Acute paracetamol toxicity-induced inflammatory and oxidative effects are relieved by Aleppo galls: a novel experimental study.

BACKGROUND: Paracetamol (acetaminophen) is an over-the-counter non-steroidal anti-inflammatory drug that may cause acute toxic overdosage particularly in neuropsychiatric patients. Paracetamol is also very commonly prescribed as an analgesic and antipyretic agent. Paracetamol toxicity causes decreased reduced glutathione and oxidative tissue damage. Aleppo galls is a promising natural remedy exerting antioxidant and tissue-protective effects that may combat acetaminophen-induced oxidative tissue damage. METHODOLOGY: Biochemical and toxicological effects of a toxic dose of paracetamol (250 mg/kg) were investigated for three consecutive days versus the tissue-protective effects of Aleppo galls. Eighteen white albino mice were randomly allocated in this study and divided into three experimental groups (six mice per group): negative control (received intraperitoneal sterile water injection), paracetamol toxicity group (received intraperitoneal paracetamol injection) and the third group (received paracetamol injection at 250 mg/kg/day together with oral Aleppo galls treatment at 250 mg/kg/day for 3 consecutive days). All mice were sacrificed by the end of the study. RESULTS: Our data revealed that paracetamol toxicity exerted significant oxidative stress damaging effects (high serum malondialdehyde, decreased serum catalase and decreased total antioxidant capacity), and significant inflammatory effects (high serum IL-6) and significant tissue-damaging effects (high serum LDH). Aleppo galls treatment significantly protected against acetaminophen toxicity-induced oxidative stress effects (P<0.001), inflammatory effects (P<0.001) and tissue-damaging effects (P<0.001). CONCLUSION: Aleppo galls are promising for future drug therapeutics and for the synthesis of natural remedies for treating paracetamol toxicity. We recommend formulating Aleppo galls extract as a pharmaceutical nutrition and to be given to those who need to take large doses of paracetamol.

Aleppo galls alleviate paracetamol-induced hepatotoxicity and tissue damage: an experimental study.

BACKGROUND: Acute paracetamol toxicity is a common and potentially life-threatening emergency causing liver failure that may necessitate liver transplantation. Unfortunately, current therapies are still defective. OBJECTIVES: To investigate the protective effects exerted by Aleppo galls (Quercus infectoria Olivier) extract against acute paracetamol toxicity in mice. METHODOLOGY: Eighteen mice were divided into three experimental groups, each included six mice in each group. The groups included: negative control group, paracetamol toxicity group that received an acute toxic intraperitoneal dose of paracetamol (250 mg/kg) for four consecutive days, and treatment group (received 250 mg/kg paracetamol followed few hours later by Aleppo galls extract for the same duration). Animals were anaesthetized using ether anaesthesia. Animals were sacrificed by decapitation and blood samples were drawn. Paracetamol toxicity effects versus Aleppo galls protection were evaluated on liver function tests, liver histology, serum cholesterol and serum triglycerides. RESULTS: Acute paracetamol toxicity caused significantly elevated serum transaminases (ALT and AST), decreased serum albumin, and increased serum cholesterol and triglycerides. Aleppo galls extract exerted significant protective effects and restored near normal serum levels of the previously-mentioned parameters. Upon histopathological evaluation, mice in the control group showed normal hepatic architecture with preserved hepatic cords and sinuses. Acute paracetamol toxicity induced peripheral zonal degeneration with focal necrosis of the hepatic tissue. The hepatocytes showed cytoplasmic vacuolation with indistinct cell borders. Central hepatic venules were congested. Administration of Aleppo galls extract reduced the tissue damaging effects induced by paracetamol toxicity with only minimal residual degenerative changes that were observed with absent necrosis. CONCLUSION: Quercus infectoria Olivier (Aleppo galls) is a promising source of phytochemicals and future therapeutics.

The Preventive and Therapeutic Effects of Ajwa Date Fruit Extract Against Acute Diclofenac Toxicity-Induced Colopathy: An Experimental Study.

Background: Studies regarding treatment of acute toxicity with diclofenac (ATD) are quite few. Diclofenac is commonly prescribed in neurology, psychiatry, and general medicine practice. This study investigated possible colon-protective effects exerted by Ajwa date fruit extract (ADFE), a prophetic medicine remedy native to Al-Madinah, Saudi Arabia against ATD. Phytochemicals in ADFE as gallic acid and quercetin have reported protective effects against ATD. Methods: Total phenols and flavonoids in ADFE were estimated as equivalents to gallic acid and quercetin. Four experimental groups were allocated each of six rats: control group, ATD group received a single dose of 150 mg diclofenac intraperitoneally, toxicity prevention group received a single dose of ADFE orally followed 4 hours later by diclofenac injection, and toxicity treatment group received a similar diclofenac dose followed 4 hours later by a single dose of ADFE. Four days later, animals were sacrificed. Histological and biochemical examinations were done. Results: ADFE has a total phenolic content of 331.7 gallic acid equivalent/gram extract and a total flavonoid content of 70.23 quercetin equivalent/gram. ATD significantly increased oxidative stress markers as serum malondialdehyde (MDA) and hydrogen peroxide (H2O2). Serum MDA and H2O2 were significantly scavenged by ADFE. ATD significantly (p<0.001) decreased antioxidant power as serum total antioxidant capacity and catalase activity. That was reversed by ADFE in both prevention and treatment groups. Histologically, ATD caused complete destruction of colonic crypts architecture, patchy loss of the crypts, loss of the surface epithelium, absent goblet cells and submucosal exudate, heavy infiltration of the lamina propria and submucosa with inflammatory cells, mainly lymphocytes and eosinophils. There were mucosal haemorrhages and submucosal dilated congested blood vessels. All that was prevented and treated using ADFE. Conclusion: ADFE is rich in quercetin and gallic acid equivalents that exert potent antitoxic effects. ADFE is strongly recommended for preventive and therapeutic colon effects against ATD.

Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (anticancer effects of 3-bromopyruvate through antagonizing Warburg effect).

Cancer cells undergo an increased steady-state ROS condition compared to normal cells. Among the major metabolic differences between cancer cells and normal cells is the dependence of cancer cells on glycolysis as a major source of energy even in the presence of oxygen (Warburg effect). In Warburg effect, glucose is catabolized to lactate that is extruded through monocarboxylate transporters to the microenvironment of cancer cells, while in normal cells, glucose is metabolized into pyruvate that is not extruded. Pyruvate is a potent antioxidant, while lactate has no antioxidant effect. Pyruvate in normal cells may be further metabolized to acetyl CoA and then through Krebs cycle with production of antioxidant intermediates e.g. citrate, malate and oxaloacetate together with the reducing equivalents (NADH.H+). Through activity of mitochondrial transhydrogenase, NADH.H+ replenishes NADPH.H+, coenzyme of glutathione reductase which replenishes reduced form of glutathione (potent antioxidant). This enhances antioxidant capacities of normal cells, while cancer cells exhibiting Warburg effect may be deprived of all that antioxidant capabilities due to loss of extruded lactate (substrate for Krebs cycle). Although intrinsic oxidative stress in cancer cells is high, it may be prevented from reaching progressively increasing levels that are cytotoxic to cancer cells. This may be due to some antioxidant effects exerted by hexokinase II (HK II) and NADPH.H+ produced through HMP shunt. Glycolytic phenotype in cancer cells maintains a high non-toxic oxidative stress in cancer cells and may be responsible for their malignant behavior. Through HK II, glycolysis fuels the energetic arm of malignancy, the mitotic arm of malignancy (DNA synthesis through HMP shunt pathway) and the metastatic arm of malignancy (hyaluronan synthesis through uronic acid pathway) in addition to the role of phosphohexose isomerase (autocrine motility factor). All those critical three arms start with the substrate G6P that is a direct product of HK II. 3-bromopyruvate (3BP, inhibitor of HK II) may prove as a promising anticancer and antimetastatic agent based on antagonizing the Warburg effect and disturbing the malignant behavior in cancer cells.

Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage.

The potential protective role of aminoguanidine (AG), gadolinium chloride (GdCl(3)) and oleanolic acid (OA) in acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity was investigated in rats. Pretreatment of rats with AG (50mg/kg) orally, GdCl(3) (10mg/kg) intramuscularly or OA (25mg/kg) intramuscularly protected markedly against hepatotoxicity and nephrotoxicity induced by an acute oral toxic dose of APAP (2.5g/kg) as assessed by biochemical measurements and by histopathological examination. None of AG-, GdCl(3)- or OA-pretreated animals died by the acute toxic dose of APAP. Concomitantly, pretreatment of rats with these agents suppressed the profound elevation of nitric oxide (NO) production and obvious reduction of intracellular reduced glutathione (GSH) levels in liver and kidney induced by the acute toxic dose of APAP. Similarly, daily treatment of rats with a smaller dose of AG (10mg/kg), GdCl(3) (3mg/kg) or OA (5mg/kg) concurrently with a smaller toxic dose of APAP (750mg/kg) for 1 week protected against APAP-induced hepatotoxicity and nephrotoxicity. This treatment also completely prevented APAP-induced mortality and markedly inhibited APAP-induced NO overproduction as well as hepatic and renal intracellular GSH levels reduction. These results provide evidence that inhibition of NO overproduction and consequently maintenance of intracellular GSH levels may play a pivotal role in the protective effects of AG, GdCl(3) and OA against APAP-induced hepatic and renal damages.