Caspase-3 In Liver Tissue Research Articles

Retinoic Acid Potentiates the Therapeutic Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) against Cisplatin-Induced Hepatotoxicity in Rats

(1) Background: Hepatotoxicity is a common health problem, and oxidative stress plays a crucial role in its underlying mechanisms. We inspected the possible effect of retinoic acid (RA) in the potentiation of hepatoprotective effect of bone marrow mesenchymal stem cells (BM-MSCs) against Cisplatin (Cis)-induced hepatotoxicity. (2) Methods: 60 male Sprague Dawley rats (SD) were separated randomly and designated to six main equal groups as follows: (1) Control group, (2) Cis group (rats got Cis 7 mg/Kg i.p.), (3) Cis + vehicle group (as group 2, but rats received the (vehicle) culture media of BM-MSCs), (4) Cis as in group 2 + BM-MSCs (1x106), (5) Cis as for group 2 + RA 1 mg/Kg i.p., and (6) Cis and BM-MSCs as for group 3 + RA as for group 4. Liver injury was assessed by measuring liver enzymes (ALT, AST), while liver toxicity was evaluated by histopathological examination. Apoptotic marker caspase-3 protein was detected immunohistochemically. Real time PCR was performed to detect NADPH oxidase and TNF-α at transcription levels. Oxidative stress was investigated by colorimetric measurement of MDA, GSH and catalase. (3) Results: Contrary to the Cis group (p < 0.05), BM-MSCs/RA supplementation resulted in a substantial decrease in serum levels of hepatic impairment indicators such as ALT, AST and oxidative stress markers such as MDA, as well as an increase in hepatic GSH, Catalase, and a decrease in expression of TNF-α and downregulation of NADPH oxidase. The improvement after therapy with BM-MSCs/RA was confirmed by histopathological examination. Moreover, the downregulation of caspase-3 in liver tissue after BM-MSCs/RA treatment was validated by immunohistochemistry investigation. (4) Conclusions: BM-MSCs and RA attenuated Cis induced hepatotoxicity through downregulation of oxidative stress resulted in modulation of anti-inflammatory TNF-α and apoptosis caspase-3 indicating a promising role in hepatotoxicity.

Combined resveratrol and vitamin D treatment ameliorate inflammation-related liver fibrosis, ER stress, and apoptosis in a high-fructose diet/streptozotocin-induced T2DM model.

A high fructose diet is a major cause of diabetes and various metabolic disorders, including fatty liver. In this study, we investigated the effects of resveratrol and vitamin D (VitD) treatments on endoplasmic reticulum (ER) stress, oxidative stress, inflammation, apoptosis, and liver regeneration in a rat model of type 2 diabetes mellitus, namely, T2DM Sprague-Dawley rats. This T2DM rat model was created through a combination treatment of a 10% fructose diet and 40mg/kg streptozotocin (STZ). Resveratrol (1mg/kg/day) and VitD (170/IU/week) were administered alone and in combination to both the diabetic and control groups. Immunohistochemical staining was performed to evaluate PCNA, NF-κB, TNF-α, IL-6, IL-1β, GRP78, and active caspase-3 in liver tissue. The TUNEL method and Sirius red staining were used to determine apoptosis and fibrosis, respectively. G6PD, 6-PGD, GR, and GST activities were measured to determine oxidative stress status. We found that the expressions of cytokines (TNF-α, IL-6, and IL-1β) correlated with NF-κB activation and were significantly increased in the T2DM rats. Increased GRP78 expression, indicating ER stress, increased in apoptotic cells, enhanced caspase-3 activation, and collagen accumulation surrounding the central vein were observed in the T2DM group compared with the other groups. The combination VitD + resveratrol treatment improved antioxidant defense via increasing G6PD, 6-PGD, GR, and GST activities compared to the diabetic groups. We concluded that the combined administration of resveratrol with VitD ameliorates the adverse effects of T2DM by regulating blood glucose levels, increasing antioxidant defense mechanisms, controlling ER stress, enhancing tissue regeneration, improving inflammation, and reducing apoptosis in liver cells. In conclusion, this study indicates that the combination treatment of resveratrol + VitD can be a beneficial option for preventing liver damage in fructose-induced T2DM.

Research on Mechanism of Superparamagnetic Iron Oxide Nanoparticles in Activating Endoplasmic Reticulum and Prompting Apoptosis of Liver Cells Through Mediation of Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1 (TNF-α/TNFR1) Pathway

The aim of this study was to assess mechanism of superparamagnetic iron oxide nanoparticles (SPIO-NPs) in activating endoplasmic reticulum (ER) and prompting apoptosis of liver cells through mediating the TNF-α/TNFR1 pathway. The SPIO-NPs were prepared and identified, and HegG2 cells were cultivated in vitro, and their apoptosis was detected. The specific pathogen-free (SPF)-grade rats were divided into several groups; which included blank group, low concentration group, high concentration group and control group. The enzymatic activity of Caspase-3 in liver tissue was tested, and expressions of Caspase-3, Bax, Bcl-2, TNF-α, p-TNFR1, IRE1α, and eIF2α were tested. The size of prepared SPIO-NPs was 7.5 nm and there was no coagulation. There was good dispersity and electric potential, and appearance was stable. The apoptotic rate in the high concentration group was notably higher than in the other groups. There was notable inflammatory cell infiltration in the high concentration group, where quantity of apoptosis was highest. The quantity of apoptosis and fluorocyte in the high concentration group were notably higher than in the other groups. Moreover, there were over expressions of Caspase-3, Bax, Caspase-3, p-TNFR1, IRE1α, and eIF2α in the high concentration group while the expression of TNF-α was lowest. The apoptosis of HegG2 cells was prompted by SPIO-NPs, and quantity of apoptosis was increased with increased adopted concentration. The active expression of p-TNFR1, IRE1α, and eIF2α could be prompted to reduce the expression of TNF-α and increase the expression of Caspase-3 and Bax for prompting the apoptosis.

Loss of RAR-α and RXR-α and enhanced caspase-3-dependent apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent.

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in N-acetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase-3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

Effect of Spatholobi Caulis Extract in Acute Liver Injury

This study aimed to examine the protective effect of the water extract from Spatholobi Caulis (SC) on rats with acute liver injury (ALI) induced by thioacetamide (TAA) and its underlying mechanism. ALI was induced by intraperitoneal injection with TAA for 3 days in a row and the rats were administered SC (100 or 200 mg/kg) 1 h 30 min prior to the TAA treatment. Myeloperoxidase (MPO) was measured in serum and malondialdehyde (MDA) was measured in serum and liver tissue, as markers related to oxidative stress. Further, inflammation-related proteins and apoptosis proteins were investigated using western blot analysis. SC treatment significantly reduced the levels of MPO and MDA. Further, SC treatment significantly reduces the mitogen-activated protein kinase (MAPK) signaling pathway, including p-JNK, p-ERK, and p-p38, and reduces the expression of pro-inflammatory signaling factors. Furthermore, it effectively decreased the expression of Bax, Cytochrome C, and Cleaved Caspase-3 in liver tissue. Taken together, SC treatment alleviate0d the severity of ALI via inhibition of inflammation through both the MAPK pathway and Matrix metalloproteinase (MMPs)-dependent apoptosis.

Protective effect of Ginseng Guipi Pill on liver injury in rats with spleen failing to control blood syndrome and its mechanism

Objective: To investigate the therapeutic effect of Ginseng Guipi pill on rats with spleen failing to control blood syndrome and its effect on liver. Methods: Forty SPF male Sprague-Dawley rats were randomly divided into normal control group (n=10) and experimental group (n=30). For the first 42 days, the experimental group swam for 30 minutes every day, eating for one day and fasting for two days (diet disorder). On the 43rd to 72nd day, the rats were injected with low-molecular-weight heparin calcium to induce hemorrhage on the basis of exhaustion of swimming and diet disorder to construct a rat model of spleen failing to control blood syndrome. Those thirty rat that successfully established the model were randomly divided into 3 groups (n=10), model control group (MD), natural rehabilitation group (NR) and Guipi Pill group (GP). On the 73rd to 103rd day, the MD group continued to apply factors (exhausted swimming, eating disorder, and injection of low-molecular-weight heparin calcium), the NR group and the GP group stopped applying the factors , the GP group was daily administered with Ginseng Guipi Pill solution (0.2 g/ml, 10 ml/(kg·d)) , and the NR group was given an equal dose of saline. After the 103 days, blood and liver samples were collected, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and total protein (TP) content were detected, the number of red blood cells (RBC), hemoglobin (HGB) content and hematocrit (HCT) were detected, the expressions of IL-6 and TNF-α in serum were determined by ELISA kit, the levels of apoptosis-related proteins Bcl-2, Bax and Caspase3 in liver tissue were detected by Western blot. The expression levels of apoptosis-related proteins Bcl-2, Bax and Caspase3 mRNA in liver tissue were detected by real-time PCR. Results: Compared with the control group, the serum levels of ALT, AST and TBil in the model group were increased significantly, while the serum level of TP was reduced significantly (P＜0.01), the number of RBC, HGB content and HCT were decreased significantly (P＜0.01), the expressions of IL-6 and TNF-α in serum were increased (P＜0.05), the Bcl-2 protein and mRNA levels were reduced, Bax and Caspase3 protein and mRNA levels were increased significantly (P＜0.01); Compared with the model group, the serum levels of ALT, AST and TBil were significantly lower in the natural rehabilitation group and the Guipi Pill group, the level of TP was increased significantly (P＜0.01), the blood RBC, HGB and HCT were increased significantly (P＜ 0.01), the expressions of IL-6 and TNF-α were decreased (P＜0.05), the levels of Bcl-2 protein and mRNA were increased significantly, the Bax, Caspase3 protein and mRNA levels were decreased (P＜0.05); Compared with the natural rehabilitation group, the serum levels of ALT, AST and TBil were reduced , and the TP content was increased significantly in the Guipi Pill group (P＜ 0.01), the number of RBC was increased significantly in the Guipi Pill group (P＜0.05), the levels of Bcl-2 protein and mRNA were increased (P＜0.05),the level of Caspase3 protein was decreased (P＜0.05), the expression of Bax mRNA was reduced significantly (P＜0.05). Conclusion: Ginseng Guipi Pill has protective effect on liver injury in rats with spleen failing to control blood syndrome. The mechanism may be related to the inhibition the liver cell apoptosis and the release of pro-inflammatory cytokines.

The Impact of L-Carnitine and Coenzyme Q10 as Protection Against Busulfan-Oxidative Stress in the Liver of Adult Rats

Background: Busulfan (Bu) is an anticancer drug with a variety of adverse effects for cancer patients. Oxidative stress has been considered as a common pathological mechanism and it has a key role in the initiation and progression of liver injury by Bu. Aim: The study aimed to evaluate the antioxidant impact of L-Carnitine and Coenzyme Q10 and their protective role against oxidative stress damage in liver tissues. Methods and Material: Thirty-six albino rats were divided equally into six groups. G1 (con), received I.P. injection of DMSO plus 1 ml of distilled water daily by oral gavages; G2 (Bu), received I.P. injection of Bu plus 1 ml of the distilled water daily; G3 (L-Car), received 1 ml of L-Car orally; G4 (Bu + L-Car) received I.P. injection of Bu plus 1 ml of L-Car, G5 (CoQ10) 1 ml of CoQ10 daily; and G6 (Bu + CoQ10) received I.P. injection of Bu plus 1 ml of CoQ10 daily. Results: The recent data showed that Bu induced significant (P<0.05) elevation in serum ALT, AST, liver GSSG, NO, MDA and 8-OHDG, while showing significant (P<0.05) decrease in liver GSH and ATP. On the other hand, L-Carnitine and Coenzyme Q10 ameliorated the negative effects prompted by Bu. Immunohistochemical expression of caspase-3 in liver tissues reported pathological alterations in Bu group while also showed significant recovery in L-Car more than CoQ10. Conclusion: L-Car, as well as CoQ10, can enhance the hepatotoxic effects of Bu by promoting energy production in oxidative phosphorylation process and by scavenging the free radicals.

Effect of oxycodone preconditioning on mitochondrion-dependent apoptosis in liver cells during intestinal ischemia-reperfusion in rats

Objective To evaluate the effect of oxycodone preconditioning on mitochondrion-dependent apoptosis in liver cells during intestinal ischemia-reperfusion (I/R) in rats. Methods Fifty-four healthy male Sprague-Dawley rats, weighing 200-300 g, were divided into 9 groups (n=6 each) using a random number table: sham operation group (group S), I/R group, oxycodone preconditioning group (group OP), μ receptor blocker CTOP group (group CTOP), δ receptor blocker naltrindole (NTD) group (group NTD), κ receptor blocker nor-binaltorphimne (BNI) group (group BNI), CTOP plus oxycodone preconditioning group (group CTOP+ OP), NTD plus oxycodone preconditioning group (group NTD+ OP), and BNI plus oxycodone preconditioning group (group BNI+ OP). The model of intestinal I/R was established by occluding the superior mesenteric artery for 45 min followed by 2 h reperfusion.Oxycodone 0.5 mg/kg was injected intravenously at 10 min prior to ischemia in OP, COTP+ OP, NTD+ OP and BNI+ OP groups.COTP 1 mg/kg and NTD 5 mg/kg were injected intravenously at 20 min prior to ischemia in COTP+ OP and NTD+ OP groups, respectively.BNI 5 mg/kg was injected intravenously at 25 min prior to ischemia in group BNI+ OP.CTOP 1 mg/kg and NTD 5 mg/kg were injected intravenously at 10 min prior to ischemia in CTOP and NTD groups, respectively.BNI 5 mg/kg was injected intravenously at 15 min prior to ischemia in group BNI.The superior mesenteric artery was only exposed but not occluded in group S. The rats were sacrificed at 2 h of reperfusion, and livers were removed for determination of apoptosis in liver cells (using TUNEL) and expression of Bcl-2 and caspase-3 in liver tissues (by immunohistochemistry). The apoptosis index (AI) was calculated. Results Compared with group S, AI was significantly increased, the expression of Bcl-2 was down-regulated and the expression of caspase-3 was up-regulated in the other eight groups (P<0.05). Compared with group I/R, AI was significantly decreased, the expression of Bcl-2 was up-regulated, and the expression of caspase-3 was down-regulated in group OP (P<0.05). Compared with group OP, AI was significantly increased, Bcl-2 expression was down-regulated, and caspase-3 expression was up-regulated in COTP+ OP, NTD+ OP and BNI+ OP groups (P<0.05). Conclusion The mechanism by which oxycodone preconditioning activates μ, δ and κ receptors and reduces intestinal I/R injury may be related to inhibiting mitochondrion-dependent apoptosis in rats. Key words: Oxycodone; Reperfusion injury; Intestines; Hepatocytes; Apoptosis; Mitochondria

Protective effects of a traditional Chinese herbal formula Jiang-Xian HuGan on Concanavalin A-induced mouse hepatitis via NF-κB and Nrf2 signaling pathways

Ethnopharmacological relevanceJiang-Xian HuGan (JXHG) formulated by five natural products including Freshwater clam (Corbicula fluminea), Curcuma longa L., Ligustrum lucidum, Eclipta prostrata (L.) L. and Paeonia lactiflora Pall., has exhibited a great hepatoprotective effect. Aim of this studyWe investigated the effect of JXHG on concanavalin A (ConA)-induced acute live injury in mice, and to elucidate its underlying molecular mechanisms. Materials and methodsJiangkanling Capsule (900 mg/kg), low-dose JXHG (LJXHG, 700 mg/kg), high-dose JXHG (HJXHG, 1400 mg/kg) were administered to mice by oral gavage daily for 20 days prior to a single intravenous injection of ConA (20 mg/kg). Liver injury was evaluated by measuring the serum levels of enzymes and cytokines as well as liver histological analysis. We also measured the hepatic expression of cytokines at mRNA levels and the proteins related to NF-κB and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathways. ResultOur results showed that JXHG pretreatment significantly alleviated ConA-induced live injury as evidenced by decreased serum levels of glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST), and reduced hepatocyte apoptosis and mortality. Furthermore, JXHG was able to significantly reduce the serum levels of proinflammatory cytokines, down-regulate the mRNA expression of interleukin-6 (IL-6) and interferon-γ (IFN-γ), and up-regulate IL-10 as well as superoxide-dimutase-1 (SOD1), glutathione reductase (GSR) and Glutathione peroxidase 2 (GPX2) mRNA in the liver tissues after Con A injection. In addition, JXHG pretreatment dramatically suppressed the phosphorylation of NF-κB p65 (p65), increased Nrf2 expression, and decreased the expression ratio of cleaved caspase-3/caspase-3 in liver tissues. ConclusionThese results suggest that JXHG protects against ConA-induced acute live injury through inhibiting NF-κB mediated inflammatory pathway and promoting Nrf2 mediated anti-oxidative stress signaling pathway.

The influence and mechanism research of bamboo leaf flavone on hepatic ischemia- reperfusion injury in rats

Objective To explore the protective effect of bamboo leaf flavone in hepatic ischemia-reperfusion injury (HIRI). Methods SD rats were divided into the sham group, the HIRI group and the bamboo leaf flavone intervention group. Rats in bamboo leaf flavone intervention group received bamboo leaf flavone (30 mg/kg) by intraperitoneal injection for 14 consecutive days before establishing the model of hepatic ischemia-reperfusion. Rats in the sham group and the HIRI group received the same volume normal saline. The serum alanine aminotransferase (ALT) and aspertate aminotransferase (AST) were detected. The serum IL-1, IL-6 were detected by ELISA. The expression of caspase-3 in liver tissue was detected by the Western Blot. Results Compared to the HIRI group, the ALT (215.31 ± 52.21 U/L vs. 343.11 ± 78.32 U/L), AST (501.59 ± 70.13 U/L vs. 863.97 ± 63.58 U/L), IL-1 (315.30 ± 88.64 U/L vs. 596.85 ± 102.34 U/L), IL-6 (106.75 ± 10.25 U/L vs. 183.64 ± 20.69 U/L) in the bamboo leaf flavone intervention group significantly decreased (P<0.05). Compared to the HIRI group, expression of caspase-3 (0.38 ± 0.05 vs. 0.86 ± 0.09) in the bamboo leaf flavone intervention group significantly decreased (P<0.05). Conclusions Bamboo leaf flavone pretreatment could reduce HIRI and the mechanism may be associated with inhibiting the expression of caspase-3 protein. Key words: Reperfusion injury; Bamboo leaf flavone; Caspase-3; Rats

The Effect of Silver Nanoparticles on the Biochemical Parameters of Liver Function in Serum, and the Expression of Caspase-3 in the Liver Tissues of Male Rats

Background: Silver nanoparticles have antibacterial properties and their use is growing in different industries. Since the toxicity of nanosilver is not well known, it is essential to examine its safety. Objectives: This experiment was undertaken to study the effects of nanosilver on rat liver function with an evaluation of blood biochemistry parameters and caspase-3 expression in the liver. Materials and Methods: In this experimental study, 40 adult male Sprague-Dawley rats were divided into five groups. In the four experimental groups, nanosilver particles were given orally for 28 consecutive days at doses of 30, 125, 300, or 700 mg/kg. Rats in the control group received equal volumes of deionized water. To evaluate the expression of caspase-3 in liver tissue, the real-time PCR method was used. Albumin, total protein, total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were measured with an RA-1000 autoanalyzer. Results: The results indicated that caspase-3 was upregulated in the treated groups compared to the control group (P 0.05). Conclusions: Based on the present study, it can be concluded that oral administration of silver nanoparticles for 28 days had no effect on rat liver function, but probably led to early apoptotic stages.

Glutamyl cysteine dipeptide suppresses ferritin expression and alleviates liver injury in iron-overload rat model.

Despite its biological importance, iron is a pro-oxidant element and its accumulation results in tissue injury. Iron overload diseases such as thalassemia and hereditary hemochromatosis are commonly associated with liver tissue injury. Glutamyl cysteine (GC) is a dipeptide with antioxidant properties owing to its cysteine residue. The aim of the current work was to investigate the hepatoprotective effect of GC against iron overload-induced liver injury. Rats were distributed into five groups; normal control, GC control, iron-treated (150 mg/kg ip injection) and both iron and GC-treated (total iron: 150 mg/kg ip and GC: 50 mg or 100 mg/kg/day ip for 30 days). Our results showed that treatment with GC at the two-dose levels attenuated iron-induced liver tissue injury as evidenced by significant reduction in serum activity of liver enzymes ALT and AST, amelioration of iron-induced histopathological alteration, suppression of iron-induced oxidative stress as demonstrated by significant reduction of malondialdehyde and protein carbonyl content beside elevation of total antioxidant capacity, reduced glutathione and the antioxidant enzymes GPx and SOD in liver tissue. In addition, GC significantly reduced levels of the proinflammatory cytokines TNF-α, IL-6 and IL-1β and activity of the apoptotic marker caspase-3 in liver tissues. To our surprise, GC reduced liver iron content and ferritin expression, denoting the possible iron chelation competency. Collectively our results highlight evidence for the hepatoprotective effect of GC against iron overload-induced liver injury that is potentially mediated through suppression of oxidative tissue injury, attenuation of inflammatory response, amelioration of hepatocellular apoptosis and possibly through iron chelation.

The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

The aim of the study was to investigate the ameliorative effects and the mechanism of action of l-2-oxothiazolidine-4-carboxylate (OTC) on acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC) as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH) production and glutathione peroxidase (GSH-px) activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

Therapeutic role of telmisartan against acetaminophen hepatotoxicity in mice

The therapeutic potential of telmisartan was investigated in mice exposed to acute hepatotoxicity induced by a single dose of acetaminophen (500mg/kg, p.o.). Telmisartan treatment (two i.p. injections, 10mg/kg, each) was given at 1 and 12h following acetaminophen administration. Telmisartan significantly reduced the level of serum alanine aminotransferase, and suppressed lipid peroxidation, prevented the depletion of the antioxidant defenses (reduced glutathione level, and catalase and superoxide dismutase activities), and attenuated the elevation of nitric oxide resulted from acetaminophen administration. Also, telmisartan ameliorated the histopathological liver tissue damage induced by acetaminophen. Immunohistochemical analysis revealed that telmisartan significantly decreased the expression of inducible nitric oxide synthase, tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-κB and caspase-3 in liver tissue of mice received acetaminophen overdose. In conclusion, telmisartan can be considered as a potential therapeutic option to protect against acute acetaminophen hepatotoxicity commonly encountered in clinical practice.

Telmisartan treatment attenuates arsenic-induced hepatotoxicity in mice

The protective effect of telmisartan, the angiotensin II-receptor antagonist, against liver toxicity induced by sodium arsenite (5mg/kg/day, p.o., for 30 days) was investigated in mice. Telmisartan treatment (10mg/kg/day, p.o.) was applied for 30 days, starting on the same day of arsenic administration. Telmisartan significantly reduced serum alanine aminotransferase level which was increased by sodium arsenite. Telmisartan significantly suppressed lipid peroxidation, and prevented the reduced glutathione depletion and nitric oxide elevation in the liver tissue resulted from arsenic administration. Also, the increase of arsenic ion, and the reductions of selenium and zinc ions in liver tissue were attenuated by telmisartan. Histopathological examination showed that liver tissue injury mediated by arsenic was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the arsenic-induced expression of inducible nitric oxide synthase, tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-κB and caspase-3 in liver tissue. It was concluded that telmisartan may represent a potential option to protect the liver tissue from the detrimental effects of arsenic toxicity.

Different Protection Mechanisms after Pretreatment with Glycine or α-Lipoic Acid in a Rat Model of Warm Hepatic Ischemia

Background/Aim: α-Lipoic (LA) acid pretreatment has previously been described to reduce ischemia/reperfusion injury (IRI) after warm liver ischemia, whereas glycine pretreatment has been shown to be protective mostly in models of cold hepatic ischemia. The aim of this study was to determine whether glycine decreases IRI after warm hepatic ischemia. Furthermore we investigated whether doses of LA other than those used previously are also protective against IRI after warm hepatic ischemia. Methods: Selective liver ischemia was maintained over a period of 90 min. In long-term as well as short-term experiments we studied IRI in several groups comparing animal survival as the pivotal endpoint. Results: Animal survival was improved by glycine and 5,000 µmol LA, whereas all animals died within 3 days after pretreatment with 50 µmol LA. In the glycine group we observed a tendency towards decreased apoptosis-related cell death measured by the activity of caspase-3 in liver tissue and the percentage of TUNEL-positive hepatocytes in comparison to the untreated group. Serum α-glutathione S-transferase, lipid peroxidation, and caspase-3 activity as well as the percentage of TUNEL-positive hepatocytes and the percentage of liver necrosis were only significantly decreased by 5,000 µmol LA pretreatment. Liver tissue levels of tumor necrosis factor (TNF)α were reduced only in the glycine group whereas TNFα was increased in the untreated as well as the LA group. Levels of TNFα mRNA were upregulated in both the glycine- and LA-pretreated groups. Conclusion: Our data show that increased animal survival by glycine was accompanied by a reduced TNFα content in liver tissue. Protection by glycine is likely to result from a reduction in adverse TNFα effects. Administration of high-dose LA on the other hand led to a significant reduction in necrosis- and apoptosis-related cell death in IRI of the liver without a reduction in liver TNFα.