Protective Role of Taurine against Arsenic-Induced Mitochondria-Dependent Hepatic Apoptosis via the Inhibition of PKCδ-JNK Pathway

BACKGROUND: Oxidative stress-mediated hepatotoxic effect of arsenic (As) is mainly due to the depletion of glutathione (GSH) in liver. Taurine, on the other hand, enhances intracellular production of GSH. Little is known about the mechanism of the beneficial role of taurine in As-induced hepatic pathophysiology. Therefore, in the present study we investigated its beneficial role in As-induced hepatic cell death via mitochondria-mediated pathway. METHODOLOGY/PRINCIPAL FINDINGS: Rats were exposed to NaAsO(2) (2 mg/kg body weight for 6 months) and the hepatic tissue was used for oxidative stress measurements. In addition, the pathophysiologic effect of NaAsO(2) (10 microM) on hepatocytes was evaluated by determining cell viability, mitochondrial membrane potential and ROS generation. As caused mitochondrial injury by increased oxidative stress and reciprocal regulation of Bcl-2, Bcl-xL/Bad, Bax, Bim in association with increased level of Apaf-1, activation of caspase 9/3, cleavage of PARP protein and ultimately led to apoptotic cell death. In addition, As markedly increased JNK and p38 phosphorylation with minimal disturbance of ERK. Pre-exposure of hepatocytes to a JNK inhibitor SP600125 prevented As-induced caspase-3 activation, ROS production and loss in cell viability. Pre-exposure of hepatocytes to a p38 inhibitor SB2035, on the other hand, had practically no effect on these events. Besides, As activated PKCdelta and pre-treatment of hepatocytes with its inhibitor, rottlerin, suppressed the activation of JNK indicating that PKCdelta is involved in As-induced JNK activation and mitochondrial dependent apoptosis. Oral administration of taurine (50 mg/kg body weight for 2 weeks) both pre and post to NaAsO(2) exposure or incubation of the hepatocytes with taurine (25 mM) were found to be effective in counteracting As-induced oxidative stress and apoptosis. CONCLUSIONS/SIGNIFICANCE: Results indicate that taurine treatment improved As-induced hepatic damages by inhibiting PKCdelta-JNK signalling pathways. Therefore taurine supplementation could provide a new approach for the reduction of hepatic complication due to arsenic poisoning

Programmed cell death and its role in inflammation

Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases

Intrathecal Morphine versus Morphine-Dexmedetomidine Combination for Postoperative Pain Control After Total Knee Replacement: A Randomized Controlled Trial

Amany F Omara,1 Hadal Hassan Mohsen,2 Alaa Mohammed Abo Hagar,1 Ahmed F Abdelrahman1 1Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Tanta University, Tanta, Egypt; 2Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Ain Shams University, Ciro, EgyptCorrespondence: Amany F Omara, Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Tanta University, Tanta, 31527, Egypt, Tel +201008372249, Email [email protected]; [email protected]: This prospective study aimed to compare the analgesic efficacy and adverse effects of intrathecal morphine, dexmedetomidine, and a combination of both in patients undergoing total knee replacement (TKR).Patients and Methods: This randomized prospective study was carried out in Tanta university hospital in orthopedic surgery for 6 months on 105 adult patients with American Society of Anesthesiologists Physical Status Class II and III, aged > 50 years, and scheduled for total knee replacement surgery randomly allocated into morphine group received 0.5% heavy bupivacaine plus 0.1 mg of morphine, morphine/ dexmedetomidine group, received 0.5% heavy bupivacaine plus 0.1 mg of morphine and 5 mcg of dexmedetomidine and dexmedetomidine group received 0.5% heavy bupivacaine plus 5 mcg of dexmedetomidine. The time of the first required analgesia, postoperative pain severity, the total dose of morphine, postoperative complication, and the patient’s level of sedation were recorded.Results: About half of the patients in the dexmedetomidine group requested first rescue analgesia 6 hours after the operation, significantly shorter than the other two groups. On the other hand, the other two groups show no significant difference between them regarding the first required analgesia. At rest, the dexmedetomidine group have significantly higher VAS with a significant increase in patients who required morphine as rescue analgesia than the other two groups. While at movement, patients in the dexmedetomidine group felt pain at 4 hrs postoperatively with significantly higher VAS than the other two groups. At the same time, the sedation score was significantly lower in the dexmedetomidine group than in the other two groups. 22.2% of cases in the morphine group developed nausea and vomiting with a significant difference between the three groups.Conclusion: Despite the absence of substantial side effects, our findings did not suggest enhanced analgesia with the combination of intrathecal morphine and dexmedetomidine.Keywords: dexmedetomidine, intrathecal, morphine, pain, total knee replacemen