Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats.

Background: Dipeptidyl peptidase-4 inhibitor (DPP4-I) is clinically used as a new oral antidiabetic agent. Although DPP4 is reportedly associated with the progression of chronic liver diseases, the effect of DPP4-I on liver fibrosis development is still obscure. This study was designed to elucidate the effect of DPP4-I on liver fibrosis development in conjunction with the activated hepatic stellate cells (Ac-HSCs).

Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development.

An effective therapeutic strategy for suppressing liver fibrosis development should improve the overall prognosis of patients with chronic liver diseases. Despite efforts to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic treatments for humans. An alternative strategy may be to employ a clinically available agent that also exhibits anti-fibrotic activities, for which the safety of long-term administration has been proven.

Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats.

Angiotensin II type I receptor blocker and iron chelator reportedly exert suppressive effects on nonalcoholic steatohepatitis (NASH) progression, including liver fibrosis and hepatocarcinogenesis. The aim of this study was to elucidate the combined effect of losartan (LOS), an angiotensin II type I receptor blocker, and deferasirox (DSX), a newly developed oral iron chelator, on the progression of NASH in rats. To induce NASH, F344 rats were fed a choline-deficient l-amino acid-defined diet for 12 wk, and the effects of LOS and DSX at clinically comparable low doses were elucidated in conjunction with oxidative stress, neovascularization, and hepatic stellate cells (HSC) activation, all known to play important roles in the progression of NASH.

The vascular endothelial growth factor (VEGF) receptor-2 is a major regulator of VEGF-mediated salvage effect in murine acute hepatic failure.

Although administration of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, could improve the overall survival of destroyed sinusoidal endothelial cells (SEC) in chemically induced murine acute hepatic failure (AHF), the mechanistic roles of the VEGF receptors have not been elucidated yet. The respective roles of VEGF receptors; namely, Flt-1 (VEGFR-1: R1) and KDR/Flk-1 (VEGFR-2: R2), in the D-galactosamine (Gal-N) and lipopolysaccharide (LPS)-induced AHF were elucidated with specific neutralizing monoclonal antibody against R1 and R2 (R1-mAb and R2-mAb, respectively). The serum ALT elevation, with a peak at 24 h after Gal-N+LPS intoxication, was markedly augmented by means of the R1-mAb and R2-mAb.

Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats.

Although non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), no effective therapeutic modalities have been fully established yet. Recent studies have shown that the renin-angiotensin-aldosterone-system plays an important role in NASH. The aim of our current study was to elucidate the effects of aldosterone (Ald) inhibition on the progression of NASH.

Selective aldosterone blocker, eplerenone, attenuates hepatocellular carcinoma growth and angiogenesis in mice.

Aim: The renin-angiotensin-aldosterone system (RAAS) has become known as a prerequisite for tumor angiogenesis, including hepatocellular carcinoma (HCC). Although angiotensin II is known to play an important role in tumor growth and angiogenesis, the role of aldosterone (Ald) is still obscure. The aim of our current study was to elucidate the effect of eplerenone, a clinically used selective Ald blocker (SAB), on murine HCC development especially in conjunction with angiogenesis.

Synergistic inhibitory effect of gemcitabine and angiotensin type-1 receptor blocker, losartan, on murine pancreatic tumor growth via anti-angiogenic activities.

Pancreatic cancer is one of the leading causes of cancer death, and represents a challenging chemotherapeutic problem. The crucial role of angiogenesis in tumor growth has been widely recognized, and several reports have revealed that the combination treatment of the conventional chemotherapeutic drugs and anti-angiogenic agents exerted synergistic anti-cancerous effects. It has been reported that the clinically used angiotensin type-1 receptor blocker (ARB) exerted potent anti-angiogenic activity.

Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat.

Background: Apart from simple steatosis, the non-alcoholic steatohepatitis (NASH) can progress into liver fibrosis and cirrhosis. To date, however, no widely accepted therapeutic modalities have been established against NASH in the clinical practice. To find out promising new therapeutic agents, it is important to employ an appropriate experimental model of NASH, such as association with insulin resistance.

Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats.

Background: Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). However, the possible mechanism is still obscure. The aim of the present study was to examine the effect of BCAAs, especially in conjunction with angiogenesis, on hepatocarcinogenesis under the condition of IR.

Impact of insulin resistance on the progression of chronic liver diseases.

Recent studies have revealed a close relationship between insulin resistance (IR) and the progression of chronic liver diseases, although relatively little is known regarding the possible mechanisms involved. The aim of this study was to elucidate the impact of IR on the development of liver fibrosis and hepatocarcinogenesis using obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Liver fibrosis development and glutathione-S-transferase placental form (GST-P)-positive pre-neoplastic lesions were both markedly accelerated in OLETF rats, being induced by pig serum and diethylnitrosamine (DEN), respectively.

Neovascularization and oxidative stress in the progression of non-alcoholic steatohepatitis.

Reactive oxygen species (ROS) is known to play an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH); however, as we previously reported, angiogenesis also plays a pivotal role in NASH progression - the development of liver fibrosis and hepatocellular carcinoma - in rats. The aim of the current study was to elucidate the role of angiogenesis in the development of fibrosis in NASH. Twenty-six patients with NASH and 11 with simple fatty liver (FL) disease were enrolled in the study and underwent clinicopathological examination.

Crosstalk between high-molecular-weight adiponectin and T-cadherin during liver fibrosis development in rats.

Adiponectin, a circulating adipocyte-derived secretory protein, reportedly plays an important role in liver fibrosis development, although the biological role of adiponectin in liver fibrogenesis is still controversial. Adiponectin is present in the serum as three oligometric complexes; namely, high-, middle-, and low-molecular weight (HMW, MMW, and LMW, respectively). Adiponectin exerts different biological activities in an oligomerization-dependent manner.

Synergistic inhibition of hepatocellular carcinoma growth and hepatocarcinogenesis by combination of 5-fluorouracil and angiotensin-converting enzyme inhibitor via anti-angiogenic activities.

Therapies aimed at destruction of the tumor vasculature are now recognized as a promising approach against cancer, and it has been reported that the combination treatment with an angiogenic inhibitor and conventional chemotherapeutic drug exerted synergistic anti-cancerous effects. We previously reported that the clinically used angiotensin-converting enzyme inhibitor (ACE-I) exerted potent-anti-angiogenic activities. The aim of our current study was to examine the combined effect of ACE-I and 5-fluorouracil (5-FU), which is widely used for hepatogastrointestinal tumors, on hepatocellular carcinoma (HCC) growth and hepatocarcinogenesis.

Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats.

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH.

Angiotensin-II and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development.

Both angiotensin-II (AT-II) and vascular endothelial growth factor (VEGF) have been shown to play important roles in the progression of liver fibrosis. However, the interaction of AT-II with VEGF in the liver fibrosis has not been elucidated yet. The aim of the current study was to elucidate a possible association between these molecules, especially in conjunction with the hepatic stellate cells (HSC).

A potent angiogenic factor, vascular endothelial growth factor, improves the survival of the on-going acute hepatic failure in rats.

Although it has been shown that a simultaneous administration of the vascular endothelial growth factor (VEGF); a potent angiogenic factor, could improve the overall survival of chemically induced acute hepatic failure (AHF) in rats, it has not been elucidated yet whether this salvage effect can be observed in the on-going AHF or not. For future clinical application, we examined the effect of VEGF on the on-going AHF. A combination of d-galactosamine (Gal-N) and lipopolysaccharide (LPS) was administered to induce AHF in rats.

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-beta with a combination of imatinib mesylate and ACE inhibitor in rats.

Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are known to be pivotal cytokines in liver fibrosis development. The aim of our current study was to elucidate the effects of dual inhibition of PDGF and TGF-beta by combination of the clinically used imatinib mesylate (STI-571) and perindopril (an ACE-inhibitor; ACE-I), respectively, on ongoing liver fibrosis development in rats. The effects of STI-571 and ACE-I at clinically comparable low doses were examined in a rat model of CCl4-induced liver fibrogenesis.

Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities.

Recent studies have revealed that angiogenesis plays a pivotal role in carcinogenesis and tumor growth. We previously reported that the clinically used vitamin K(2) (VK) and angiotensin-converting enzyme inhibitor (ACE-I) exerted potent anti-angiogenic activities. The aim of our current study was to examine the combination effect of VK and ACE-I on hepatocarcinogenesis induced by diethyl-nitrosamine, and orthotopic hepatocellular carcinoma (HCC) growth in rats.

Salvage effect of the vascular endothelial growth factor on chemically induced acute severe liver injury in rats.

Background/aims: The role of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, in liver regeneration following acute severe liver injury (ALI) has not been elucidated. The aims of the current study were to investigate the role of VEGF, and to find out whether VEGF can improve the outcome of ALI in rats.

Methods: ALI was induced in male rats by combination of D-galactosamine (Gal-N) and lipopolysaccharide (LPS).

Suppression of renin-angiotensin system attenuates hepatocarcinogenesis via angiogenesis inhibition in rats.

Recent studies have shown that the renin-angiotensin system (RAS) as well as angiogenesis is involved in tumor development. The aim of the present study was to examine the interaction of RAS, angiogenesis and a potent angiogenic factor, namely the vascular endothelial growth factor (VEGF), in the hepatocarcinogenesis process. In a diethylnitrosamine-induced rat hepatocarcinogenesis model, a clinically used angiotensin-converting enzyme inhibitor, perindopril (PE), significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions along with inhibition of neovascularization in the liver.

Combination of copper-chelating agent, trientine, and methotrexate attenuates colorectal carcinoma development and angiogenesis in mice.

Recent studies have suggested that an anti-angiogenic agent could improve the inhibitory effects of standard chemotherapeutic drugs against tumor development. We previously reported that the clinically used copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited tumor growth. The aim of the current study was to examine the combined effect of trientine and methotrexate on the development and angiogenesis of xenograft human colorectal carcinoma (CRC) cells at clinically comparable low doses.

Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression.

Background/aims: Chemoprevention should be a promising approach to improve the prognosis of the patients with hepatocellular carcinoma (HCC). Angiogenesis is now recognized as a crucial step not only in tumor growth, but also in early carcinogenesis. The aim of this study was to elucidate the combination effect of the clinically used vitamin K(2) (VK) and the angiotensin-converting enzyme inhibitor, perindopril (PE), on hepatocarcinogenesis, especially in conjunction with angiogenesis.

Different cascades in the signaling pathway of two vascular endothelial growth factor (VEGF) receptors for the VEGF-mediated murine hepatocellular carcinoma development.

It has been shown that the interaction between the potent angiogenic factor; the vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2), plays a pivotal role in tumor development, including hepatocellular carcinoma (HCC). However, the properties of the respective VEGF receptor in the signaling transduction pathway of VEGF-mediated effects in HCC have not been elucidated yet. The aim of this study was to examine the respective signaling pathway of two VEGFRs in the VEGF-mediated murine HCC development and angiogenesis.

Combination of interferon and angiotensin-converting enzyme inhibitor, perindopril, suppresses liver carcinogenesis and angiogenesis in mice.

Angiogenesis is now recognized as playing a pivotal role in hepatocarcinogenesis. The aim of our current study was to examine the combination effect of the clinically used interferon-beta (IFN) and angiotensin-converting enzyme inhibitor, perindopril (PE), on hepatocarcinogenesis induced by diethylnitrosamine, especially in conjunction with angiogenesis. Single treatment with either IFN or PE significantly attenuated the development of hepatocellular carcinoma (HCC), and the combination of IFN and PE nearly abolished hepatocarcinogenesis.