Myocardial infarct-sparing effect of ischemic preconditioning abrogated in cirrhotic rat through involvement of mitochondrial permeability transition pore

Despite all studies undertaken mechanism of cirrhotic cardiomyopathy the role of cirrhosis on ischemia-reperfusion (I/R) injury and ischemic preconditioning (IPC) phenomenon hasn't been explored yet. The aim of present study is to assess the relation between cirrhosis and IPC and the mitochondrial permeability transition pore (mPTP) role in IPC cardioprotective effects in cirrhotic rats. Material and method: Rat's heart were isolated and perfused with Krebs buffer by Langendorff method. Animals were equally divided into six groups (n=6): (I) I/R; hearts were subjected to 30 min ischemia and 45 min reperfusion, (II) IPC; IPC was induced via four cycle of 5 min regional ischemia followed by 5 min of reperfusion (III) common bile duct ligated (CBDL); hearts were subjected ischemia and reperfusion in cirrhotic rats, (IV) IPC-CBDL; four cycle of 5 min regional ischemia followed by 5 min of reperfusion in cirrhotic rats (V) CSA; Cyclosporine A was added 40 min prior to main ischemia (VI) CBDL+CSA. Results: Infarct size was increased significantly in IPC-CBDL group in comparison with IPC group (p< 0.05). Addition of CSA in CBDL+CSA group significantly decreased infarct size in comparison with IPC-CBDL group (p< 0.05). Ventricular arrhythmia severity was decreased significantly in IPC group compared to IR group, whereas it was increased significantly in IPC-CBDL group compared to IPC group (p< 0.05). CSA did not decrease arrhythmia score in CBDL group. Conclusion: The results showed that the cardioprotective effects of IPC are eliminated in cirrhosis. MPTP signaling in partly involve in cirrhotic cardiomyopathy

Cromakalim, a potassium channel opener, ameliorates the organophosphate and carbamate-induced seizure in mice

Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100 of the animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg significantly increased the latency of both seizure and death (P&lt;0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P&lt;0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P&lt;0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates-induced seizure. © 2018 Tehran University of Medical Sciences. All rights reserved

Cromakalim, a potassium channel opener, ameliorates the organophosphate and carbamate-induced seizure in mice

Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100 of the animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg significantly increased the latency of both seizure and death (P&lt;0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P&lt;0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P&lt;0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates-induced seizure. © 2018 Tehran University of Medical Sciences. All rights reserved

Effect of chronic lithium administration on endothelium-dependent relaxation of rat corpus cavernosum: The role of nitric oxide and cyclooxygenase pathways

OBJECTIVE: To verify the effect of chronic lithium administration on the endothelium-dependent relaxation of rat corpus cavernosum, as lithium is a major drug for treating bipolar disorder and some studies showed that lithium might cause erectile dysfunction in such patients, by a mechanism as yet unknown. MATERIALS AND METHODS: LiCl (600 mg/L) was dissolved in drinking water and Sprague-Dawley rats received the solution for 30 days; control rats received tap water. After 30 days corporeal strips were prepared from both groups, mounted under tension in oxygenated organ baths, and pre-contracted with phenylephrine (7.5 μm). After equilibration, the strips were relaxed by acetylcholine (10 nm to 1 mm) in the presence or absence of indomethacin (a cyclooxygenase inhibitor; 20 μm). Furthermore, the relaxant responses to sodium nitroprusside (1 nm to 1 mm), a nitric oxide (NO) donor, were investigated in both groups. NADPH-diaphorase histochemistry was used to identify NO synthase within cavernosal tissue strips of both groups. RESULTS: The acetylcholine-dependent relaxation was significantly lower in lithium-treated rats than in controls. Although indomethacin decreased significantly the relaxant responses to acetylcholine in controls, it increased the relaxant responses in lithium-treated rats. NADPH-diaphorase staining was greater in the chronic lithium-treated than in control preparations. Sodium nitroprusside produced similar relaxation in both groups. CONCLUSION: Chronic lithium administration can impair the endothelium-dependent relaxation of rat corpus cavernosum; NO availability might decrease after lithium administration and the cyclooxygenase pathways might have a role in this effect. © 2006 The Authors

NADPH diaphorase staining of the corpus cavernosum in cholestatic rats: Role of nitrergic and opioid systems

Background: Relaxation of the corpus cavernosum plays an important role in penile erection. Previous studies have suggested that nitric oxide (NO) appears to be the most important relaxant involved in the erection process. The aim of the present study was to evaluate the effect of cholestasis in nNOS and eNOS activity of corpus cavernosum. Methods: forty-two adult male Sprague-Dawley rats were divided equally into seven groups: control, sham operated, 2-, 7-, and 14-day bile duct-ligated animals, 7-day bile duct-ligated chronically treated with L-NAME (3mg/kg/day, i.p.) and 7-day bile duct-ligated animals chronically treated with Naltrexone (20 mg/kg/day, i.p.). The animals in each group were killed and the cavernosal tissues analyzed histologically by light and transmission electron microscopy, with NOS activity detected on NANC nerves and endothelium using an NADPH-diaphorase staining technique. Results: our results showed that NADPH diaphorase staining in corporal NANC nerves and endothelium of sham-operated and control group had equal intensity. The staining was more intense in 2-day cholestatic rats than in control group, the staining intensity increased in 7-, and 14-day groups too. There were no significant differences between control group and 7-day cholestatic rats that had been treated chronically with L-NAME or Naltrexone. Conclusions: These results state that in corpus cavernosum of cholestatic rats there is a time-dependent increase in NOS activity of the corporal NANC nerves and endothelium. inhibition of nitric oxide and endogenous opioids by L-NAME or Naltrexone during cholestasis may play a key role in preventing the adverse effects of cholestasis. © 2008, Tehran University of Medical Sciences. All rights reserved

The role of opioid and nitrergic systems in dual modulation of seizure susceptibility

Epilepsy is a chronic disorder presented by recurrent episodes of seizures and affect worldwide individuals. The underlying mechanism of seizure is still elusive. Hence, there is still a need to determine the contribution of various systems in neurobiology and treatment of seizure. Evidence shows that opioid and nitrergic systems within the brain interact to modulate various physiological and pathological conditions including memory, pain, reward, addiction, depression, and seizure. Various studies revealed that diverse dose of opioids such as morphine has dual modulation in seizure susceptibility. For instance, it is reported that morphine at lower doses (0.5, 1, and 3 mg/kg) exerts an anticonvulsant effect in experimental seizure models, whereas at higher doses (15, 30, and 60 mg/kg) it could exacerbate the seizure. Similarly, nitrergic system has also been observed to possess dual effects in modulating the seizure threshold. Therefore, understanding of opioidergic and nitrergic systems interaction in seizure seems important to achieve the successful goal of seizure management. This review aimed to clarify and provide insight into how opioidergic and nitrergic systems interact in brain and mediate seizure behavior. © 2020 UNIV CARLOSIII MADRID. All rights reserved

Metformin attenuates streptozotocin-induced diabetic nephropathy in rats through activation of AMPK signaling pathway

Background: Nephropathy is the main problem of diabetes and can be classified into several phases according to the presence of albuminuria. Adenosine monophosphate-activated protein kinase (AMPK) operates as a sensor of energy charge. Objectives: The aim of our study was to evaluate the reno-protective properties of AMPK signaling pathway against streptozotocin (STZ)-induced nephropathy in the rat. Materials and Methods: Forty male Wistar rats were randomly distributed into four groups. Group 1 was normal rats (N group); group 2 was diabetic rats (D group); group 3 received diabetic rats + metformin (DM group), and group 4 received giabetic rats + metformin + dorsomorphin (DMD group). Serum albumin, uric acid, total protein and creatinine for estimation of renal injury were measured. Finally, the histological study was evaluated. Results: Reduction of body weight, albumin and total protein in the diabetic rat was reversed by metformin administration. Our results showed that serum uric acid and creatinine were significantly increased in diabetic rats and decreased after treatment with metformin in diabetic rats. AMPK improved the histopathology and morphological changes in STZ-induced diabetic rats. Administration of dorsomorphin (AMPK inhibitor) with metformin can reverse the beneficial effects of AMPK. Conclusions: AMPK signaling pathway ameliorates diabetic nephropathy by modifications of serum albumin, uric acid, total protein, creatinine and attenuation of kidney damage

Clinical grade human adipose tissue-derived mesenchymal stem cell banking

In this study, our aim was to produce a generation of GMP-grade adipose tissue-derived mesenchymal stem cells for clinical applications. According to our results, we fulfill to establish consistent and also reproducible current good manufacturing practice (cGMP) compliant adipose tissue-derived mesenchymal stem cells from five female donors. The isolated cells were cultured in DMEM supplemented with 10 fetal bovine serum and characterized by standard methods. Moreover, karyotyping was performed to evaluate chromosomal stability. Mean of donors� age was 47.6 ± 8.29 year, mean of cell viability was 95.6 ± 1.51, and cell count was between 9�106 and 14�106 per microliter with the mean of 12.2�106 ± 2863564.21 per microliter. The main aim of this project was demonstrating the feasibility of cGMP-compliant and clinical grade adipose tissue-derived mesenchymal stem cells preparation and banking for clinical cell transplantation trials. © 2015 Tehran University of Medical Sciences. All rights reserved

Role of the nitric oxide pathway and the endocannabinoid system in neurogenic relaxation of corpus cavernosum from biliary cirrhotic rats

Background and purpose: Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model. Experimental approach: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation. Key results: The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB 1 antagonist) or capsazepine (vanilloid VR 1 antagonist), but not AM630 (CB 2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups. Conclusions and implications: Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB 1 and vanilloid VR 1 receptors. © 2007 Nature Publishing Group All rights reserved

Clinical Grade Human Adipose Tissue-Derived Mesenchymal Stem Cell Banking

In this study, our aim was to produce a generation of GMP-grade adipose tissue-derived mesenchymal stem cells for clinical applications. According to our results, we fulfill to establish consistent and also reproducible current good manufacturing practice (cGMP) compliant adipose tissue-derived mesenchymal stem cells from five female donors. The isolated cells were cultured in DMEM supplemented with 10 fetal bovine serum and characterized by standard methods. Moreover, karyotyping was performed to evaluate chromosomal stability. Mean of donors' age was 47.6 ± 8.29 year, mean of cell viability was 95.6 ± 1.51, and cell count was between 9�106 and 14�106 per microliter with the mean of 12.2�106 ± 2863564.21 per microliter. The main aim of this project was demonstrating the feasibility of cGMP-compliant and clinical grade adipose tissue-derived mesenchymal stem cells preparation and banking for clinical cell transplantation trials