|
|
|
题名
|
作者
|
年代
|
出处
|
被引量
|
| 1 | Cirrhotic portal hypertension: From pathophysiology to novel therapeutics显示文摘Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis. | Lakmie S Gunarathne Harinda Rajapaksha Nicholas Shackel Peter W Angus Chandana B Herath | 2020 | World Journal of Gastroenterology2020，26，40： | 24 |
| 2 | Therapeutic potential of targeting the renin angiotensin system in portal hypertension显示文摘Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered 'alternate axis' of the RAS. | Chandana B Herath Josephine A Grace Peter W Angus | 2013 | World Journal of Gastrointestinal Pathophysiology2013，4，1： | 9 |
| 3 | Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease显示文摘AIM To determine if manipulation of dietary advanced glycation end product(AGE), intake affects nonalcoholic fatty liver disease(NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol(HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mR NA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content(a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/-animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD. | Christopher Leung Chandana B Herath Zhiyuan Jia Sof Andrikopoulos Bronwyn E Brown Michael J Davies Leni R Rivera John B Furness Josephine M Forbes Peter W Angus | 2016 | World Journal of Gastroenterology2016，22，35： | 7 |
| 4 | Comparative assessment of expression of the inhibitor of growth 1 gene (ING1) in normal and neoplastic tissnos显示文摘 | Nouman GS Angus B Lunec J | 2002 | Hybridoma2002，21，1： | 1 |
| 5 | Cooperation and competition in pathogenic bacteria显示文摘 | ASHLEIGH S G STUART A W ANGUS B | 2004 | Letters to Nature2004，430，10： | 1 |
| 6 | Islet encapsulation:strategies to enhance islet cell functions显示文摘 | Beck J Angus R Madsen B | 2007 | Tissue Eng2007，13，： | 1 |
| 7 | Cyclin DI expression in transitional cell carcinoma of the baladder:correlation with p53,wafl pRb and Ki-67显示文摘 | Tut VM Braithwaite AL Angus B | 2001 | Br J Cancer2001，84，2： | 1 |
| 8 | Electron diffraction based techniques in scanning electron microscopy of bulk matericals 显示文摘 | Angus J Wilkinson Peter B Hirsch | 1997 | Micron1997，28，4： | 1 |
| 9 | Hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated COPD显示文摘 | Chakrabarti B Angus RM Agarwal S | 2009 | Thorax2009，64，10： | 1 |
| 10 | Epidermal growth fac- tor receptor status of histological sub-types of breast cancer显示文摘 | Sainsbury JR Nicholson S Angus B | 1988 | Br J Cancer1988，58，4： | 1 |
| 11 | Diversity peaks at intermediate productivity in a laboratory micro- cosm 显示文摘 | KASSEN R ANGUS B GRAHAM B | 2000 | Nature2000，406，6795： | 1 |
| 12 | Cyclin D expression in transitional cell carlinoma of the bladder correlation with p53wafl PRb and Ki67显示文摘 | Tut VM Braithwaite AL Angus B | 2001 | BrJCancer2001，84，2： | 1 |
| 13 | Cyclin DI expression in transitional cell carcinoma of the bladder:correlation with p53,wall,pRb and Ki67显示文摘 | Tut VM Braithwaite AL Angus B | 2001 | Br J Cancer2001，84，2： | 1 |
| 14 | Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation显示文摘 | Vaughan R B Angus P W Chin Dusting J P F | 2003 | Gut2003，52，10： | 1 |
| 15 | Epidemiology of severe sepsis显示文摘 | Mayr F B Yende S Angus D C | 2014 | Virulence2014，5，： | 1 |
| 16 | Diversity peaks at intermediate productivity in a laboratory microcosm显示文摘 | Kassen R Angus B Graham B | 2000 | Nature2000，406，： | 1 |
| 17 | Relationship between C - erbB -2 protein product expression and response to endocrine therapyin advanced breast cancer 显示文摘 | wright C Nichoison S Angus B | 1992 | Br J Cancer1992，65，1： | 1 |
| 18 | Multiple regulatory events controlling the expression and localization of utrophin in skeletal muscle fibers:insights into a therapeutic strategy for Duchenne muscular dystrophy显示文摘 | Jasmin B J Angus LM Bé1anger G | 2002 | J Physiol Paris2002，96，12： | 1 |
| 19 | Relationship between C-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer显示文摘 | Wright C Nicholson S Angus B | 1992 | Br J Cancer1992，65，1： | 1 |
| 20 | Hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated COPD显示文摘 | Chakrabarti B Angus RM Agarwal S | 2009 | Thorax2009，64，10： | 1 |
您所在的机构暂未开通此部分的功能，请联系管理员