Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis

Wang, Dong; Wang, Qin; Yin, Jun-Feng; Dong, Rui; Wang, Qing; Du, Xin; Lu, Jianguo

doi:10.1111/jgh.13207

Cited by 15 publications

(12 citation statements)

References 35 publications

(56 reference statements)

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“…There is increasing evidence that angiogenesis and neovascularization play an important role in the development of splenomegaly and hypersplenism. For example, the mammalian target of rapamycin (mTOR) and Janus kinase-2 (JAK2/STAT3) signaling pathways, which are known regulators of angiogenesis, have been implicated in the development of portal hypertension and splenomegaly, and inhibition of these signaling pathways has been shown to reduce splenomegaly ( Mejias et al., 2010 ; Wang et al., 2015 ; Chen et al., 2016 ; Wang et al., 2016 ). Furthermore, it has been reported that elevated levels of vascular endothelial growth factor (VEGF), a critical regulator of angiogenesis and neovascularization, are associated with splenomegaly in patients with chronic myeloid leukemia ( Liu et al., 2005 ) and polycythemia vera ( Murphy et al., 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Thalidomide for the Treatment of Thrombocytopenia and Hypersplenism in Patients With Cirrhosis or Thalassemia

Chen¹,

Cai²,

Lai

et al. 2020

Front. Pharmacol.

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Hypersplenism and thrombocytopenia are common complications of liver cirrhosis or thalassemia, but current treatment strategies are limited. This study aimed to evaluate the efficacy and safety of thalidomide in the treatment of hypersplenism and thrombocytopenia in patients with liver cirrhosis or thalassemia. A total of 31 patients with hepatic cirrhosis (n=19) or thalassemia (n=12) diagnosed with hypersplenism and thrombocytopenia (platelet count [PLT] <100×10 9 /L) were included in this prospective cohort study between January 2015 and May 2017. Patients were treated with thalidomide (150–200 mg/d) plus conventional therapy. Spleen length, PLT, leukocyte count (WBC), absolute neutrophil count (ANC), and hemoglobin level (Hb) were measured at baseline, 3, 6, and 12 months. Any adverse events were noted. All of the 31 patients were showed a progressive increase PLT during the 12-month follow-up, and similar results were obtained when subgroup analyses were performed based on the primary disease (cirrhosis or thalassemia). WBC, ANC, and Hb also increased progressively during the 12-month follow-up. Spleen length decreased progressively during the follow-up. No serious adverse events occurred. Thalidomide is a potential treatment for thrombocytopenia caused by hypersplenism in patients with cirrhosis or thalassemia.

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Section: Discussionmentioning

confidence: 99%

Thalidomide for the Treatment of Thrombocytopenia and Hypersplenism in Patients With Cirrhosis or Thalassemia

Chen¹,

Cai²,

Lai

et al. 2020

Front. Pharmacol.

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“…VEGF is one of the cytokines involved in the development of angiogenesis[ 50 , 51 ]. Wang et al[ 52 ] found that AG490, a specific antagonist of JAK2, decreased the formation of new blood vessels in the liver by inhibiting the expression of JAK2/STAT3 signaling, which suppressed the activation of HSCs and reduced the expression of VEGF. JAK2/STAT3 signaling may stimulate vascular hyperplasia and decrease vascular tone by increasing the expression of VEGF, thus promoting the development of PHT.…”

Section: Jak2/stat3 Signalingmentioning

confidence: 99%

“…Endogenous angiogenesis and increased eNOS-derived nitric oxide levels in PHT have been considered important in the maintenance of PHT, and JAK2/STAT3 has been reported to promote eNOS protein expression[ 52 , 55 ].…”

Section: Jak2/stat3 Signalingmentioning

confidence: 99%

“…Visceral inflammation is usually present in patients with PHT, especially in those with advanced PHT, and the inflammation can accentuate endothelial dysfunction and angiogenesis[ 56 ]. Relevant studies[ 52 ] have shown that enhanced JAK2/STAT3 signaling accelerates intestinal inflammation in PHT rats by upregulating TGF-β and iNOS expression. These findings suggest that JAK2/STAT3 participates in the pathogenesis of PHT by regulating factors such as VEGF, eNOS, TGF-β and iNOS.…”

Section: Jak2/stat3 Signalingmentioning

confidence: 99%

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Research progress on signaling pathways in cirrhotic portal hypertension

Liu

2018

WJCC

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Portal hypertension (PHT) is an important consequence of liver cirrhosis, which can lead to complications that adversely affect a patient’s quality of life and survival, such as upper gastrointestinal bleeding, ascites, and portosystemic encephalopathy. In recent years, advances in molecular biology have led to major discoveries in the pathological processes of PHT, including the signaling pathways that may be involved: PI3K-AKT-mTOR, RhoA/Rho-kinase, JAK2/STAT3, and farnesoid X receptor. However, the pathogenesis of PHT is complex and there are numerous pathways involved. Therefore, the targeting of signaling pathways for medical management is lagging. This article summarizes the progress that has been made in understanding the signaling pathways in PHT, and provides ideas for treatment of the disorder.

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“…Indeed, the Janus kinase inhibitor AG490 significantly attenuated liver fibrosis in vivo and in vitro and decreased hepatic vascular resistance and portal pressure in cirrhotic rats [210–212]. In contrast to ACEi/ARB, add-on therapy with AG490 to propranolol resulted in an additive portal pressure-lowering effect in cirrhotic animals [213]. Similarly, the Rho-kinase inhibitor Y-27632 decreased fibrosis and lowered portal pressure without major systemic side effects [144,145] in animal studies.…”

Section: Renin–angiotensin–aldosterone Systemmentioning

confidence: 99%

Novel treatment options for portal hypertension

Schwabl

Laleman

2017

Gastroenterology Report

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Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.

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Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis

Abstract: The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment.

Cited by 15 publications

References 35 publications

Thalidomide for the Treatment of Thrombocytopenia and Hypersplenism in Patients With Cirrhosis or Thalassemia

Thalidomide for the Treatment of Thrombocytopenia and Hypersplenism in Patients With Cirrhosis or Thalassemia

Research progress on signaling pathways in cirrhotic portal hypertension

Novel treatment options for portal hypertension

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