Oral administration of cilostazol improves survival rate after rat liver ischemia/reperfusion injury

Fujii, Taku; Obara, Hideaki; Murakami, Kentaro; Fujimura, Naoki; Yagi, Hiroshi; Hibi, Taizo; Abe, Yuta; Kitago, Minoru; Shinoda, Masahiro; Itano, Osamu; Tanabe, Minoru; Masugi, Yohei; Sakamoto, Michiie; Kitagawa, Yuko

doi:10.1016/j.jss.2017.02.020

Cited by 13 publications

(4 citation statements)

References 41 publications

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“…Cilostazol, a selective phosphodiesterase III (PDE III) inhibitor, has been widely used in clinical trials as an anti- platelet drug for the treatment of peripheral vascular diseases [10, 11]. In addition, cilostazol has shown protective effects in various liver injury models including hepatectomy [12], ischemia-reperfusion injury [13] and hepatic steatosis [14]. Very recently, it has been reported that cilostazol exerts protective effects on ethanol-induced hepatocyte damage through suppression of oxidative stress [15].…”

Section: Introductionmentioning

confidence: 99%

Cilostazol protects hepatocytes against alcohol-induced apoptosis via activation of AMPK pathway

et al. 2019

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Alcoholic liver disease (ALD) is a worldwide health problem and hepatocyte apoptosis has been associated with the development/progression of ALD. However, no definite effective pharmacotherapy for ALD is currently available. Cilostazol, a selective type III phosphodiesterase inhibitor has been shown to protect hepatocytes from ethanol-induced apoptosis. In the present study, the underlying mechanisms for the protective effects of cilostazol were examined. Primary rat hepatocytes were treated with ethanol in the presence or absence of cilostazol. Cell viability and intracellular cAMP were measured. Apoptosis was detected by Hoechst staining, TUNEL assay, and caspase-3 activity assay. The roles of cAMP and AMP-activated protein kinase (AMPK) pathways in the action of CTZ were explored using pharmacological inhibitors and siRNAs. Liver from mice received ethanol (5 g/kg body weight) by oral gavage following cilostazol treatment intraperitoneally was obtained for measurement of apoptosis and activation of AMPK pathway. Cilostazol inhibited ethanol-induced hepatocyte apoptosis and potentiated the increases in cAMP level induced by forskolin. However, the anti-apoptotic effect of cilostazol was not reversed by an inhibitor of adenylyl cyclase. Interestingly, cilostazol activated AMPK and increased the level of LC3-II, a marker of autophagy. The inhibition of AMPK abolished the effects of cilostazol on LC3-II expression and apoptosis. Moreover, the inhibition of LKB1 and CaMKK2, upstream kinases of AMPK, dampened cilostazol-inhibited apoptosis as well as AMPK activation. In conclusion, cilostazol protected hepatocytes from apoptosis induced by ethanol mainly via AMPK pathway which is regulated by both LKB1 and CaMKK2. Our results suggest that cilostazol may have potential as a promising therapeutic drug for treatment of ALD.

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Section: Introductionmentioning

confidence: 99%

Cilostazol protects hepatocytes against alcohol-induced apoptosis via activation of AMPK pathway

et al. 2019

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“…Drugs in this category have a description of DILI in a boxed warning or warnings and precautions on the package insert, but have not been verified as the causal drug for DILI ( Chen et al, 2016 ). Additionally, cilostazol has a protective effect on liver injury induced by ischemia-reperfusion or tioacetamide, which is a hepatotoxin ( Joe et al, 2015 ; Fujii et al, 2017 ). Therefore, these drugs do not individually affect the risk of abnormal elevation of ALT.…”

Section: Discussionmentioning

confidence: 99%

Detection of Synergistic Interaction on an Additive Scale Between Two Drugs on Abnormal Elevation of Serum Alanine Aminotransferase Using Machine-Learning Algorithms

et al. 2022

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Drug-induced liver injury (DILI) is a common adverse drug reaction, with abnormal elevation of serum alanine aminotransferase (ALT). Several clinical studies have investigated whether a combination of two drugs alters the reporting frequency of DILI using traditional statistical methods such as multiple logistic regression (MLR), but this model may over-fit the data. This study aimed to detect a synergistic interaction between two drugs on the risk of abnormal elevation of serum ALT in Japanese adult patients using three machine-learning algorithms: MLR, logistic least absolute shrinkage and selection operator (LASSO) regression, and extreme gradient boosting (XGBoost) algorithms. A total of 58,413 patients were extracted from Nihon University School of Medicine’s Clinical Data Warehouse and assigned to case (N = 4,152) and control (N = 54,261) groups. The MLR model over-fitted a training set. In the logistic LASSO regression model, three combinations showed relative excess risk due to interaction (RERI) for abnormal elevation of serum ALT: diclofenac and famotidine (RERI 2.427, 95% bootstrap confidence interval 1.226–11.003), acetaminophen and ambroxol (0.540, 0.087–4.625), and aspirin and cilostazol (0.188, 0.135–3.010). Moreover, diclofenac (adjusted odds ratio 1.319, 95% bootstrap confidence interval 1.189–2.821) and famotidine (1.643, 1.332–2.071) individually affected the risk of abnormal elevation of serum ALT. In the XGBoost model, not only the individual effects of diclofenac (feature importance 0.004) and famotidine (0.016), but also the interaction term (0.004) was included in important predictors. Although further study is needed, the combination of diclofenac and famotidine appears to increase the risk of abnormal elevation of serum ALT in the real world.

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“…Segmental (70%) hepatic warm ischemia was performed under isoflurane (Pfizer Inc.) anesthesia, as previously described 27 . Briefly, an aneurysm clip (Sugita, Tokyo, Japan) was used to clamp the bile duct, portal vein, and hepatic artery of the median and left lobes of the liver.…”

Section: Methodsmentioning

confidence: 99%

Adipose-Derived Mesenchymal Stromal/Stem Cell Line Prevents Hepatic Ischemia/Reperfusion Injury in Rats by Inhibiting Inflammasome Activation

et al. 2022

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Mesenchymal stromal/stem cells (MSCs) have shown potential in the treatment of degenerative diseases, including ischemia/reperfusion injury (IRI), which occurs during organ transplantation and represents the main cause of post-transplant graft dysfunction. However, MSCs have heterogeneous characteristics, and studies of MSCs therapy have shown a variety of outcomes. To establish a new effective MSCs therapy, we developed an adipose-derived mesenchymal stromal/stem cell line (ASCL) and compared its therapeutic effects on primary adipose-derived MSCs (ASCs) using a hepatocyte co-culture model of hypoxia/reoxygenation in vitro and a rat model of hepatic IRI in vivo. The results showed that both ASCL and ASCs protect against hypoxia by improving hepatocyte viability, inhibiting reactive oxygen species release, and upregulating transforming growth factor-β in vitro. In vivo, ASCL or ASCs were infused into the spleen 24 h before the induction of rat hepatic IRI. The results showed that ASCL significantly improved the survival outcomes compared with the control (normal saline infusion) with the significantly decreased serum levels of liver enzymes and less damage to liver tissues compared with ASCs. Both ASCL and ASCs suppressed NOD-like receptor family pyrin domain-containing 3 inflammasome activation and subsequently reduced the release of activated IL-1β and IL-18, which is considered an important mechanism underlying ASCL and ASCs infusion in hepatic IRI. In addition, ASCL can promote the release of interleukin-1 receptor antagonist, which was previously reported as a key factor in hampering the inflammatory cascade during hepatic IRI. Our results suggest ASCL as a new candidate for hepatic IRI treatment due to its relatively homogeneous characteristics.

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Oral administration of cilostazol improves survival rate after rat liver ischemia/reperfusion injury

Cited by 13 publications

References 41 publications

Cilostazol protects hepatocytes against alcohol-induced apoptosis via activation of AMPK pathway

Cilostazol protects hepatocytes against alcohol-induced apoptosis via activation of AMPK pathway

Detection of Synergistic Interaction on an Additive Scale Between Two Drugs on Abnormal Elevation of Serum Alanine Aminotransferase Using Machine-Learning Algorithms

Adipose-Derived Mesenchymal Stromal/Stem Cell Line Prevents Hepatic Ischemia/Reperfusion Injury in Rats by Inhibiting Inflammasome Activation

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