Protective and therapeutic potential of melatonin against intestinal diseases: updated review of current data based on molecular mechanisms.

INTRODUCTION: Intestinal diseases, a leading global cause of mortality and morbidity, carry a substantial socioeconomic burden. Small and large intestines play pivotal roles in gastrointestinal physiology and food digestion. Pathological conditions, such as gut dysbiosis, inflammation, cancer, therapy-related complications, ulcers, and ischemia, necessitate the urgent exploration of safe and effective complementary therapeutic strategies for optimal intestinal health. AREAS COVERED: This article evaluates the potential therapeutic effects of melatonin, a molecule with a wide range of physiological actions, on intestinal diseases including inflammatory bowel disease, irritable bowel syndrome, colon cancer, gastric/duodenal ulcers and other intestinal disorders. EXPERT OPINION: Due to anti-inflammatory and antioxidant properties as well as various biological actions, melatonin could be a therapeutic option for improving digestive disorders. However, more researches are needed to fully understand the potential benefits and risks of using melatonin for digestive disorders.

Melatonin and neuroblastoma: a novel therapeutic approach.

Neuroblastoma is a deadly and serious malignancy among children. Although many developments have been occurred for the treatment of this disease, the rate of mortality is still high. Therefore, it is necessary to search for novel complementary and alternative therapies. Melatonin, a hormone secreted from pineal gland, is a multifunctional agent having anticancer potentials. Recently, several investigations have been conducted indicating melatonin effects against neuroblastoma. In this paper, we summarize current evidence on anti-neuroblastoma effects of melatonin based on cellular pathways.

An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress.

Cancers are serious life-threatening diseases which annually are responsible for millions of deaths across the world. Despite many developments in therapeutic approaches for affected individuals, the rate of morbidity and mortality is high. The survival rate and life quality of cancer patients is still low. In addition, the poor prognosis of patients and side effects of the present treatments underscores that finding novel and effective complementary and alternative therapies is a critical issue. Melatonin is a powerful anticancer agent and its efficiency has been widely documented up to now. Melatonin applies its anticancer abilities through affecting various mechanisms including angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Regarding the implication of mentioned cellular processes in cancer pathogenesis, we aimed to further evaluate the anticancer effects of melatonin via these mechanisms.

Efficacy and Safety of a Traditional Herbal Combination in Patients with Type II Diabetes Mellitus: A Randomized Controlled Trial.

BACKGROUND: Capparis spinosa, Rosa canina, Securidaca securigera, Silybum marianum, Urtica dioica, Trigonella foenum-graecum and Vaccinium arctostaphylos are used traditionally as an herbal combination for treatment of diabetic patients in Iran. Despite the clinical evidence supporting their use in solitary form, no controlled human study has determined the efficacy and safety of their combination in treatment of diabetic patients. METHODS: A total 150 type II diabetic patients of both sexes under the oral anti-hyperglycemic drugs treatment (maximum 10 mg glyburide and 1000 mg metformin daily) were randomly assigned to three groups. The patients in each group received either herbal combination or placebo or metformin capsule daily for three months, without any change in their previous oral anti-hyperglycemic drugs dosage. Herbal combination, placebo and metformin capsules matched by shape and color were prepared in the Institute of Medicinal Plants Karaj, Iran. To assess the efficacy and safety of the treatments, the patients fasting plasma glucose, HbA1c, lipid profile, liver enzymes and renal function were determined at the beginning of the study and after three months. RESULTS: Results showed that after three months, the fasting plasma glucose, HbA1c and cholesterol levels in herbal combination were decreased significantly as compared to placebo group (20% and 12% respectively) and also compared to base line (25% and 15% respectively). The herbal combination was as effective as metformin in reduction of FPG (p = 0.001, p = 0.001) and HbA1c (p = 0.028 and p = 0.050 respectively) compared to placebo. No notable hepatic, renal and gastrointestinal side effects were observed in the trial groups. CONCLUSION: The results suggest that traditional herbal combination may safely improve glycemic control in type II diabetic patients with no significant adverse effect. [Formula: see text].

Melatonin and urological cancers: a new therapeutic approach.

Urological cancers are responsible for thousands of cancer-related deaths around the world. Despite all developments in therapeutic approaches for cancer therapy, the absence of efficient treatments is a critical and vital problematic issue for physicians and researchers. Furthermore, routine medical therapies contribute to several undesirable adverse events for patients, reducing life quality and survival time. Therefore, many attempts are needed to explore potent alternative or complementary treatments for great outcomes. Melatonin has multiple beneficial potential effects, including anticancer properties. Melatonin in combination with chemoradiation therapy or even alone could suppress urological cancers through affecting essential cellular pathways. This review discusses current evidence reporting the beneficial effect of melatonin in urological malignancies, including prostate cancer, bladder cancer, and renal cancer.

Melatonin potentials against viral infections including COVID-19: Current evidence and new findings.

Viral infections are dangerous diseases for human health worldwide, which lead to significant morbidity and mortality each year. Because of their importance and the lack of effective therapeutic approaches, further attempts should be made to discover appropriate alternative or complementary treatments. Melatonin, a multifunctional neurohormone mainly synthesized and secreted by the pineal gland, plays some roles in the treatment of viral infections. Regarding a deadly outbreak of COVID-19 across the world, we decided to discuss melatonin functions against various viral infections including COVID-19. Therefore, in this review, we summarize current evidence on melatonin therapy for viral infections with focus on possible underlying mechanisms of melatonin actions.

Therapeutic application of nutraceuticals in diabetic nephropathy: Current evidence and future implications.

Diabetes mellitus (DM) is a common metabolic disease which may cause several complications, such as diabetic nephropathy (DN). The routine medical treatments used for DM are not effective enough and have many undesirable side effects. Moreover, the global increased prevalence of DM makes researchers try to explore potential complementary or alternative treatments. Nutraceuticals, as natural products with pharmaceutical agents, have a wide range of therapeutic properties in various pathologic conditions such as DN. However, the exact underlying mechanisms have not been fully understood. The purpose of this review is to summarize recent findings on the effect of nutraceuticals on DN.

Melatonin in the treatment of fibromyalgia symptoms: A systematic review.

The available pharmacological modalities for the treatment of fibromyalgia (FM) are associated with a variety of adverse effects and limited benefits. In this study, we systematically reviewed the impact of melatonin in the treatment of FM. Interventional studies, either controlled or uncontrolled and randomized or non-randomized, were included. PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were searched without time limitation. Primary outcome measures were the effect of melatonin on the disease impact, pain, sleep quality, tender point count, fatigue, anxiety, stiffness, and depression in FM patients. Four studies, reporting the effect of melatonin on 98 patients, were eligible to include. All the studies reported the positive effect of melatonin on the FM symptoms. No major adverse event was reported. A significant level of heterogeneity was observed between the studies. Therefore, further high-quality controlled clinical trials are needed to understand the role of melatonin in FM treatment fully.

Effects of Aloe vera and Eucalyptus methanolic extracts on experimental toxoplasmosis in vitro and in vivo.

Toxoplasmosis is a worldwide disease caused by the protozoan parasite Toxoplasma gondii (T. gondii), which is most commonly treated by pyrimethamine and sulfadiazine. However, this treatment presents several adverse side effects; Thus, new drugs with lower toxicities are urgently needed. In this study the anti-T. gondii activity of A. vera and Eucalyptus extracts were evaluated in vitro using a MTT (3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide) assay and in vivo by measuring the survival rates of mice infected with 2 × 103 tachyzoites of RH strain of T. gondii and then injected intraperitoneally by different concentrations of extracts for 4 days. Biochemical parameters such as Ferric Reducing Antioxidant Potential (FRAP) and malondialdehyde (MDA) assay were also evaluated. As results, in the in vitro assay, the IC50 values were 13.2, 24.7, 2.63 µg/ml, and the selectivity indexes were 3.3, 2.4, 3.03 for the A. vera, Eucalyptus and pyrimethamine, respectively. The mice treated with Eucalyptus showed a better survival rate than others (P < 0.05). The increased weight of liver and spleen, due to infection, was reduced by treatments. In FRAP assay Eucalyptus showed a better antioxidant activity than the other extracts. MDA levels in both liver and spleen were reduced by treatment. The results show that A. Vera and Eucalyptus possess anti-T. gondii activities in vitro and in vivo, in addition, Eucalyptus shows antioxidant activity with a higher survival rate. Therefore, Eucalyptus may be a useful candidate for treating Toxoplasma infection. Moreover, further studies are required to investigate the fractionations of this plant against T. gondii.

The Effects of Boswellia serrata Gum Resin on the Blood Glucose and Lipid Profile of Diabetic Patients: A Double-Blind Randomized Placebo-Controlled Clinical Trial.

Regarding preclinical evidence for antidiabetic effects of Boswellia serrata, we evaluated antihyperglycemic and lipid-lowering effects of Boswellia serrata gum resin in type 2 diabetic patients. Fifty-six diabetic patients were randomly allocated to 2 groups to receive 250 mg of the Boswellia serrata gum resin or placebo twice daily for 8 weeks in addition to their routine antidiabetic treatments. Although there was a considerable reduction after the intervention in the field of fasting blood sugar, glycosylated hemoglobin, and triglyceride in the Boswellia serrata gum resin group, no significant difference was observed in all outcome measures between the 2 groups at the end of the study. The current study showed that 8 weeks of complementary use of Boswellia serrata gum resin with a daily dose of 500 mg had no better glucose and lipid-lowering effect than placebo in diabetic patients.

Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats.

Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p<0.001). It also, increases MDA, PC, NO levels and MPO activity (p<0.001, p<0.01, p<0.05 and p<0.01 respectively). Moreover, MTX decreases hepatic GSH level, SOD, GPx and CAT activities (all p<0.001). Pre-treatment with BBR for 10days prevented some of these changes. Serum levels of AST and ALT decreased (all p<0.001). Hepatic MDA level decreased (p<0.001) and GSH level as well as GPx activity increased (p<0.05 and p<0.01 respectively). Our results indicated that BBR might be useful for prevention of the hepatotoxicity induced by MTX via ameliorative effects on biochemical and oxidative stress indices.

Silymarin, Olibanum, and Nettle, A Mixed Herbal Formulation in the Treatment of Type II Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.

Silybum marianum (L) Gaertn (milk thistle) seeds, Urtica dioica L (nettle) leaves, and Boswellia serrata (olibanum gum) resin are used traditionally by Iranian diabetic patients. The aim of this study was to evaluate the antihyperglycemic effects of these herbs in an herbal formulation in patients with type II diabetes mellitus. Sixty patients diagnosed as type II diabetes mellitus with fasting blood glucose level from 150 to 180 mg/dL, glycosylated hemoglobin level from 7.5% to 8.5%, and on oral antihyperglycemic drugs, were allocated to receive the mix herbal formulation or placebo for 90 days in a double-blind randomized placebo-controlled clinical trial. The mean serum fasting blood glucose, glycosylated hemoglobin, and triglyceride in the herbal drug group were significantly less than placebo group's values after 3 months of the intervention. The study showed a potential antihyperglycemic and triglyceride lowering effect of the herbal formulation, while it did not have any significant cholesterol or blood pressure lowering effect.

Effects of an Herbal Combination on Glycemic Control and Lipid Profile in Diabetic Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

The present study was conducted to explore the efficacy and safety of a herbal combination in the treatment of women with hyperlipidemic type 2 diabetes. The herbal combination capsule (600 mg) contained Terminalia chebula fruit extract (200 mg), Commiphora mukul (200 mg), and Commiphora myrrha oleo-gum-resin (200 mg), and the placebo capsule contained 600 mg toast powder. The patients in one group took the herbal combination and those in the other group took placebo capsules 3 times a day for 3 months. In the herbal combination-treated patients, the fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol levels were decreased and hidh-density lipoprotein cholesterol levels was increased significantly at the endpoint compared with the placebo and baseline. Other blood parameters such as glycosylated hemoglobin, triglyceride, blood urea nitrogen, creatinine, SGOT, and SGPT levels were not significantly changed after 3 months in both groups. In conclusion, the herbal combination improves glycemic control and lipid profile in women with hyperlipidemic type 2 diabetes without any adverse events.

Anticonvulsant Effects of Aerial Parts of Verbena officinalis Extract in Mice: Involvement of Benzodiazepine and Opioid Receptors.

To evaluate the anticonvulsant activity of the aerial parts of Verbena officinalis used traditionally by local Iranians for the treatment of convulsion. The anticonvulsant activity of the extract was assessed in pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Diazepam was used as reference drug. In addition, for investigating the mechanism of V officinalis in PTZ model, flumazenil and naloxone were injected before V officinalis. The extract showed no toxicity and significantly increased the period taken before the onset and decreased the duration of the seizures induced by PTZ. In the MES test, V officinalis displayed significant reduction in hind limb tonic extension duration in a dose-dependent manner. The results propose that V officinalis ethanolic extract has anticonvulsant activity against seizure. It seems that these effects may be related to potentiating of GABAergic system. Moreover, this study supports the use of this plant by local Iranians in order to treat convulsion.

The Efficacy of Boswellia Serrata Gum Resin for Control of Lipid Profile and Blood Glucose in Diabetic Patients.

BACKGROUND: Regarding preclinical evidence for antidiabetic effects of Boswellia serrata, we evaluated anti-hyperglycemic and lipid-lowering effects of Boswellia serrate gum resin in type 2 diabetic patients in a double-blind randomized placebo-control trial. METHODS: Fifty-six diabetic patients were randomly allocated to two groups to receive 250 mg of the Boswellia serrate gum resin or placebo twice daily for 8 weeks, in addition to their routine antidiabetic treatments. Fasting blood sugar (FBS), glycosylated hemoglobin (HbA1c), insulin level, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride of serum were measured before and after the intervention. RESULTS: Although there was a considerable reduction after the intervention in FBS (P=0.04), HbA1c (P=0.02) and triglyceride (P=0.01) in the Boswellia serrate gum resin group, no significant difference was observed in all outcome measures between the two groups at the end of the study (FBS P=0.09, HbA1c P=0.20, total cholesterol P=0.31, LDL P=0.49, HDL P=0.10, triglyceride P=0.78 and insulin level P=0.86). CONCLUSION: The current study showed the 8 weeks complementary use of Boswellia serrate gum resin with a daily dose of 500 mg had no better glucose and lipid lowering effect than placebo in diabetic patients.

The efficacy of herbal medicines against Toxoplasma gondii during the last 3 decades: a systematic review.

The objective of the current study was to systematically review papers discussing the efficacy of medicinal herbs against Toxoplasma gondii. Data were systematically collected from published papers about the efficacy of herbs used against T. gondii globally from 1988 to 2015, from PubMed, Google Scholar, ISI Web of Science, EBSCO, Science Direct, and Scopus. Forty-nine papers were included in the current systematic review reporting the evaluation of medicinal plants against T. gondii globally, both in vitro and in vivo. Sixty-one plants were evaluated. Most of the studies were carried out on Artemisia annua. The second highest number of studies were carried out on Glycyrrhiza glabra extracts. RH and ME49 were the predominant parasite strains used. Additionally, Swiss-Webster and BALB/c mice were the major animal models used. Alcoholic and aqueous extracts were used more than other types of extracts. Natural compounds mentioned here may be developed as novel and more effective therapeutic agents that improve the treatment of toxoplasmosis due to their lower side effects, higher availability, and better cultural acceptance compared with those of the chemical drugs that are currently being used.

Protective effect of Berberis vulgaris fruit extract against Paraquat-induced pulmonary fibrosis in rats.

BACKGROUND: Pulmonary fibrosis induced by paraquat (PQ) has caused a large number of human fatalities all over the world, especially in Asian region. The main potential mechanism of PQ toxicity has been thought to be mediated by ROS. The present study was designed to evaluate the efficacy of the Berberis vulgaris fruit extract (BVFE) against PQ-induced pulmonary fibrosis in rats. METHODS: Forty male rats were randomly divided into five experimental groups each containing eight rats. Groups 1 and 2, served as a negative and positive control and received a single dose of intratracheal instillation of saline and PQ (20mg/kg), respectively. Groups 3-5 were treated with different doses of BVFE (100, 200, 400mg/kg/day, orally) 1 week before the PQ injection and continued for 3 weeks. The rats were sacrificed 21days after PQ. Malondialdehyde (MDA), Hydroxyproline, inflammatory and fibrogenic cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-ß1 in lung tissue were determined. Presence of fibrosis, inflammatory cells, connective tissue and collagen deposition in lung were evaluated microscopically by hematoxylin and eosin (H&E) staining. Dried extract was standardized by amount of berberine by HPTLC methods by silica gel plate. RESULTS: The results showed that PQ could significantly increase the lung MDA, hydroxyproline, TNF-α, IL-6 and TGF-ß1 levels. BVFE ameliorated the biochemical and histological lung alterations induced by PQ. CONCLUSIONS: The present study indicates the hydroalcolic extract of Berberis vulgaris fruit has beneficial effects in rat pulmonary fibrosis induced by PQ in a dose-dependent manner, possibly by anti-oxidant and anti- inflammatory properties, which might be due to its berberine alkaloid content.

Nanotechnology in hyperthermia cancer therapy: From fundamental principles to advanced applications.

In this work, we present an in-depth review of recent breakthroughs in nanotechnology for hyperthermia cancer therapy. Conventional hyperthermia methods do not thermally discriminate between the target and the surrounding normal tissues, and this non-selective tissue heating can lead to serious side effects. Nanotechnology is expected to have great potential to revolutionize current hyperthermia methods. To find an appropriate place in cancer treatment, all nanotechnology-based hyperthermia methods and their risks/benefits must be thoroughly understood. In this review paper, we extensively examine and compare four modern nanotechnology-based hyperthermia methods. For each method, the possible physical mechanisms of heat generation and enhancement due to the presence of nanoparticles are explained, and recent in vitro and in vivo studies are reviewed and discussed. Nano-Photo-Thermal Therapy (NPTT) and Nano-Magnetic Hyperthermia (NMH) are reviewed as the two first exciting approaches for targeted hyperthermia. The third novel hyperthermia method, Nano-Radio-Frequency Ablation (NaRFA) is discussed together with the thermal effects of novel nanoparticles in the presence of radiofrequency waves. Finally, Nano-Ultrasound Hyperthermia (NUH) is described as the fourth modern method for cancer hyperthermia.

Protective Effect of Ocimum basilicum Essential Oil Against Acetic Acid-Induced Colitis in Rats.

Ocimum basilicum L has been traditionally used for the treatment of inflammatory bowel disease in Iran. This study investigates the ameliorative effect of Ocimum basilicum essential oil on an acetic acid-induced colitis model in rats. Ocimum basilicum essential oil with 2 doses (200 and 400 µL/kg) significantly ameliorated wet weight/length ratio of colonic tissue compared to the control group. Higher doses of essential oil (200 and 400 µL/kg) significantly reduced ulcer severity, ulcer area, and ulcer index. On the other hand, histological examination revealed the diminution of total colitis index as a marker for inflammatory cell infiltration in the colonic segments of rats treated with Ocimum basilicum essential oil (200 and 400 µL/kg). The increased level of myeloperoxidase was significantly decreased after the treatment with the essential oil (200 and 400 µL/kg). These results suggest that Ocimum basilicum exhibits protective effect against acetic acid-induced colitis.

Anticonvulsant Activity of Hydroalcoholic Extract of Citrullus colocynthis Fruit: Involvement of Benzodiazepine and Opioid Receptors.

This study investigated the anticonvulsant activity of Citrullus colocynthis fruit extract used traditionally in the treatment of convulsion. Albino mice were pretreated with extract in different doses (10, 25, 50, and 100 mg/kg), prior to injection of pentylenetetrazole. Animals received pretreatments with naloxone and flumazenil to further clarify the mechanisms of anticonvulsant action. The total flavonoid content of Citrullus colocynthis extract was also determined. Citrullus colocynthis hydroalcoholic extract with doses 25 and 50 mg/kg prolonged the onset of seizures and decreased the duration compared with control group. Pretreatment by flumazenil could inhibit the effect of Citrullus colocynthis on latency of seizure to some extent and administration of naloxone significantly inhibited changes in latency and duration of seizure produced by Citrullus colocynthis This study showed that Citrullus colocynthis has significant anticonvulsant effect in pentylenetetrazole-induced seizures in mice, and these effects may be related to its effect on γ-aminobutyric acid-ergic and opioid systems. These results confirmed the traditional use of Citrullus colocynthis in Iranian traditional medicine.