Saffron as a promising therapy for diabetes and Alzheimer's disease: mechanistic insights.

The prevalence of both Alzheimer's disease (AD) and diabetes mellitus is increasing with the societies' aging and has become an essential social concern worldwide. Accumulation of amyloid plaques and neurofibrillary tangles (NFTs) of tau proteins in the brain are hallmarks of AD. Diabetes is an underlying risk factor for AD. Insulin resistance has been proposed to be involved in amyloid-beta (Aß) aggregation in the brain. It seems that diabetic conditions can result in AD pathology by setting off a cascade of processes, including inflammation, mitochondrial dysfunction, and ROS and advanced glycation end products (AGEs) synthesis. Due to the several side effects of chemical drugs and their high cost, using herbal medicine has recently attracted attention for the treatment of diabetes and AD. Saffron and its active ingredients have been used for its anti-inflammatory, anti-oxidant, anti-diabetic, and anti-AD properties. Therefore, in the present review paper, we take account of the clinical, in vivo and in vitro evidence regarding the anti-diabetic and anti-AD effects of saffron and discuss the preventive or postponing properties of saffron or its components on AD development via its anti-diabetic effects.

The effect of Salvia officinalis on blood glycemic indexes and blood lipid profile in diabetic patients: a systematic review and meta-analysis.

Diabetes is one of the most common endocrine disorders that increases the economic burden on the public health system. In this regard, understanding the effect of available herbs on diabetes can be useful. This systematic review was performed to determine the effect of Salvia officinalis on blood glycemic indexes and blood lipid profile (primary outcomes) and 2 h postprandial blood glucose (2HPPG), alanine transaminase (ALT) (U/L) and aspartate transaminase (AST) (U/L) and its side effects (secondary outcomes) in diabetic patients. A systematic search was conducted in the English (Cochrane Library, Medline (PubMed), Scopus, CINAHL, ProQuest and Persian databases since inception to March 2021, without publication time restriction. Two authors separately evaluated the quality of the articles using Cochrane Collaboration's tool for assessing the risk of bias in randomized trials and extracted the data. Heterogeneity of data was evaluated by squared I (I 2). Three studies included in the review and all of them included in meta-analysis. The results of meta-analysis showed that S. officinalis reduced fasting blood sugar (FBS) (mg/dL) (MD: -31.15; 95% CI: -37.56 to -24.73; p<0.00001). It also reduced HbA1c (%) (MD: -0.94; 95% CI: -1.25 to -0.63; p<0.00001) and total cholesterol (mg/dL) (MD: -43.64; 95% CI: -83.26 to -4.02; p=0.03) and reduction of low-density protein (LDL) (mg/dL) (MD: -19.23; 95% CI: -35.81 to -2.65; p=0.02) but it did not have a significant effect on triglyceride (mg/dL) (p=0.09), and high-density lipoprotein (HDL) (mg/dL) (p=0.18). Regarding the secondary outcomes, S. officinalis also had significant effect on 2HPPG, but it did not have a significant effect on ALT (U/L) and AST (U/L). No specific side effects for this plant were reported in these three studies. The results showed that S. officinalis has a positive effect on blood glycemic status and blood lipid profile in diabetes except for triglyceride and HDL. However, due to the small number of included articles, it is recommended that stronger clinical trials be conducted in this field.

The effect of saffron supplementation on glycemic parameters: An overview of systematic reviews.

Due to the widespread use of herbal medicine and evidence pointing to the health benefits of saffron supplementation, this review was performed to evaluate the effects of saffron supplementation on glycemic parameters and lipid profiles based on previous reviews. Relevant articles were retrieved from various databases, which included PubMed, Scopus, ProQuest, Web of Science, Embase, and Cochrane until 2020, with no date restrictions. The quality of the included reviews was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Finally, of 877 obtained articles, eight reviews meeting the inclusion criteria were included for analysis. Among the eight included reviews, seven articles were meta-analyses. In addition, one review had an average quality while seven had a good quality. A narrative description of the included reviews was performed, while a network meta-analysis was not conducted. A brief review of the results was reported according to the weighted mean difference and mean difference. Seven included reviews assessed the effects of saffron or crocin supplementation on glycemic parameters, and six examined these effects on lipid profile parameters. Almost half of the articles reported significant effects of these supplements on glycemic parameters and lipid profiles. Taken together, results suggest that saffron supplementation may improve glycemic and lipid profile parameters; however, further high-quality studies are needed to confirm the clinical efficacy of saffron on glycemic parameters and lipid profiles.

Effects of saffron (Crocus sativus L.) on anthropometric and cardiometabolic indices in overweight and obese patients: A systematic review and meta-analysis of randomized controlled trials.

The worldwide prevalence of obesity is approximately tripled between 1975 and 2016 according to World Health Organization; therefore, obesity is now considered a global pandemic that needs academic and clinical focus. In search of antiobesity agents, Crocus sativus, known widely as saffron, has been praised for its beneficial effects. Several randomized controlled trials (RCTs) have been conducted to investigate the weight lowering effect of saffron. Following PRISMA guidelines, several medical databases were comprehensively searched for RCTs with a population consisting of obese individuals. A random-effects meta-analysis was used to pool estimates across studies, and standardized mean difference (SMD) was used to synthesize quantitative results. Twenty-five RCTs met the inclusion criteria. Meta-analysis showed a nonsignificant decrease for weight (-0.32 kg; CI: -3.15, 2.51; p = 0.82), BMI (-0.06 kg/m2 ;CI:-1.04,0.93; p = .91), waist circumference (-1.23 cm; CI: -4.14, 1.68; p = .41), and hip circumference (-0.38 cm; CI: -5.99, 5.23; p = .89) and a significant decrease of waist-to-hip ratio (SMD = -0.41; CI: -0.73, -0.09; p = .01; I2  = 0%). The mean difference in fasting blood sugar showed a significant reduction in patients with metabolic syndrome (SMD = -0.30; 95% CI: -0.63, 0.03; p = .07; I2  = 0.37%) but a nonsignificant change in the HbA1C level (WMD = 0.05; 95% CI: 0.32, 0.41; p = .79). Despite bearing several limitations, mainly as a result of heterogeneity among included studies, the available evidence indicates saffron supplementation shows promising effects on some cardiometabolic factors among overweight to obese patients; however, further investigations and high-quality evidence are required for more generalizable and comprehensive results.

Anti-diabetic potential of Urtica Dioica: current knowledge and future direction.

Aim: This review summarizes studies on the anti-diabetic effect of Urtica Dioica (UD) in Type-2-diabetes. Materials and methods: We studied worldwide traditional medicines, old texts, and published literature for anti-diabetic effect of UD. Electronic databases comprising PubMed, Web of Science, Science Direct, Scopus and Google Scholar were searched to collect articles published between 1990 and 2021 years. Results: Our literature investigation suggests UD as a glucose lowering, blood lipid regulating, anti-inflammatory and anti-oxidation plant. Conclusions: UD's anti-diabetic properties make it potential traditional therapeutics for lowering the clinical manifestations of T2DM through affecting hyperglycemia and therefore suggest it as a proper medication with no or limited side effects.

Medicinal Plants in the Treatment of Hypertension: A Review.

Traditional medicine is a comprehensive term for ancient, culture-bound health care practices that existed before the use of science in health matters and has been used for centuries. Medicinal plants are used to treat patients with cardiovascular diseases, which may occur due to ailments of the heart and blood vessels and comprise heart attacks, cerebrovascular diseases, hypertension, and heart failure. Hypertension causes difficulty in the functioning of the heart and is involved in atherosclerosis, raising the risk of heart attack and stroke. Many drugs are available for managing these diseases, though common antihypertensive drugs are generally accompanied by many side effects. Medicinal herbs have several active substances with pharmacological and prophylactic properties that can be used in the treatment of hypertension. This review presents an overview of some medicinal plants that have been shown to have hypotensive or antihypertensive properties.

The effects of lemon balm (Melissa officinalis L.) on depression and anxiety in clinical trials: A systematic review and meta-analysis.

A systematic review and a meta-analytic approach were considered to investigate the effects of lemon balm as a medicinal herb on anxiety and depression in clinical trials and its side effects. All randomized clinical trials published up to October 30, 2020 that examined lemon balm in patients with symptoms of depression or anxiety, with acute or chronic manifestations, were searched in 12 online databases. Statistical analysis was performed using RevMan software. Continuous data were analyzed using standardized mean differences. Statistical heterogeneity was assessed using Chi2 , I2 , and p value tests. Based on meta-analysis results, lemon balm significantly improved mean anxiety and depression scores compared with the placebo (SMD: -0.98; 95% CI: -1.63 to -0.33; p = 0.003), (SMD: -0.47; 95% CI: -0.73 to -0.21; p = 0.0005) respectively, without serious side effects. Current evidence suggests that lemon balm may be effective in improving anxiety and depressive symptoms, particularly in the acute setting. Due to the high level of heterogeneity between studies, results should be interpreted with caution. The small number of clinical trials and differences between their methods were the limitations of the present study. Further high-quality studies are needed to firmly establish the clinical efficacy of the lemon balm.

The role of hippocampal GABAA receptors on anxiolytic effects of Echium amoenum extract in a mice model of restraint stress.

Echium amoenum (EA), a popular medicinal plant in Persian medicine, has anxiolytic, antioxidant, sedative, and anti-inflammatory effects. This study examined whether GABA-ergic signaling is involved in the anxiolytic effects of EA in mice. Sixty BALB/c mice (25-30 g) were divided into six groups (n = 10) as follows: the (I) control group received 10 ml/kg normal saline (NS). In the stress groups, the animals underwent 14 consecutive days of restraint stress (RS), and received following treatments simultaneously; (II) RS + NS; (III) RS + Diaz (Diazepam); (IV) RS + EA; (V) RS + Flu (Flumazenil) + EA; (VI) RS + Flu + Diaz. Behavioral tests including the open field test (OFT) and elevated plus maze (EPM) were performed to evaluate anxiety-like behaviors and the effects of the regimens. The plasma level of corticosterone and the hippocampal protein expressions of IL-1ß, TNF-α, CREB, and BDNF, as well as p-GABAA/GABAA ratio, were also assessed. The findings revealed that chronic administration of EA alone produced anxiolytic effects in both behavioral tests, while diazepam alone or in combination with Flu failed to decrease the anxiety-like behaviors. Furthermore, the p-GABAA/GABAA and p-CREB/CREB ratios, and protein levels of BDNF were significantly increased in the EA-received group. On the other hand, plasma corticosterone levels and the hippocampal IL-1ß and TNF-α levels were significantly decreased by EA. However, pre-treatment with GABAA receptors (GABAA Rs) antagonist, Flu, reversed the anxiolytic and molecular effects of EA in the RS-subjected animals. Our findings confirmed that alternation of GABAAR is involved in the effects of EA against RS-induced anxiety-like behaviors, HPA axis activation, and neuroinflammation.

A double-blind, randomized pilot study for comparison of Melissa officinalis L. and Lavandula angustifolia Mill. with Fluoxetine for the treatment of depression.

BACKGROUND: Depression has rapidly progressed worldwide, and the need for an efficient treatment with low side effect has risen. Melissa officinalis L and Lavandula angustifolia Mill have been traditionally used in Asia for the treatment of depression. Many textbooks of traditional Persian medicine refer to these herbs for the treatment of depression while there are no adequate clinical trials to support this claim. The present study aimed to evaluate the efficacy of M. officinalis and L. angustifolia compared to fluoxetine for the treatment of mild to moderate depression in an 8-week randomized, double-blind clinical trial. METHODS: Forty-five adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) for major depression, were randomly assigned to 3 groups to daily receive either M. officinalis (2 g) or L. angustifolia (2 g) or fluoxetine (20 mg) and were assessed in weeks 0, 2, 4 and 8 by the Hamilton Rating Scale for Depression (HAM-D) including 17 items. RESULTS: Our study showed that M. officinalis and L. angustifolia effect similar to fluoxetine in mild to moderate depression. (F = 0.131, df = 2,42, p = 0.877). CONCLUSION: Due to some restrictions in this study including absence of placebo group, large-scale trials are needed to investigate the anti-depressant effect of these two herbs with more details. TRIAL REGISTRATION: IRCT2014061718126N1 . Registration date: 2015-06-04-"Retrospectively registered".

Nano-based delivery systems for berberine: A modern anti-cancer herbal medicine.

Berberine (BBR) is an isoquinoline alkaloid belonging to the structural class of protoberberines. BBR has been used in traditional medicine to treat diseases, such as type 2 diabetes and hypercholesterolemia. BBR inhibits cancer cell growth and induces apoptosis. However, BBR has significant drawbacks as a chemotherapeutic agent, including poor solubility, and induction of drug resistance, limiting its application in chemotherapy. Hence, combination therapy could not only deal with the problems related to single-agent chemotherapy but could also improve the therapeutic index of anticancer drugs. Co-administration of drugs may show pharmaceutical incompatibility due to conflicting physicochemical features. BBR can be used in nanoparticle-based single drug delivery, and in co-delivery systems designed to accommodate drugs and deliver them simultaneously into cancer cells. In this review, we will summarize the use of BBR, including BBR as a single chemotherapeutic agent and the combination of BBR with traditional anti-cancer drugs or herbal medicines in nanoparticle-based delivery systems.

Clinical effects of date palm (Phoenix dactylifera L.): A systematic review on clinical trials.

PURPOSE: The aim of present study was to review and categorize the clinical trials investigating the clinical effects of different botanical parts of dates compared with any controls. METHODS: All clinical trials (randomized, pilot, quasi-experimental, cross-over. and non-randomized clinical trials) evaluating the clinical effects of date palm from 2000 until August 2019 in English and Persian languages were included in this systematic review. The methodological quality of the included studies was evaluated according to the risk of bias assessment of Cochrane handbook of systematic reviews, and then reported using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. RESULTS: Twenty-six studies met the inclusion criteria. Studies were performed in 8 categories based on different botanical parts of date palm. These categories were obstetrics, gynecology, oncology, dermatology, hematology, gastroenterology, endocrinology, metabolism, and infertility. A total of 38 % of included studies were randomized controlled trials. Further, 80 % of the included studies had performance and detection bias. Finally, about 50 % of them had selection bias and about 20 % had attrition and reporting bias. CONCLUSION: The widespread consumption of date palm as medicinal and botanical plant suggests the importance of this plant in human healthcare. The clinical trials conducted so far have explained a number of clinical effects of date palm. However, there is not enough clinical evidence to support the clinical effects in other review articles and traditional medical systems, and further randomized controlled trials with robust designs and methods are required.

Melissa officinalis L. hydro-alcoholic extract inhibits anxiety and depression through prevention of central oxidative stress and apoptosis.

NEW FINDINGS: What is the central question of this study? How does an extract of Melissa officinalis L. ameliorate anxiety- and depressive-like behaviour of mice? What is the main finding and its importance? An extract of Melissa officinalis L. possessed anxiolytic and anti-depressant effects, which could mainly be mediated through its antioxidant and anti-apoptotic properties. ABSTRACT: This study evaluated the effects of a hydro-alcoholic extract of Melissa officinalis (HAEMO) on anxiety- and depressive-like behaviours, oxidative stress and apoptosis markers in restraint stress-exposed mice. In order to induce a depression-like model, mice were subjected to restraint stress (3 h day-1 for 14 days) and received normal saline or HAEMO (50, 75 and 150 mg kg-1  day-1 ) for 14 days. The administered doses of HAEMO were designated based on the concentration of one of the main phenolic compounds present in the extract, rosmarinic acid (2.55 mg kg-1 at lowest dose); other phytochemical analyses including assays for antioxidant activity, total phenols and flavonoids were also carried out. The behavioural changes in an open field task, elevated plus maze, tail suspension and forced swimming tests were evaluated. Also, malondialdehyde (MDA) levels and enzyme activities of superoxide dismutase and glutathione peroxidase, and total antioxidant capacity were assessed in the prefrontal cortex and hippocampus. Moreover, levels of Bcl-2, Bax and caspase 3 in the brain as well as serum concentration of corticosterone were evaluated. HAEMO (75 and 150 mg kg-1 ) significantly reversed anxiety- and depressive-like behaviours. Also, HAEMO reduced MDA levels, enhanced enzymatic antioxidant activities and restored serum levels of corticosterone. An immunoblotting analysis also demonstrated that HAEMO decreased levels of pro-apoptotic markers and increased anti-apoptotic protein levels in the prefrontal cortex and hippocampus of restraint stress-exposed mice. Our findings suggested that HAEMO reduced inflammation and had anxiolytic and antidepressant effects in mice.

A Close Look at Echium amoenum Processing, Neuroactive Components, and Effects on Neuropsychiatric Disorders.

Pharmacological researches in the area of herbal medicine have considerably increased over the last two centuries. Echium amoenum (known as Gol-e-Gavzaban in Persian) is a medicinal plant that has been widely used in Iranian folk medicine. In this review, databases including PubMed, Scopus, and Google Scholar were searched up. Data collecting was completed by January 2019 and available scientific reports regarding the processing methods, main chemical constituents, and effects of E. amoenum on different neuropsychiatric disorders are summarized. Thirteen five studies met the inclusion criteria. According to results, the important phytochemicals of the plant was phenolic compounds, fatty acids, rosmarinic acid, anthocyanidins, and flavonoids. Also, experimental and clinical studies demonstrated the effectiveness of E. amoenum in the treatment of several neuropsychiatric disorders such as anxiety, depression, ischemic stroke, seizure, Alzheimer's disease, and pain. Many of these effects are, at least in part, due to its rosmarinic acid or polyphenolic compounds such as flavonoids and natural pigments such as anthocyanins. Also, fatty acids such as gamma-linolenic acid play critical role in neuroactive properties of this herb. Among these effects, only the antidepressant and anxiolytic properties of the plant extract have been examined both experimentally and clinically. There was some controversy over its toxicity effects. It seems that E. amoenum protects neurons via attenuation of oxidative stress and inflammation as well as blocking of apoptosis in the nervous system. However, more studies are necessary for assessing exact mechanisms of action in neuropsychiatric disorders, finding of bioactive ingredients, and processing methods of this plant.