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Saffron, the stigmas of Crocus sativus L., has been mentioned extensively in the traditional reference texts as a herbal medicine. Many clinical trials have been conducted on this valuable herbal substance and its main constituents following numerous cellular and animal assessments. In the present review, we have collected almost all of these clinical studies to clarify how much knowledge has clinically been achieved in this field so far and which scientific gaps are needed to be filled by more studies. A comprehensive literature review was conducted through a two-round search. First, we performed a general search for identifying the human disorders against which saffron was studied. Then, we searched specifically for the combination of saffron keywords and each disease name. Scientific databases including Scopus, PubMed, and Web of science were used for this search. Studies were collected through electronic databases from their inception up to August 2021. The largest number of these clinical studies represent the investigations into saffron efficacy in different neurological and mental disorders, particularly depression. This substance has clinically revealed significant protective effects against various types of depression, age-related macular degeneration, and allergic asthma. In some cases, such as sexual dysfunction, cognitive and metabolic disorder, the effects of saffron are still clinically open to dispute, or there are limited data on its positive influences. Overall, saffron and its constituents have promising effects on human disorders; however, it needs more clinical evidence or meta-analyses to be confirmed.

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AIMS: During heart ischemia, the lack of oxygen in the myocardial cells causes pH and ion disturbances and cell death through opening mitochondrial permeability transition pores (mPTP). Considering the inhibitory effects of mitochondrial ATP-dependent potassium channels (mt-KATP) on these pores and anti-ischemic effects of morin, we hypothesized that it may exert its positive effects via activating mt-KATP as well as its anti-oxidative effects. MAIN METHODS: Isolated rat hearts were perfused by Krebs-Henseleit solution enriched with the morin (0.25, 0.5 and 1 mg/L) or 5-hydroxydecanoate (5-HD, a mt-KATP blocker;100 µM) or both as needed 5 min before starting regional ischemia till the first 10 min of the reperfusion period. The reperfusion was developed with Krebs-Henseleit solution 60 or 120 min respectively for biochemical evaluations (lactate dehydrogenase and malondialdehyde level) or the assessment of myocardial infarct size. During the experiments, hemodynamic functions were recorded and cardiac arrhythmias were determined. KEY FINDINGS: Our findings demonstrated that morin reduced the infarct size. Also, morin perfusion could remarkably prevent the malondialdehyde over-production during ischemia. Total ventricular ectopic beats had the same significant changes as the malondialdehyde level, in both ischemia and reperfusion phases. Morin could also relatively improve the ischemia-induced hemodynamic dysfunction. All mentioned protective effects of morin were reversed by concomitant perfusion of 5-HD. SIGNIFICANCE: Morin has protective effects against ischemic hearts through anti-oxidative effects. It also suggests a link between the cardioprotective effects of morin and mt-KATP. However, additional studies are required to prove this preliminary hypothesis.

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OBJECTIVES: One of the most important problems of taking nitroglycerin is the nitrate tolerance phenomenon and endothelial dysfunction. Oxidative stress is a high-emphasized one of tolerance mechanisms. The possible effect of crocin, one of the anti-oxidant ingredients of saffron, on the nitrate tolerance model was investigated. MATERIALS AND METHODS: In the present study, lipid peroxidation and the level of activated and deactivated forms of eNOS were measured. Animals were administered subcutaneously with 25 mg/kg of nitroglycerin, twice a day for 3 days to induce nitrate tolerance model. For evaluation of crocin effects, 20, 40 and 80 mg/kg/day of this compound were injected intraperitoneally in concomitant with nitroglycerin. In the isolated aorta test, after preparation of aorta rings, different concentrations of acetylcholine, sodium nitroprusside and nitroglycerin were added to the organ bath after inducing contraction by phenylephrine and the responsiveness of tissues was recorded. RESULTS: Findings showed that nitroglycerin administration caused a remarkable overproduction of malondialdehyde (MDA) in the cells and crocin treatment significantly decreased the MDA level. In the nitrate tolerance group, the level of activated eNOS decreased and the level of deactivated eNOS increased. Crocin partly alleviated these changes: however, its effects were not remarkable. Nitroglycerin injection for 3 days developed tolerance to nitroglycerin and cross-tolerance to acetylcholine (endothelial dysfunction) and sodium nitroprusside. Crocin failed to influence significantly on the nitrate tolerance. CONCLUSION: Crocin effectiveness is possibly time-dependent; therefore, increasing the duration of treatment with crocin may lead to a significant prevention of nitrate tolerance and endothelial dysfunction.

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Aging is a progressive process which is associated with liver dysfunction and it is due to oxidative stress, inflammation, and cell apoptosis. Long-term D-galactose (D-gal) administration is able to develop an aging model in animals. Crocin as a major active ingredient in saffron has shown anti-inflammatory and hepatoprotective effects via its antioxidant capacity. Thus, the aim of the present study was the assessment of crocin effects on hepatic and metabolic disorders induced by D-gal in rats. Aging model was induced in rats by 56-day administration of D-gal (400 mg/kg/day subcutaneously). Protective effects of different doses of crocin (7.5, 15 and 30 mg/kg/day) in concomitant with D-gal administration were evaluated. Malondialdehyde (MDA) and reduced glutathione (GSH) amounts were measured by means of their reaction, respectively, with thiobarbituric acid and 5,5'-Dithiobis (2-nitrobenzoic acid) (DTNB) under a specific condition. Cyclooxygenase-2 (COX-2), ß-galactosidase, induced nitric oxide synthase (iNOS), and carboxymethyllysine (CML) levels were determined by western blotting method. Additionally, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in serum. D-gal administration significantly elevated ALT, AST, ALP levels, which were markedly inhibited by crocin administration. Crocin suppressed the overgeneration of lipid peroxidation products such as MDA. iNOS was elevated by D-gal administration and was returned to the normal extent by crocin. Therefore, Crocin as a powerful antioxidant and radical scavenger, totally exhibited hepatoprotective effects against D-gal-induced toxicity in rats.

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Nowadays in our developing and industrial world, humans' health or even their life is threatened by exposure to poisons. In this situation, detecting a protective compound could be helpful and interesting. In the present article, we collected and reviewed all studies, which have been conducted so far about the protective effects of Ginkgo biloba L. (GB), one of the most ancient medicinal tree species, against toxicities induced by chemical toxic agents, natural toxins, and also radiation. In overall, investigations showed that GB exerts the antioxidant, antiinflammatory, antiapoptotic, and antigenotoxicity effects in different toxicities. There are also some special mechanisms about its protective effects against some specific toxic agents, such as acetylcholine esterase inhibition in the aluminium neurotoxicity or membrane-bond phosphodiesterase activation in the triethyltin toxicity. Ginkgolide A was the most investigated active ingredient of G. biloba leaf extract as a protective compound against toxicities, which had the similar effects of total extract. A few clinical studies have been conducted in this field, which demonstrated the beneficial effects of GB against toxic agents. However, the promising effects of this valuable herbal extract will practically remain useless without carrying out more clinical studies and proving its effects on human beings.

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