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| 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 | Plasma MMP-2 and MMP-7 levels are elevated first month after surgery and may promote growth of residual metastases显示文摘BACKGROUND MMP-2 also known as gelatinase A and MMP-7(matrilysin)are members of the zinc-dependent family of MMPs(Matrix metalloproteinase).MMP-2 and MMP-7 are remodeling enzymes that digest extracellular matrix;MMP-2 is extensively expressed during development and is upregulated at sites of tissue damage,inflammation,and in stromal cells of metastatic tumors.MMP-7 is expressed in the epithelial cells and in a variety of cancers including colon tumors.Plasma MMP-2 and MMP-7 levels were assessed before and after minimally invasive colorectal resection for cancer pathology.AIM To determine plasma MMP-2 and MMP-7 levels before and after minimally invasive colorectal resection for cancer pathology.METHODS Patients enrolled in a plasma bank for whom plasma was available were eligible.Plasma obtained from preoperative(Preop)and postoperative blood samples was used.Only colorectal cancer(CRC)patients who underwent elective minimally invasive cancer resection with preop,post-operative day(POD)1,3 and at least 1 late postop sample(POD 7-34)were included.Late samples were bundled into 7 d blocks(POD 7-13,14-20,etc.)and treated as single time points.Plasma MMP-2 and MMP-7 levels were determined via enzyme-linked immunosorbent assay in duplicate.RESULTS Total 88 minimally invasive CRC resection CRC patients were studied(right colectomy,37%;sigmoid,24%;and LAR/AR 18%).Cancer stages were:1,31%;2,30%;3,34%;and 4,5%.Mean Preop MMP-2 plasma level(ng/mL)was 179.3±40.9(n=88).Elevated mean levels were noted on POD1(214.3±51.2,n=87,P<0.001),POD3(258.0±63.9,n=80,P<0.001),POD7-13(229.9±62.3,n=65,P<0.001),POD 14-20(234.9±47.5,n=25,P<0.001),POD 21-27(237.0±63.5,n=17,P<0.001,)and POD 28-34(255.4±59.7,n=15,P<0.001).Mean Preop MMP-7 level was 3.9±1.9(n=88).No significant differences were noted on POD 1 or 3,however,significantly elevated levels were noted on POD 7-13(5.7±2.5,n=65,P<0.001),POD 14-20(5.9±2.5,n=25,P<0.001),POD 21-27(6.1±3.6,n=17,P=0.002)and on POD 28-34(6.8±3.3,n=15 P<0.001,)vs preop levels.CONCLUSION MMP-2 levels are elevated for 5 wk and MMP-7 levels elevated for weeks 2-6.The etiology of these changes in unclear,trauma and wound healing likely play a role.These changes may promote residual tumor growth and metastasis. | HMC Shantha Kumara Hiromichi Miyagaki Sajith A Herath Erica Pettke Xiaohong Yan Vesna Cekic Richard L Whelan | 2021 | World Journal of Gastrointestinal Oncology2021，13，8： | 3 |
| 5 | Incorporating community objectives in improved wetland management: the use of the analytic hierarchy process显示文摘 | Gamini Herath | 2004 | Journal of Environmental Management2004，，3： | 2 |
| 6 | Encouraging information security behaviors in organizations: Role of penalties, pressures and perceived effectiveness显示文摘 | Tejaswini Herath H.R. Rao | 2009 | Decision Support Systems2009，，2： | 2 |
| 7 | Epstein-Barr Virus-Associated Lymphoepithelioma-like Gastric Carcinoma显示文摘 | Herath Chaturika Harshini Pavithra Chetty Runjan | 2008 | Archives of Pathology & Laboratory Medicine2008，，4： | 2 |
| 8 | 2,2,6,6-Tetramethyl piperidine-1-oxyl (TEMPO)-mediated catalytic oxidation of benzyl alcohol in acetonitrile and ionic liquid 1-butyl-3-methyl-imidazolium hexafluorophosphate [BMIm][PF 6 ]: Kinetic analysis显示文摘 | Ajith C. Herath James Y. Becker | 2008 | Electrochimica Acta2008，，12： | 2 |
| 9 | Phaeochromocytoma of the urinary bladder presenting with malignant hypertension and hypertensive retinopathy显示文摘Dear Editor,Phaeochromocytoma of thelurinary bladder is a rare tumour that originates from chromaffin tissue of the sympathetic nervous system situated within the urinary bladder wall[1].These are tumours of the sympathetic nervous tissue and the symptom profile will depend on the secretory function[1].These account for less than 0.05%of all bladder tu-mours and less than 1%of all phaeochromocytoma[1].As phaeochromocytoma of the urinary bladder is such a rare condition,only limited literature is available to direct clinical decision making. | Umesh Jayarajah Kasun Bandara Herath Manoj Hilary Fernando Serozsha Goonewardena | 2020 | Asian Journal of Urology2020，7，1： | 2 |
| 10 | Incorporating community objectives in improved wetland management: The use of the analytic hierarchy process 显示文摘 | Herath G | 2004 | Journal of Environmental Management2004，70，： | 1 |
| 11 | Fluorescence in situ hybridization for rapid differentiation of zygosity in transgenic mice显示文摘 | Nishino H Herath JF Jenkins RB | 1995 | Bio Techniques1995，18，： | 1 |
| 12 | Latest Trends and Issues in the ASP Service Market 显示文摘 | Atul Gupta Siriyama Kanthi Herath | 2005 | Industrial Management & data Systems2005，105，1： | 1 |
| 13 | Antifungal constituent from Gordonia dassanayakei显示文摘 | Athukoralage P S Herath H M T B Deraniyagala S A | 2001 | Fitoterapia2001，72，5： | 1 |
| 14 | Angiotensin-(1- 7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotie activity in the bile-duct-ligated rat显示文摘 | Lubel JS Herath CB Tehongue J | 2009 | Clin Sci (Lond)2009，117，11： | 1 |
| 15 | Development of a geomorphology-based hydrological model for large catchments 显示文摘 | Yang D Herath S Musiake K | 1998 | Annual Journal of Hydraulic Engineering JSCE1998，42，： | 1 |
| 16 | Study of betaendorphin metabolism in inflamed tissue,serum andtrypsin solution by liquid chromatography -tandem massspectrometric analysis显示文摘 | Herath HM Cabot PJ Shaw PN | 2012 | Anal Bioanal Chem2012，402，6： | 1 |
| 17 | Isolation and structure of antagonists of chemokine receptor(CCR5)显示文摘 | JAYASURIYA H HERATH K B ONDEYKA J G | | 0，，06： | 1 |
| 18 | Bacterial li- popolysaccharide induces an endocrine switch from prostaglandin F2alpha to prostaglandin E2 in bovine endometrium 显示文摘 | Herath S Lilly S T Fischer D P | 2009 | Endocrinol2009，150，4： | 1 |
| 19 | Porphy romonas gingivalis lipopolysaccharide lipid A hetero- geneity differentially modulates the expression of IL-6 and IL-8 in human gingival fibmblasts显示文摘 | Herath TDK Wang Y Seneviratne CJ | 2011 | J Clin Peri- odontol2011，38，8： | 1 |
| 20 | Portal pressure responses and angiotensin peptide production in rat hver are determined by relative activity of angiotensin convetting enzyme ( ACE ) and ACE2 显示文摘 | Herath CB Lubel JS Jia Z | 2009 | Am J Physiol Gastrointest Liver Physiol2009，297，7： | 1 |
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