dephosphorylation,and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination.Studies have even found parvalbumin to be an unexpected regulator of the NCC.In recent years,there have been considerable advances in our understanding of NCC control mechanisms,particularly via the pathway containing the with-no-lysine[K](WNK)and its downstream target kinases,SPS/Ste20-related proline-alanine-rich kinase(SPAK)and oxidative stress responsive 1(OSR1),which has led to the discovery of novel inhibitory molecules.This review summarizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeutic targets for treating hypertension.
