Aloperine Attenuates Hepatic Ischemia/Reperfusion-Induced Liver Injury via STAT-3 Signaling in a Murine Model.

Hepatic ischemia/reperfusion (I/R) damage is one of the most common side effects of liver surgery. This pathophysiological process may lead to excessive hepatic damage. Aloperine is an active ingredient isolated from Sophora alopecuroides Linn and has a variety of therapeutic effects, including organ protection. However, the hepatoprotective effect of aloperine against hepatic I/R damage has not yet been determined. C57BL/6 mice were allocated to the sham-operated (sham), hepatic ischemia/reperfusion (I/R), and aloperine (ALO) groups. The mice were exposed to 30 min of hepatic hilum occlusion. Then a 3-hour reperfusion was performed. Mice in the sham group underwent sham surgery. Hepatic injury was evaluated by plasma aspartate aminotransferase (AST) and transaminase alanine aminotransferase (ALT) levels, histological evaluation, cell apoptosis, the number of activated inflammatory cells, and the expression levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The protein phosphorylation status of the reperfusion-associated survival pathways was evaluated. Mice with hepatic I/R injury presented increased plasma ALT and AST levels, increased hepatic apoptosis, abnormal histological structure, and elevated inflammatory responses. However, aloperine ameliorated hepatic I/R-induced injury. Moreover, aloperine enhanced the level of signal transducer and activator of transcription (STAT)-3 phosphorylation after I/R. Ag490, an agent that inhibits STAT-3 activity, abolished aloperine-induced STAT-3 phosphorylation and liver protection. Aloperine ameliorates hepatic I/R-induced liver injury via a STAT-3-mediated protective mechanism. Patients with hepatic I/R injury may benefit from aloperine treatment. Significance Statement Hepatic ischemia/reperfusion (I/R) can cause excessive liver damage. This study revealed that aloperine, an active component isolated from Sophora alopecuroides Linn., ameliorates hepatic I/R injury and related liver damage in vivo The underlying protective mechanism may involve the STAT-3 signaling pathway. These findings may lead to the development of a novel approach for treating hepatic I/R damage in clinical practice.

A novel sulindac derivative protects against oxidative damage by a cyclooxygenase-independent mechanism.

Oxidative damage is believed to play a major role in the etiology of many age-related diseases and the normal aging process. We previously reported that sulindac, a cyclooxygenase (COX) inhibitor and FDA approved anti-inflammatory drug, has chemoprotective activity in cells and intact organs by initiating a pharmacological preconditioning response, similar to ischemic preconditioning (IPC). The mechanism is independent of its COX inhibitory activity as suggested by studies on the protection of the heart against oxidative damage from ischemia/reperfusion and retinal pigmented endothelial (RPE) cells against chemical oxidative and UV damage . Unfortunately, sulindac is not recommended for long-term use due to toxicities resulting from its COX inhibitory activity. To develop a safer and more efficacious derivative of sulindac, we screened a library of indenes and identified a lead compound, MCI-100, that lacked significant COX inhibitory activity but displayed greater potency than sulindac to protect RPE cells against oxidative damage. MCI-100 also protected the intact rat heart against ischemia/reperfusion damage following oral administration. The chemoprotective activity of MCI-100 involves a preconditioning response similar to sulindac, which is supported by RNA sequencing data showing common genes that are induced or repressed by sulindac or MCI-100 treatment. Both sulindac and MCI-100 protection against oxidative damage may involve modulation of Wnt/ß-catenin signaling resulting in proliferation while inhibiting TGFb signaling leading to apoptosis. In summary MCI-100, is more active than sulindac in protecting cells against oxidative damage, but without significant NSAID activity, and could have therapeutic potential in treatment of diseases that involve oxidative damage. Significance Statement In this study, we describe a novel sulindac derivative, MCI-100, that lacks significant COX inhibitory activity, but is appreciably more potent than sulindac in protecting retinal pigmented epithelial (RPE) cells against oxidative damage. Oral administration of MCI-100 markedly protected the rat heart against ischemia/reperfusion damage. MCI-100 has potential therapeutic value as a drug candidate for age-related diseases by protecting cells against oxidative damage and preventing organ failure.

The effect of hydrogen sulfide on ischemi̇a /reperfusion injury in an experimental testicular torsion model.

INTRODUCTION: Testicular torsion is an acute pediatric surgical emergency requiring rapid diagnosis to prevent the permanent ischaemic damage of the testicles. Hydrogen Sulfide (H2S) have shown to cure tissue damage and has a role in the prevention of I/R damage. We aimed to evaluate the effect of H2S in testicular torsion. MATERIALS AND METHODS: Eighteen male, Wistar albino rats were divided into 3 groups. The sham group which is applied surgical stress. The ischemia/reperfusion group (I/R) which detorsion performed 1 h later than testicular torsion application. I/R + NaHS treatment group, NaHS solution was injected intraperitoneally for 1 week. On the 7th day of the detorsion all left testes were fixed in Bouin solution and sent to Pathology Department for histopathological examination. All right testes were washed with normal saline, dried in a sterile way and stored in - 80 °C deepfreeze up to the date of biochemical processes. Testicular tissues were obtained for the detection of myeloperoxidase (MPO), malondialdehyde (MDA), AOPP (advanced oxidation protein product) for oxidant markers and ferric reducing antioxidant power (FRAP) levels, superoxide dismutase (SOD),glutathione peroxidase (GSH-Px) activities for antioxidant markers and histopathological exploration. RESULTS: The effects of NaHs administration on oxidation were evaluated by determination of testicular MPO, MDA and AOPP levels. Increased testicular MPO (58.6%) activity was observed in the I/R group compared to the sham group. Following NaHS treatment, MPO (26.7%) activity was significantly decreased in rats exposed to I/R injury (Figure 1). MDA levels did not alter. Increases in AOPP (20.9%) levels were observed in the I/R group. NaHS treatment resulted in significant decreases in AOPP (25.1%) levels in testes tissues of rats exposed to I/R injury. The effects of NaHS treatment on antioxidant system FRAP, SOD, GSH and GSH-Px activities were evaluated. GSH levels were significantly increased in the IR + NaHS group compared to the I/R group. In histopathological examination degeneration of seminiferous tubules and spermatogenic cells were observed in the I/R group. After NaHS treatment, normal spermatogenic activity with many spermatozoa in the lumen of most seminiferous tubules were observed in the I/R injured rats. According to Johnsen's scoring (JS), the I/R group was significantly decreased compared to the sham group. JS values for the I/R + NaHS group were significantly increased compared to the I/R group. CONCLUSION: Our study supports that ischemia/reperfusion injury plays an important role in the testicular torsion injury, and it is a pioneer study showing that H2S may have a potential for therapeutic effect. The limitation of this work is this is an experimental study with limited number of animals. According to the results of our study, hydrogen sulfide treatment has beneficial effects on biochemical and histopathological results of testicular injury in testic torsion.

Possible involvement of α1-adrenergic receptor and K(ATP) channels in cardioprotective effect of remote aortic preconditioning in isolated rat heart.

BACKGROUND: Remote preconditioning is a phenomenon in which brief episodes of ischemia and reperfusion to remote organs protect the target organ against sustained ischemia/reperfusion (I/R)-induced injury. Protective effects of remote aortic preconditioning (RAPC) are well established in the heart, but their mechanisms still remain to be elucidated. OBJECTIVE: This study has been designed to investigate the possible involvement of α-1-adrenergic receptor (AR) and K(ATP) channels in cardio-protective effect of RAPC in isolated rat heart. MATERIALS AND METHODS: Four episodes of ischemia and reperfusion, each comprising of 5 min occlusion and 5 min reperfusion, were used to produce RAPC. Isolated perfused rat heart was subjected to global ischemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analyzed for LDH and CK-MB release to assess the degree of cardiac injury. Myocardial infarct size was estimated macroscopically using TTC staining. RESULTS: Phenylephrine (20 µ/kg i.p.), as α-1-AR agonist, was noted to produce RAPC-like cardio-protection. However, administration of glibenclamide concomitantly or prior to phenylephrine abolished cardioprotection. Moreover, prazocin (1 mg/kg. i.p), as α-1-AR antagonist and glibenclamide (1 mg/kg i.p), a K(ATP) channel blocker, abolished the cardioprotective effect of RAPC. CONCLUSION: These data provide the evidence that α-1-AR activation involved in cardioprotective effect of RAPC-mediated trough opening of K(ATP) channels.