Yosuke Aihara

Nara Medical University, Kashihara, Nara, Japan

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Publications (30)72.07 Total impact

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    ABSTRACT: Ursodeoxycholic acid (UDCA) is considered to be effective in the treatment of nonalcoholic steatohepatitis (NASH), particularly in combination with other pharmacological agents. UDCA reportedly counteracts the effects of endotoxemia. Previously, we demonstrated attenuated hepatic fibrogenesis and suppression of activated hepatic stellate cells (Ac-HSC) with an angiotensin-II (AT-II) type 1 receptor blocker (ARB). Here we evaluated the simultaneous effect of both agents on hepatic fibrogenesis in a rat model of NASH. Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 8 weeks. The therapeutic effect of UDCA and ARB was evaluated along with hepatic fibrogenesis, lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. The direct inhibitory effect of both UDCA and ARB on Ac-HSC was assessed in vitro. Both UDCA and ARB had a potent inhibitory effect on hepatic fibrogenesis with suppression of the HSC activation and hepatic expression of transforming growth factor (TGF)-β1 and TLR4. UDCA decreased intestinal permeability by ameliorating zonula occuludens-1 (ZO-1) disruption induced by the CDAA diet. ARB was found to directly suppress regulation of Ac-HSC. UDCA and ARB have a synergistic repressive effect on hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing the activation of Ac-HSC. Because both agents are currently used in clinical practice, combined UDCA and ARB may represent a promising novel therapeutic approach for NASH.
    No preview · Article · Jul 2015 · Journal of Gastroenterology
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    ABSTRACT: A woman in her 70s with fever and abdominal distension was referred to our hospital for investigation. She had just finished a course of pegylated interferon and ribavirin combination therapy for chronic hepatitis C. Abdominal computed tomography revealed peritoneal thickening and ascites. QuantiFERON(®)-TB Gold was positive, ascitic adenosine deaminase was high, and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed diffuse accumulation in the peritoneum. Although these findings suggested tuberculous peritonitis, we did not detect Mycobacterium tuberculosis in any bacterial cultures, ascites, or other specimens. However, laparoscopic peritoneal biopsy demonstrated a large number of miliary white nodules in the parietal and visceral peritonea. Pathological examination of these nodules revealed epidermoid granuloma with giant Langhans' cells and caseous necrosis. Finally, the diagnosed of tuberculous peritonitis was established. It is important to consider tuberculosis in patients presenting with new symptoms while receiving interferon therapy.
    No preview · Article · Dec 2014 · Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology
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    ABSTRACT: Previous clinical studies have demonstrated that endotoxin/toll‑like receptor 4 (TLR4) signaling is critical in the inflammatory pathways associated with non‑alcoholic steatohepatitis (NASH). In human and animal studies, NASH was associated with portal lipopolysaccharide (LPS) and the plasma LPS level was hypothesized to be associated with small intestinal bacterial overgrowth, change in composition of the microbiota and increased intestinal permeability. The aim of the present study was to investigate the roles of endogenous endotoxin and TLR4 in the pathogenesis of NASH. The effects of antibiotics were assessed in vivo using a choline deficiency amino acid (CDAA)‑induced experimental liver fibrosis model. Antibiotics, including polymyxins and neomycins, were orally administered in drinking water. Antibiotics attenuated hepatic stellate cell (HSC) activation and liver fibrosis via TGF‑β and collagen in an experimental hepatic fibrosis model. The mechanism by which antibiotics attenuated LPS‑TLR4 signaling and liver fibrosis was assessed. Notably, TLR4 mRNA level in the liver was elevated in the CDAA group and the CDAA‑induced increase was significantly reduced by antibiotics. However, no significant differences were observed in the intestine among all groups. Elevated mRNA levels of LPS binding protein, which was correlated with serum endotoxin levels, were recognized in the CDAA group and the CDAA‑induced increase was significantly reduced by antibiotics. The intestinal permeability of the CDAA group was increased compared with the choline‑supplemented amino acid group. The tight junction protein (TJP) in the intestine, determined by immunohistochemical analysis was inversely associated with intestinal permeability. Antibiotics improved the intestinal permeability and enhanced TJP expression. Inhibition of LPS‑TLR4 signaling with antibiotics attenuated liver fibrosis development associated with NASH via the inhibition of HSC activation. These results indicated that reduction of LPS and restoration of intestinal TJP may be a novel therapeutic strategy for treatment of liver fibrosis development in NASH.
    Full-text · Article · Nov 2014 · Molecular Medicine Reports
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    ABSTRACT: Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. Using a non-diabetic rat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.
    No preview · Article · Nov 2013 · Journal of Gastroenterology

  • No preview · Article · Aug 2013 · Cancer Research

  • No preview · Article · Aug 2013 · Cancer Research
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    ABSTRACT: 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). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI) >15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS) >110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions.
    Full-text · Article · May 2013 · Oncology Reports
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    ABSTRACT: 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). Methods: The antifibrotic effect of DPP4-I was assessed in vivo and in vitro using porcine serum-induced experimental liver fibrosis model. DPP4-I, sitagliptin, at a clinically comparable low dose was administered by gavage daily. Results: DPP4-I significantly attenuated liver fibrosis development along with the suppression of hepatic transforming growth factor (TGF)-β1, total collagen, and tissue inhibitor of metalloproteinases-1 in a dose-dependent manner. These suppressive effects occurred almost concurrently with the attenuation of HSCs activation. Our in vitro studies showed that DPP4-I inhibited platelet-derived growth factor-BB-mediated proliferation of the Ac-HSCs as well as upregulation of TGF-β1 and α1(I)-procollagen at magnitudes similar to those of the in vivo studies. The inhibitory effects of DPP4-I against HSCs proliferation and fibrogenic gene expression are mediated through the inhibition of the phosphorylation of ERK1/2, p38 and Smad2/3, respectively. Conclusions: DPP4-I markedly inhibits liver fibrosis development in rats via suppression of HSCs proliferation and collagen synthesis. These suppressive effects are associated with dephosphorylation of ERK1/2, p38 and Smad2/3 in the HSCs. Since DPP4-I is widely used in clinical practice, this drug may represent a potential new therapeutic strategy against liver fibrosis in the near future.
    No preview · Article · Mar 2013 · Journal of Gastroenterology
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    ABSTRACT: AimRenin is a rate-limiting enzyme of the renin-angiotensin system (RAS), and several reports have shown that renin plays an important role in several pathological processes. Although RAS is known to play a pivotal role in the progression of non-alcoholic steatohepatitis (NASH), the role of renin is still obscure. The aim of the current study was to examine the effect of the clinically used direct renin inhibitor (DRI), aliskiren, on the progression of NASH in a rat model. Methods The effects of DRI on the choline-deficient L-amino acid-defined (CDAA) diet-induced rat NASH model was examined in conjunction with the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which are known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. ResultsDRI exerted a marked inhibitory effect against liver fibrosis development and glutathione-S-transferase placental form (GST-P) positive preneoplastic lesions along with suppression of the Ac-HSC and neovascularization in a dose-dependent manner. DRI also inhibited the hepatic expressions of transforming growth factor-beta 1 (TGF-beta 1), angiotensin-II (AT-II) and vascular endothelial growth factor (VEGF). These results indicated that renin played a pivotal role in the liver fibrosis development and hepatocarcinogenesis of NASH. Conclusion Because DRI is already widely used in the clinical practice with safety, this drug may represent a potential new strategy against the progression of NASH in the future.
    No preview · Article · Jan 2013 · Hepatology Research
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    ABSTRACT: Background and aim: The innate immune system, including toll-like receptor-4 (TLR4) signaling cascade and angiotensin-II (AT-II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT-II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT-II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT-II in the rat model of non-alcoholic steatohepatitis. Methods: Fischer 344 rats were fed a choline-deficient, L-amino-acid-defined diet for 8 weeks and the effects of losartan were elucidated in conjunction with activated hepatic stellate cells (Ac-HSC) activation, TLR4, nuclear factor-κB (NF-κB), and transforming growth factor-β (TGF-β) expressions. In vitro study was carried out to elucidate the effect of AT-II on several indices including TLR4, myeloid differentiation factor 88, NF-κB, and TGF-β expressions in the rat HSC. Results: ARB markedly inhibited liver fibrosis development along with suppression of the number of Ac-HSC and TGF-β. These inhibitory effects of ARB were almost in parallel with suppression of the hepatic TLR4 and NF-κB expressions. This in vitro study showed that AT-II significantly augmented the TLR4 expression in a dose- and time-dependent manner via AT-II type 1 receptor in the Ac-HSC. AT-II also augmented the lipopolysaccharide-induced myeloid differentiation factor 88 (MyD88), NF-κB, and TGF-β and these increments were attenuated by treatment with ARB. Conclusions: These studies indicated that the cross talk between TLR4 signaling cascade and AT-II plays a pivotal role in liver fibrosis development in non-alcoholic steatohepatitis.
    Full-text · Article · Jan 2013 · Journal of Gastroenterology and Hepatology
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    ABSTRACT: AimBoth angiotensin‐II (AT‐II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT‐II and Ald with angiotensin‐converting enzyme inhibitor (ACE‐I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE‐I and SAB in the progression of a non‐diabetic rat model of steatohepatitis, and the possible mechanisms involved. Methods In the choline‐deficient L‐amino acid‐defined (CDAA) diet‐induced model, the effects of ACE‐I and SAB on liver fibrosis development and hepatocarcinogenesis were elucidated, especially in conjunction with neovascularization. ResultsTreatment with both ACE‐I and SAB suppressed the development of liver fibrosis and glutathione‐S‐transferase placental form (GST‐P) positive pre‐neoplastic lesions. The combined treatment with both agents exerted more inhibitory effects as compared with either a single agent along with suppression of the activated hepatic stellate cells (Ac‐HSC) and neovascularization, both of which play important roles in these processes. Our in vitro study showed that AT‐II type 1 receptor blocker (ARB) and SAB inhibited Ac‐HSC proliferation and in vitro angiogenesis along with suppression of the in vivo studies. Conclusion Dual blockade of AT‐II and Ald suppresses the progression of a non‐diabetic rat model of steatohepatitis. Because both agents are widely and safely used in clinical practice, this combination therapy could be an effective new strategy against steatohepatitis in the future.
    No preview · Article · Jan 2013 · Hepatology Research
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    ABSTRACT: Aim: Both angiotensin-II (AT-II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT-II and Ald with angiotensin-converting enzyme inhibitor (ACE-I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE-I and SAB in the progression of a non-diabetic rat model of steatohepatitis, and the possible mechanisms involved. Methods: In the choline-deficient L-amino acid-defined (CDAA) diet-induced model, the effects of ACE-I and SAB on liver fibrosis development and hepatocarcinogenesis were elucidated, especially in conjunction with neovascularization. Results: Treatment with both ACE-I and SAB suppressed the development of liver fibrosis and glutathione-S-transferase placental form (GST-P) positive pre-neoplastic lesions. The combined treatment with both agents exerted more inhibitory effects as compared with either a single agent along with suppression of the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which play important roles in these processes. Our in vitro study showed that AT-II type 1 receptor blocker (ARB) and SAB inhibited Ac-HSC proliferation and in vitro angiogenesis along with suppression of the in vivo studies. Conclusion: Dual blockade of AT-II and Ald suppresses the progression of a non-diabetic rat model of steatohepatitis. Because both agents are widely and safely used in clinical practice, this combination therapy could be an effective new strategy against steatohepatitis in the future.
    No preview · Article · Nov 2012 · Hepatology Research
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    ABSTRACT: In this study, we examined the features of patients with advanced unresectable squamous cell carcinoma of the thoracic esophagus in our hospital and validated our strategy of intensive treatment. The average age of our patients was higher than those reported by other facilities and our elderly patients had various kinds of complications. We basically performed either chemoradiation (CRT) or radiation (RT) therapy for these patients with unresectable esophageal cancer. Median survival time of the intensively treated patients with CRT / RT was almost twice longer than those with only best supportive care. An improved food intake was noted in two-thirds of our patients after CRT / RT because of tumor shrinkage. For the less collapsing ratio of CRT, we chose concurrent CRT with low-dose cisplatin (CDDP) plus continuous infusion of 5-fluorouracil (LDFP) especially to elderly patients. Actually, in our hospital, the incidence of hematotoxicity by LDFP was distinctly lower compared with the standard-dose CDDP plus continuous infusion of 5-fluorouracil (SDFP). Additionally, new combination chemoradiotherapy with cisdiammine-glycolate platinum (Nedaplatin) and 5-fluorouracil was given to patients with advanced esophageal cancer and other organ metastasis. Nedaplatin has been known to be less toxic for kidney and digestive organs and to show much stronger antitumor activity compared to CDDP in patients with esophageal cancer. Our overall CRT / RT outcome should be acceptable, if taking patients' ages and their various complications into consideration. We recognized the necessity of making an appropriate medical decision in each elderly patient receiving intensive treatment against unresectable advanced esophageal cancer and of managing adverse effects of CRT / RT promptly for attaining good prognosis and high quality of life.
    No preview · Article · Aug 2012 · Journal of Nara Medical Association
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    ABSTRACT: Sorafenib, a multikinase inhibitor, is the first and only drug, which improves significantly the overall survival in patients with advanced hepatocellular carcinoma (HCC). However, many patients experience diverse side effects, some of them severe and unexpected. To date, acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib. Here, we report the case of a 43-year-old woman with hepatitis C virus-related advanced HCC. She received sorafenib, and later complained of a sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense. Laboratory examination showed mild elevation of transaminases, biliary enzymes, bilirubin, inflammation markers, and a marked peripheral eosinophilia. Abdominal computed tomography (CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris. Consequently, sorafenib treatment was stopped immediately, and steroid-pulse therapy was performed. Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings, eosinophilia, and liver functions. In summary, we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.
    Full-text · Article · May 2012
  • K Kaji · H Yoshiji · Y Ikenaka · R Noguchi · Y Aihara · Y Shirai · A Douhara · H Fukui
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    ABSTRACT: Angiogenesis plays a pivotal role in many pathological processes including chronic liver diseases. Various factors, such as renin-angiotensin-aldosterone system (RAAS), insulin resistance (IR), and reactive oxygen species (ROS) contribute reciprocally to promote angiogenesis. Blockade of RAAS by angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II (AngII) receptor blocker (ARB) markedly attenuates liver fibrosis and hepatocellular carcinoma (HCC) along with suppression of angiogenesis, IR, and ROS. Aldosterone (Ald), a downstream component of AngII, is also involved in these processes, and a selective Ald blocker (SAB) significantly suppressed the progression of chronic liver diseases. The IR status itself has shown to directly accelerate the progression of chronic liver diseases whereas inhibition of ROS by iron chelator suppressed it through augmentation and inhibition of neovascularization. The combination therapy of ACE-I/ARB/SAB with other clinically used agents, such as interferon, imatinib mesylate, vitamin K, iron chelator, and branched-chain amino acids (BCAA) exerted more potent inhibitory effects on the development of liver fibrosis and HCC than the treatment using a single agent alone. Collectively, the anti-angiogenic treatment targeting RAAS, IR, ROS with clinically available agents may become a new therapeutic strategy against the progression of chronic liver diseases.
    No preview · Article · Feb 2012 · Current Medicinal Chemistry
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    ABSTRACT: An effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases. Although enormous efforts are ongoing to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic agents for humans. Insulin resistance (IR) is reportedly involved in the progression of liver fibrosis. The aim of the present study was to evaluate the effect of combination treatment with a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with liver cirrhosis under the condition of IR. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly improved the progression of serum fibrosis markers, whereas single treatment with either BCAA or ACE-I did not exert these inhibitory effects. The plasma level of transforming growth factor-β was significantly attenuated almost in parallel with the suppression of serum fibrosis markers. Furthermore, the combined treatment with BCAA and ACE-I improved the serum albumin level and IR, which was evaluated using the homeostasis model assessment method for IR. Taken together, since both BCAA and ACE-I are widely used with safety in clinical practice, these results indicate that this combination therapy may represent a potential new future strategy against liver fibrosis development in patients with liver cirrhosis under the condition of IR.
    Preview · Article · Nov 2011 · Molecular Medicine Reports
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    ABSTRACT: Sarcoidosis is a chronic multi-systemic granulomatous disease, and liver involvement frequently occurs. in most cases, no evidence of liver dysfunction is observed, and portal hypertension due to sarcoid liver diseases is a rareoccurrence. Moreover, no case of liver sarcoidosis has ever been reported with confirmation of the disease progression. Herein we describe a patient having hepatic sarcoidosis with severe portal hypertension and liver dysfunction. The diagnosis was histologically confirmed from granulomatous status to established liver cirrhosis over 10 years. A 46-year-old woman developed massive hematemesis due to the rupture of gastric cardial varices. She underwent emergency endoscopic injection sclerotherapy, and clear evidence of chronic hepatic failure. Twelve years ago, she was diagnosed as having sarcoidosis with respiratory clinicalsymptoms. Liver biopsy revealed asymptomatic incidental granulomas without fibrosis development. After a couple of years, features of liver dysfunction were manifest and progressed. Ten years after the first biopsy, a second liver biopsy was performed, and well established dense fibrosis was revealed. Although significant liver dysfunction with portal hypertension is rarely seen in sarcoidosis, this case indicates that we have to consider the possibility that sarcoidosis may cause end-stage liver cirrhosis.
    Full-text · Article · Oct 2011 · World Journal of Hepatology
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    ABSTRACT: Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Since neovascularization plays an important role in hepatocarcinogenesis and IR, an angiostatic therapy may be considered as one of the promising approaches for chemoprevention against HCC. The aim of the current study was to examine the combination effect of a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I), both reportedly possess anti-angiogenic and IR-improving activities, on the cumulative recurrence after curative therapy. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered after the curative therapy for HCC, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly inhibited the cumulative recurrence of HCC under IR conditions, whereas neither single treatment exerted a significant inhibition. The soluble form of the vascular endothelial growth factor (VEGF; a central angiogenic factor) receptor-2 (sVEGFR2) was significantly decreased only three months after the treatment without recurrence. We also observed that IR, determined by the homeostasis model assessment (HOMA-IR), was significantly improved by this regimen, indicating that an inhibitory effect was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. In conclusion, since both BCAA and ACE-I are widely used in clinical practice with safety, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC recurrence in the future. Moreover, sVEGFR2 may become a useful clinical predictive marker of this combination treatment.
    No preview · Article · Aug 2011 · Oncology Reports
  • H. Yoshiji · R. Noguchi · Y. Ikenaka · K. Kaji · Y. Aihara · H. Fukui
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    ABSTRACT: Angiogenesis is a complex and critical process essential for supporting the growth of hepatocellular carcinoma (HCC) as well as hepatocarcinogenesis. Recent studies have revealed that renin-angiotensin system (RAS) is involved in many types of cancer including HCC. Some studies have proven that suppression of angiotensin-II (AT-II) by a clinically used angiotensin-converting enzyme inhibitor (ACE-I) significantly attenuated the HCC growth and hepatocarcinogenesis along with down-regulation of a potent angiogenic factor; namely, the vascular endothelial growth factor (VEGF). When used in combination with the clinical available drugs such as interferon (IFN) and vitamin K (VK), ACE-I exerted more potent anti-tumor activities as compared with either single agent in addition to suppression of the intra-tumoral angiogenesis both in experimental models and clinical practice. It is well known that AT-II plays an important role in the insulin resistance (IR), and IR is reportedly involved in the progression of HCC. The combination of ACE-I and branched-chain amino acids (BCAA) exerted a marked chemopreventive effect against HCC under the condition of IR. In addition to AT-II, aldosterone (Ald), which plays a role in the downstream of AT-II, is also involved in the HCC development, and a clinically used selective Ald blocker (SAB) significantly suppressed the HCC growth and hepatocarcinogenesis. Since ACE-I, IFN, VK, BCAA, and SAB are already in widespread clinical use without any serious adverse effects, they may represent a potential new strategy for cancer therapy and chemoprevention against HCC especially in combination with other angiostatic agents.
    No preview · Article · Apr 2011 · Current Cancer Drug Targets
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    ABSTRACT: We report herein a rare case of ileum perforation by fish bone associated with severe manifestations of peritonitis. A 54-year-old man with chronic hepatitis C (CHC) and nephrotic syndrome was admitted into our hospital to receive interferon therapy. A couple of days after admission, he suddenly complained of a severe abdominal pain with diffuse tenderness. Enhanced computed tomography revealed an ileum perforation by a sharp thin object. Since he had severe clinical manifestations of peritonitis, an emergency operation was performed. This surgery revealed an ileum perforation by needle-like material and opaque ascites. Histological examination showed acute mucosal inflammation of the ileum with a fish bone. In most cases, the perforation hole is small, and the main clinical manifestation is usually localized limited abdominal pain but not diffuse tenderness. In these cases, conservative therapies such as endoscopic approach can be selected but not an emergency operation. However, when there is ascites, severe peritonitis can immediately result from leak of several toxic substances such as the ileum juice, endotoxin, and microbacteria into the peritoneal cavity. We have to take into account that even a small perforation by a fish bone may rapidly cause diffuse peritonitis under the condition of ascites such as nephrotic syndrome.
    No preview · Article · Apr 2011 · Journal of Nara Medical Association