Protective mechanisms of piperine against acetaminophen-induced hepatotoxicity may be mediated through TGFBRAP1.

OBJECTIVE: To investigate the possible protective mechanisms of piperine against acetaminophen (APAP)-induced hepatotoxicity in mice. MATERIALS AND METHODS: Mice were given APAP (650 mg/kg i.p. once) with or without pretreatment with piperine (50 mg/kg/day orally for 3 days). RESULTS: APAP caused liver toxicity as indicated by increased serum alanine aminotransferase and liver microscopic pathology, decreased hepatic superoxide dismutase and glutathione reductase activities, without affecting nuclear factor erythroid 2-related factor 2 (Nrf2) expression. APAP administration induced inflammation and apoptosis manifested as increased NF-κB p65 and dysregulation of caspase 3/Bcl2 expression, respectively. In addition, APAP increased the expression of transforming growth factor-ß receptor-associated binding protein 1 (TGFBRAP1). On the other hand, pretreatment with piperine improved liver function and structure, reserved hepatic antioxidative defense, and attenuated inflammatory and apoptotic markers. Interestingly, piperine administration enhanced hepatic TGFBRAP1 expression compared to APAP alone. CONCLUSIONS: The hepatoprotective effects of piperine against APAP are mediated via its antioxidant, anti-inflammatory, and anti-apoptotic effects, in addition to regulation of TGFBRAP1.

New pathways driving the experimental hepatoprotective action of tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) against acute hepatotoxicity.

PURPOSE: In absence of liver protective drugs, a large number of hepatopathies may arise during drug administration. This study was executed to investigate the possible new pathways underlying the hepatoprotective effect of Tempol (4-hydroxy-2,2,6,6- tetramethylpiperidine-1-oxyl), following oral administration of carbon tetrachloride in mice. METHODS AND RESULTS: Thirty albino mice were randomized into 3 equal groups. The duration of study was 28 days. The groups were classified as follows: Group I (healthy control): received saline, in the same volume of CCl4 dose, daily, orally, for 14 days, then sacrificed. Group II: received CCl4, as a single oral dose only, of 1 ml/kg body weight, dissolved in olive oil (1:1 v/v), the animals of this group were sacrificed 14 days after CCl4 single dose intoxication. Group III (protective Tempol treated): received a single dose of Tempol, 20mg/kg, orally, daily for 14 days. Two hours after the last Tempol dose, animals of group III received a single oral dose of CCl4. Fourteen days later, animals were scarified to collect blood and liver tissues for analysis. Tempol pretreatment significantly captured elevated levels of ALT and AST activities, lipid peroxidation, total bilirubin and increased total thiol and catalase contents. Notably, it significantly reduced the expression of tumor necrosis factor-alpha (TNF-α), Caspase-3 and endoplasmic reticulum (ER) inositol-requiring enzyme 1(IRE1) mRNAs, which is an ER trans membrane sensor that activates the unfolded protein response (UPR) to maintain the ER and cellular function. CONCLUSION: Pretreatment with Tempol has potential hepatoprotective effects against acute liver injury, induced by CCl4, through antioxidant and anti-inflammatory activities.

The effect of co-administration of Lawsonia inermis extract and octreotide on experimental hepatocellular carcinoma.

OBJECTIVES: To investigate the effect of Lawsonia inermis total methanolic extract (LIE) and octreotide (OC) on hepatocellular carcinoma (HCC) progression, depending on somatostatin receptor 2 (SSTR-2) and Alfa fetoprotein (AFP) perturbations. METHODS: Sixty albino mice, divided into five groups (12/each); all except control were injected with single diethyl nitrosamine (DENA) dose of 90 mg/kg body weight, intraperitoneally (IP). DENA group was killed at the last day of week 18. LIE group was given 200 mg/100 ml drinking water from first day of DENA injection until end of week 18. OC group received OC (0.1 mg/kg body weight, twice daily by subcutaneous injection, SC from the first day of week 17 till end of week 18. LIE + OC was given medications till the last day of week 18. Serum AFP, liver tissue SSTR-2 mRNA, its protein expression, reduced glutathione (GSH) and malondialdehyde (MDA) were analyzed. RESULTS: A significant increase in plasma AFP and hepatic mRNA, associated to liver tissue neoplastic changes, SSTR-2 expression and MDA with decreased hepatic GSH were observed in DENA group. These changes were significantly improved by LIE and/or OC. CONCLUSIONS: LIE and/or OC treatment has effective chemopreventive action due to their ability to alleviate oxidative stress, desensitizing cellular growth receptor to SST.

Hepatic somatostatin receptor 2 expression during premalignant stages of hepatocellular carcinoma.

Growth and antigrowth hormones were occasionally investigated in hepatocarcinoma. Somatostatin regulates cell proliferation and inhibits the secretion of many growth factors engaged to tumors through a group of receptors, including somatostatin receptor type 2 (SSTR2). Caspase-3 is a transcription factor which is elevated in liver cancers. The most commonly approved marker for liver cancer is alpha fetoprotein (AFP), although it has no more than 65% sensitivity and specificity. Hepatocarcinoma is also mediated by oxidative stress. Four groups of mice were used in this work: a control group and another three groups (Gp 2, 3, and 4) used for induction of HCC with a single subnecrotic dose of diethylnitrosamine (DENA). Gp 2 was sacrificed on the last day after 8 weeks, Gp 3 after 16 weeks, and Gp 4 after 24 weeks. Both liver tissue SSR2 protein and mRNA, liver AFP, and caspase-3 mRNA expression, concomitant to tissue malondialdehyde (MDA), were significantly elevated with depressed reduced glutathione (GSH). The change was much more prominent and stage dependent for SSR2. These effects were supported by graded histological abnormalities. The study encourages the use of liver tissue SSR2 protein and mRNA as a reliable tumor marker for liver cancer rather than AFP which is always misleading during silent stages of hepatocarcinogenesis.