A systematic review on the role of melatonin and its mechanisms on diabetes-related reproductive impairment in non-clinical studies.

Background: Diabetes-induced reproductive complications can lead to subfertility and infertility, raising the need to protect reproductive organs. There are limited medications used to improve reproductive health in diabetic patients. Melatonin, mainly produced by the pineal gland, may improve diabetes-associated reproductive complications through various mechanisms and may be a preferred candidate to protect the reproductive system. The present review aims to elucidate the underlying mechanisms of melatonin's effect on the reproductive system adversely affected by diabetes mellitus (DM). Methods: A comprehensive systematic literature electronic search was done using the PRISMA guidelines. Web of Science, PubMed, Embase, and Scopus were searched for publications up to June 2022. Search terms were selected based on the study purpose and were explored in titles and abstracts. After screening, out of a total of 169 articles, 14 pertinent articles were included based on our inclusion and exclusion criteria. Results: The results of studies using rats and mice suggest that DM adversely affects reproductive tissues, including testes and epididymis, prostate, corpus cavernosum, and ovary leading to alterations in histological and biochemical parameters compared to the normal groups. Treatment with melatonin improves oxidative stress, blocks apoptosis induced by endoplasmic reticulum stress and caspase activation, reduces pro-inflammation cytokines, and enhances steroidogenesis. Conclusion: Melatonin exerted a protective action on the impaired reproductive system in in-vivo and in-vitro models of DM. The topic has to be followed up in human pregnancy cases that will need more time to be collected and approved.

The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies.

Backgrounds: Diabetes can cause diabetic neuropathy (DN), a nerve injury. High blood sugar (glucose) levels can harm nerves all over your body. The nerves in your legs and feet are the most commonly affected by DN. The purpose of this study was to conduct a review of melatonin's potential neuroprotective properties against DN. Method: A full systematic search was conducted in several electronic databases (Scopus, PubMed, and Web of Science) up to March 2022 under the PRISMA guidelines. Forty-seven studies were screened using predefined inclusion and exclusion criteria. Finally, the current systematic review included nine publications that met the inclusion criteria. Result: According to in vivo findings, melatonin treatment reduces DN via inhibition of oxidative stress and inflammatory pathways. However, compared to the diabetes groups alone, melatonin treatment exhibited an anti-oxidant trend. According to other research, DN also significantly produces biochemical alterations in neuron cells/tissues. Additionally, histological alterations in neuron tissue following DN were detected. Conclusion: Nonetheless, in the majority of cases, these diabetes-induced biochemical and histological alterations were reversed when melatonin was administered. It is worth noting that the administration of melatonin ameliorates the neuropathy caused by diabetes. Melatonin exerts these neuroprotective effects via various anti-oxidant, anti-inflammatory, and other mechanisms.

A Systematic Review of Nonclinical Studies on the Effect of Curcumin in Chemotherapy- induced Cardiotoxicity.

BACKGROUND: Various anticancer drugs are effective therapeutic agents for cancer treatment; however, they cause severe toxicity in body organs. Cardiotoxicity is one of the most critical side effects of these drugs. Based on various findings, turmeric extract has positive effects on cardiac cells. OBJECTIVE: This study aims to evaluate how curcumin, as the main component of turmeric, may affect chemotherapy- induced cardiotoxicity. METHODS: A database search was performed up to April 2021 using "curcumin OR turmeric OR Curcuma longa" and "chemotherapy-induced cardiac disease", including their equivalents and similar terms. After screening the total articles obtained from the electronic databases, 25 relevant articles were included in this systematic review. RESULTS: The studies demonstrate lower body weight and increased mortality rates due to doxorubicin administration. Besides, cancer therapeutic agents induced various morphological and biochemical abnormalities compared to the non-treated groups. Based on most of the obtained results, curcumin at nontoxic doses can protect the cardiac cells mainly through modulating antioxidant capacity, regulation of cell death, and antiinflammatory effects. Nevertheless, according to a minority of findings, curcumin increases the susceptibility of the rat cardiomyoblast cell line (H9C2) to apoptosis triggered by doxorubicin. CONCLUSION: According to most nonclinical studies, curcumin could potentially have cardioprotective effects against chemotherapy-induced cardiotoxicity. However, based on limited, contradictory findings demonstrating the function of curcumin in potentiating doxorubicin-induced cardiotoxicity, well-designed studies are needed to evaluate the safety and effectiveness of treatment with new formulations of this compound during cancer therapy.

Modification of the hemodynamic and molecular features of phosphine, a potent mitochondrial toxicant in the heart, by cannabidiol.

Aluminum phosphide (AlP) poisoning is common in many countries responsible for high mortality. The heart is the main target organ in AlP poisoning. Several studies have reported the beneficial effects of cannabidiol (CBD) in reducing heart injuries. This study aimed to investigate the possible protective effect of CBD on cardiac toxicity caused by AlP poisoning. Study groups included almond oil, normal saline, sole CBD (100 µg/kg), AlP (11.5 mg/kg), and four groups of AlP + CBD (following AlP gavage, CBD administrated at doses of 5, 25, 50, and 100 µg/kg via intravenous (iv) injection). Thirty minutes after AlP treatment, an electronic cardiovascular device (PowerLab) was used to record electrocardiographic (ECG) changes, heart rate (HR), and blood pressure (BP) for three hours. Cardiac tissue was examined for the activities of mitochondrial complexes, ADP/ATP ratio, the release of cytochrome C, mitochondrial membrane potential (MMP), apoptosis, oxidative stress parameter, and cardiac biomarkers at 12 and 24 hours time points. AlP administration caused abnormal ECG, decreased HR, and BP. AlP also significantly reduced mitochondrial complex I and IV activity and ADP/ATP ratio. The level of cytochrome C release, apoptosis, oxidative stress, and cardiac biomarkers was considerably increased by AlP, which was compensated following CBD administration. CBD was able to improve hemodynamic function to some extent in AlP poisoned rats. CBD restored ATP levels and mitochondrial function and decreased oxidative damage and thus, prevented the heart cells from entering the apoptotic stage. Further clinical trials are needed to explore any possible benefits of CBD in AlP-poisoned patients.

Sensing of oxidative stress biomarkers: The cardioprotective effect of taurine & grape seed extract against the poisoning induced by an agricultural pesticide aluminum phosphide.

Aluminum phosphide is a well-known hazardous agent used as an agricultural pesticide to protect stored grains from insect damage. However, accidental consumption of a trivial amount of it caused irreversible damage to the human body or even death in acute cases. The present study used taurine and grape seed extract as a natural cardioprotective medicine against aluminum phosphide poisoning by decreasing oxidative stress. The activity of oxidative stress biomarkers (Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase) were evaluated in the cell line model on Human Cardiac Myocyte cells. In the beginning, to clarify the pure impact of aluminum phosphide poison, taurine, and grape seed extract on the human heart cells, their effects on the biomarkers quantity in cell line were measured. Subsequently, the effect of taurine and grape seed extract with various concentrations as a treatment on the oxidative stress biomarkers of the poisoned heart cells were studied. Data analysis reveals that taurine and grape seed extract treatment can successfully diminish the poisoning effect by their antioxidant properties. The oxidative markers values of the poisoned cells were recovered by taurine and grape seed extracts treatment. Taurine (2 g/l) can recover Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase by 56%, 78%, 88%, 78%, when the recovering power of grape seed extract (100 g/l) for the aforementioned enzymes are 56%, 0.71%,74%, 51%, respectively. Therefore, it is clear that the performance of taurine in the recovery of the biomarkers' value is better than grape seed extract.

Electrocardiographic, hemodynamic, and biochemical evidence on the protective effects of exenatide against phosphine-induced cardiotoxicity in rat model.

Aluminum phosphide (AlP) poisoning can be deadly in most cases targeting the heart. To overcome AlP toxicity, exenatide has been studied in the present study due to its pleiotropic effects on cardiac damages. In this study, the rats were exposed to LD50 of AlP (10 mg/kg) by gavage, and exenatide at doses (0.05, 0.1, and 0.2 mg/kg) injected intraperitoneally 30 min after poisoning. The cardiac parameters including heart rate (HR), blood pressure (BP), QRS, corrected QT (QTc), and ST were monitored for 180 min. Blood glucose level was measured in the study groups 30 min after exenatide injection. Evaluation of biochemical parameters including mitochondrial complexes I, II, and IV activities, adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio, malondialdehyde (MDA), apoptosis, lactate, troponin I, and brain natriuretic peptide (BNP) was done on heart tissues after 12 and 24 h. Additionally, the tissues were analyzed for any pathological damages including necrosis, hemorrhage, or hyperemia 24 h post-treatment. Our results showed that AlP-induced HR, BP, and electrocardiographic changes were improved by exenatide at all doses. The blood glucose levels of poisoned animals reached control levels after exenatide treatment. Besides, treatment with exenatide at all doses improved complexes I and IV activity, ADP/ATP ratio, and apoptosis. Malondialdehyde, lactate, troponin I, and BNP levels were also diminished after exenatide co-treatment in poisoned animals. On the other hand, administration of exenatide doses improved the histopathology of AlP-induced tissues. Based on our findings, exenatide has a protective effect against phosphine-induced cardiotoxicity in an almost dose-dependent way. However, further investigations are needed on the potential clinical use of exenatide in this poisoning.

The role of levosimendan in phosphine-induced cardiotoxicity: evaluation of electrocardiographic, echocardiographic, and biochemical parameters.

Aluminum phosphide (AlP) causes serious poisoning in which severe cardiac suppression is the significant lethal consequence. According to evidence, levosimendan can exert outstanding cardiac support and protection in different pathological conditions. This study aimed to investigate the mechanisms by which levosimendan may alleviate cardiovascular toxicity due to AlP intoxication in the rat model. The groups included control group (normal saline only), sole levosimendan groups (12, 24, 48 µg/kg), AlP group (10 mg/kg), and AlP + levosimendan groups receiving 12, 24, 48 µg/kg levosimendan intraperitoneally 30 min after AlP administration. Electrocardiographic (ECG) parameters (QRS and PR duration and ST height), heart rate, and blood pressure were monitored for 180 minutes. Also, after 24 h of poisoning, echocardiography was applied to assess left ventricle function. Evaluation of the biochemical parameters in heart tissue, including mitochondrial complexes I, II, IV activity, ADP/ATP ratio, the rate of apoptosis, malondialdehyde (MDA), lactate, and troponin I levels, were done after 12 and 24 h. AlP-induced ECG abnormalities (PR duration and ST height), reduction in heart rate, blood pressure, cardiac output, ejection fraction, and stroke volume were improved by levosimendan administration. Besides, levosimendan significantly improved complex IV activity, the ADP/ATP ratio, apoptosis, MDA, lactate, and troponin I level following AlP-poisoning. Our results suggest that levosimendan might alleviate AlP-induced cardiotoxicity by modulating mitochondrial activity and improving cardiac function. However, the potential clinical use of levosimendan in this toxicity needs more investigations.

On the mechanisms of taurine in alleviating electrocardiographic, hemodynamic, and biochemical parameters following aluminum phosphide cardiotoxicity.

BACKGROUND: Aluminum phosphide (AlP) causes severe cardiotoxicity. Taurine has been chosen for the present study because of its positive known effects on cardiac injuries. METHOD: To evaluate AlP-induced cardiotoxicity, the animals were divided into seven groups, including the control group, the taurine group (500 mg/kg), AlP with LD50 dose, AlP + taurine 20, 50, 100, and 200 mg/kg group. To assess cardiac hemodynamic parameters, Wistar rats received taurine intraperitoneally 60 min after AlP gavage. Cardiac hemodynamic parameters were evaluated for 180 min. To study biochemical parameters, 24 h after AlP treatment, the animals were sacrificed, and heart tissues were collected. RESULT: ECG, BP, and HR abnormalities of AlP poisoning were improved by taurine treatment. AlP induced biochemical alterations including complexes I and IV activities, the ADP/ATP ratio, mitochondrial membrane potential, cytochrome C release, and oxidative stress biomarkers ameliorated by taurine. Moreover, taurine improved apoptosis, as well as lessened CK-MB and troponin I levels. Also, there were no significant changes between taurine 500 mg/kg and the control group in tests. CONCLUSION: The present findings showed that taurine could be a possible candidate for AlP cardiotoxicity treatment via the effect on mitochondrial electron transfer chain and maintaining intracellular ATP balance.

Caffeine attenuates seizure and brain mitochondrial disruption induced by Tramadol: the role of adenosinergic pathway.

Tramadol (TR) is an analgesic drug used to treat moderate-to-severe pain but it induces seizure even at therapeutic doses. The exact mechanism of TR-inducing seizure is not clear but inhibition of the serotonin, GABA, and nitrous oxide (NOS) pathways are the commonly proposed mechanisms. Adenosinergic system has a crucial function in the modulation of seizure. Also, oxidative damage is an unavoidable effect of the seizure. This study was conducted to evaluate the role of the adenosinergic system on the seizure and oxidative stress biomarkers induced by TR using antagonist of the adenosinergic receptors in the Albino mice. For that purpose, generated clonic seizure, as seizure threshold, was evaluated by TR. Caffeine (CAF; 8 mg/kg, i.p.), a nonselective antagonist of adenosine receptors, was administered 1 hour before the seizure induction. The seizure threshold significantly increased by CAF-treated group when compared to TR group (p < 0.001). Oxidative stress biomarkers such as reactive oxygen species, protein carbonyl content, and lipid peroxidation significantly decreased and glutathione content significantly increased by CAF in brain mitochondria compared to the TR group, whereas oxidative biomarkers significantly increased in the TR group compared to the control group. The results of the present study suggested that the adenosinergic system is involved in seizure induced by TR and meanwhile, inhibition of adenosine receptors can decrease the TR seizure threshold and also decrease the induced oxidative damage in the brain mitochondria.

The role of taurine on chemotherapy-induced cardiotoxicity: A systematic review of non-clinical study.

AIMS: Although chemotherapeutic agents have highly beneficial effects against cancer, they disturb the body's normal homeostasis. One of the critical side effects of chemotherapeutic agents is their deleterious effect on the cardiac system, which causes limitations of their clinical usage. Taurine constitutes more than 50% of the amino acids in the heart. The use of taurine might prevent chemotherapy-induced cardiotoxicity. This systematic study aims to evaluate the protective role of taurine against cardiotoxicity induced by chemotherapy. METHODS: A systematic search was performed in databases up to November 2020, and the review is designed on PRISMA guidelines. The search keywords were selected based on our study target and were searched in the title and abstract. After the consecutive screening, out of a whole of 94 articles, 8 articles were included according to our inclusion and exclusion criteria. KEY FINDINGS: According to the study results, chemotherapy decreases body and heart weight and increases mortality. Also, it induces some biochemical and histological changes compared to the control group. By co-administration of taurine with chemotherapy, alterations returned near to the average level. These protective effects of taurine are mediated through anti-oxidant, anti-inflammatory, and anti-apoptotic properties. SIGNIFICANCE: Based on evaluated non-clinical studies, taurine ameliorates chemotherapy-induced cardiotoxicity, but its possible interaction with the efficacy of anti-cancer medicines that mostly act through induction of oxidants remains to be elucidated in the future. This needs conducting well-designed studies to assess the effectiveness and safety of this combination simultaneously.

Evidence for the Involvement of the Dopaminergic System in Seizure and Oxidative Damage Induced by Tramadol.

Tramadol (TR) is a synthetic analgesic drug with central function that can induce seizures even at therapeutic doses. The exact mechanism of TR effect on seizure generation is not clear, but inhibition of the serotonin and nitric oxide pathways and inhibitory effects on GABA receptors are the most common hypotheses about the seizure-inducing mechanism of the TR. This study aimed to evaluate the role of dopaminergic system on the seizure and oxidative damage induced by TR using agonist and antagonist drugs of this system in the Albino mice. Clonic seizure induced by TR was evaluated as seizure threshold. Haloperidol (0.2 mg/kg, IP), a predominantly D2 receptor antagonist, and cabergolin (0.5 mg/kg, IP), a dopamine agonist specific for the D2 receptors, were injected 60 minutes before the seizure induction. The seizure threshold was significantly increased by dopaminergic antagonist, but it was decreased significantly by pretreatment with the selective agonist. Oxidative stress biomarkers (reactive oxygen species, lipid peroxidation, and protein carbonyl content) significantly increased and glutathione content significantly decreased in brain mitochondria by TR compared with the control group, whereas oxidative markers were decreased significantly after pretreatment with haloperidol compared with the TR group. This study revealed that the dopaminergic system is involved in TR-induced seizure, and meanwhile, inhibition of dopamine D2 receptors can increase the TR threshold seizure and decrease the oxidative damage in the brain mitochondria. Conversely, stimulation of dopamine D2 receptors by cabergolin can decrease the TR threshold seizure and glutathione content in the brain mitochondria.