OBJECTIVES:Chemotherapy is one of the major treatments of cancer. However, the emergence of resistance to chemotherapeutic agents is still a major obstacle in the successful management of resistant tumors. Therefore, development of new mechanisms to overcome drug resistance is essential and may be further developed into effective therapies that can flip the switch from drug resistance to susceptibility. The aim of this study was to evaluate a combination consisting of a ketogenic diet and melatonin to determine whether it would inhibit cisplatin- and vincristine-resistant breast cancer.

METHODS:In the in vitro part of the study, drug-resistant cell lines were treated with melatonin and real-time polymerase chain reaction was used to measure levels of gene expression involved in apoptosis and resistance. On the protein level, the activity of caspase-3 and the level of vascular endothelin growth factor protein were determined. In the in vivo part, tumor-bearing mice received one of the following treatments: ketogenic diet, melatonin, combination of melatonin and ketogenic diet, vehicle, or chemotherapy.

RESULTS:Successful inhibition of resistant cell lines was achieved by melatonin. This inhibition was mediated by induction of apoptosis, inhibition of angiogenesis, and downregulation of resistance genes. A synergistic anticancer effect was observed between melatonin and the ketogenic diet against resistant breast tumors inoculated in mice with a cure rate of 70%.

CONCLUSIONS:The combination of melatonin and a ketogenic diet represents a promising option to overcome drug resistance in cancer chemotherapy. However, further testing on the protein level using flow cytometry is important to better understand the mechanisms of action.

CONTEXT:Major depressive disorder (MDD) in elderly individuals is prevalent and debilitating. It is accompanied by circadian rhythm disturbances associated with impaired functioning of the suprachiasmatic nucleus, the biological clock of the brain. Circadian rhythm disturbances are common in the elderly. Suprachiasmatic nucleus stimulation using bright light treatment (BLT) may, therefore, improve mood, sleep, and hormonal rhythms in elderly patients with MDD.

OBJECTIVE:To determine the efficacy of BLT in elderly patients with MDD.

DESIGN:Double-blind, placebo-controlled randomized clinical trial.

SETTING:Home-based treatment in patients recruited from outpatient clinics and from case-finding using general practitioners' offices in the Amsterdam region.

PARTICIPANTS:Eighty-nine outpatients 60 years or older who had MDD underwent assessment at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2). Intervention Three weeks of 1-hour early-morning BLT (pale blue, approximately 7500 lux) vs placebo (dim red light, approximately 50 lux).

MAIN OUTCOME MEASURES:Mean improvement in Hamilton Scale for Depression scores at T1 and T2 using parameters of sleep and cortisol and melatonin levels.

RESULTS:Intention-to-treat analysis showed Hamilton Scale for Depression scores to improve with BLT more than placebo from T0 to T1 (7%; 95% confidence interval, 4%-23%; P = .03) and from T0 to T2 (21%; 7%-31%; P = .001). At T1 relative to T0, get-up time after final awakening in the BLT group advanced by 7% (P<.001), sleep efficiency increased by 2% (P = .01), and the steepness of the rise in evening melatonin levels increased by 81% (P = .03) compared with the placebo group. At T2 relative to T0, get-up time was still advanced by 3% (P = .001) and the 24-hour urinary free cortisol level was 37% lower (P = .003) compared with the placebo group. The evening salivary cortisol level had decreased by 34% in the BLT group compared with an increase of 7% in the placebo group (P = .02).

CONCLUSIONS:In elderly patients with MDD, BLT improved mood, enhanced sleep efficiency, and increased the upslope melatonin level gradient. In addition, BLT produced continuing improvement in mood and an attenuation of cortisol hyperexcretion after discontinuation of treatment.

TRIAL REGISTRATION:clinicaltrials.gov Identifier NCT00332670.

The treatment of alopecia is limited by a lack of therapies that induce and sustain disease remission. Given the negative psychosocial impact of hair loss, patients that do not see significant hair restoration with conventional therapies often turn to complementary and alternative medicine (CAM). Although there are a variety of CAM treatment options on the market for alopecia, only a few are backed by multiple randomized controlled trials. Further, these modalities are not regulated by the Food and Drug Administration and there is a lack of standardization of bioactive in gredients in over-the-counter vitamins, herbs, and supplements. In this article, we provide a comprehensive review of the efficacy, safety, and tolerability of CAM, including natural products and mind and body practices, in the treatment of hair loss. Overall, there is a need for additional studies investigating CAM for alopecia with more robust clinical design and standardized, quantitative outcomes.

This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.

Depression, anxiety and sleep disturbances are known problems in patients with breast cancer. The effect of melatonin as an antidepressant in humans with cancer has not been investigated. We investigated whether melatonin could lower the risk of depressive symptoms in women with breast cancer in a three-month period after surgery and assessed the effect of melatonin on subjective parameters: anxiety, sleep, general well-being, fatigue, pain and sleepiness. Randomized, double-blind, placebo-controlled trial undertaken from July 2011 to December 2012 at a department of breast surgery in Copenhagen, Denmark. Women, 30-75 years, undergoing surgery for breast cancer and without signs of depression on Major Depression Inventory (MDI) were included 1 week before surgery and received 6 mg oral melatonin or placebo for 3 months. The primary outcome was the incidence of depressive symptoms measured by MDI. The secondary outcomes were area under the curve (AUC) for the subjective parameters. 54 patients were randomized to melatonin (n = 28) or placebo (n = 26) and 11 withdrew from the study (10 placebo group and 1 melatonin group, P = 0.002). The risk of developing depressive symptoms was significantly lower with melatonin than with placebo (3 [11 %] of 27 vs. 9 [45 %] of 20; relative risk 0.25 [95 % CI 0.077-0.80]), giving a NNT of 3.0 [95 % CI 1.7-11.0]. No significant differences were found between AUC for the subjective parameters. No differences in side effects were found (P = 0.78). Melatonin significantly reduced the risk of depressive symptoms in women with breast cancer during a three-month period after surgery.

STUDY OBJECTIVES:Chronic sleep onset insomnia with late melatonin onset is prevalent in childhood, and has negative daytime consequences. Melatonin treatment is known to be effective in treating these sleep problems. Bright light therapy might be an alternative treatment, with potential advantages over melatonin treatment. In this study, we compare the effects of melatonin and bright light treatment with a placebo condition in children with chronic sleep onset insomnia and late melatonin onset.

METHODS:84 children (mean age 10.0 years, 61% boys) first entered a baseline week, after which they received melatonin (N=26), light (N=30), or placebo pills (N=28) for three to four weeks. Sleep was measured daily with sleep diaries and actigraphy. Before and after treatment children completed a questionnaire on chronic sleep reduction, and Dim Light Melatonin Onset (DLMO) was measured. Results were analysed with linear mixed model analyses.

RESULTS:Melatonin treatment and light therapy decreased sleep latency (sleep diary) and advanced sleep onset (sleep diary and actigraphy), although for sleep onset the effects of melatonin were stronger. In addition, melatonin treatment advanced DLMO and had positive effects on sleep latency and sleep efficiency (actigraphy data), and sleep time (sleep diary and actigraphy data). However, wake after sleep onset (actigraphy) increased with melatonin treatment. No effects on chronic sleep reduction were found.

CONCLUSIONS:We found positive effects of both melatonin and light treatment on various sleep outcomes, but more and stronger effects were found for melatonin treatment.

NEDERLANDS TRIAL REGISTER (NTR):NTR4045 (http://www.trialregister.nl).

Reactive oxygen species (ROS) may be involved in the toxicity of chlorpyrifos-ethyl (CE) [O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate]. We have, therefore, examined the in vivo effects of CE on the rat erythrocyte antioxidant system and evaluated the ameliorating effects of melatonin and a combination of vitamin E and vitamin C on the oxidative damage induced by CE. The experimental groups were: (1) control group, (2) CE-treated group (CE), (3) vitamin E plus vitamin C treatment group (Vit), (4) melatonin-treated group (Mel), (5) vitamin E plus vitamin C plus CE treatment group (Vit + CE), and (6) melatonin plus CE treatment group (Mel + CE). Vitamin E and vitamin C were administered intramuscularly once a day for 6 consecutive days at 150 and 200 mg/kg, respectively, in the Vit and Vit + CE groups. Melatonin was administered intramuscularly at 10 mg/kg per day for 6 consecutive days in the Mel and Mel + CE groups. At the end of the fifth day, the rats of CE, Vit + CE and Mel + CE groups were treated orally with the first of two equal doses of 41 mg/kg CE, the second oral dose being given 21 h later. Blood samples were taken 24 h after the first CE administration. Levels of thiobarbituric acid reactive substance (TBARS), antioxidant defence potential (AOP), and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were determined in erythrocytes. In comparison with the control group, oral administration of CE significantly (P<0.05) stimulated TBARS activity while significantly (P<0.05) inhibiting AOP and the activities of SOD and CAT. However, GSH-Px activity remained unchanged by CE treatment. Treatment with melatonin and vitamins E plus C significantly (P<0.05) reduced the CE-induced increase of TBARS, and overcame the inhibitory effect of CE on SOD and CAT, but not on AOP. Melatonin treatment significantly (P<0.05) increased only GSH-Px activity, irrespective of the effect of CE. These results suggest that CE treatment increases in vivo lipid peroxidation and decreases antioxidant defence by increasing oxidative stress in erythrocytes of rats, and melatonin and a combination of vitamin E and vitamin C can reduce this lipoperoxidative effect.

Generally, the development and progression of neurodegenerative diseases are associated with advancing age, so they are usually diagnosed in late adulthood. A primary mechanism underlying the onset of neurodegenerative diseases is neuroinflammation. Based on this background, the concept of"neuroinflammaging"has emerged. In this deregulated neuroinflammatory process, a variety of immune cells participate, especially glial cells, proinflammatory cytokines, receptors, and subcellular organelles including mitochondria, which are mainly responsible for maintaining redox balance at the cellular level. Senescence and autophagic processes also play a crucial role in the neuroinflammatory disease associated with aging. Of particular interest, melatonin, cannabinoids, and the receptors of both molecules which are closely related, exert beneficial effects on the neuroinflammatory processes that precede the onset of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases. Some of these neuroprotective effects are fundamentally related to its anti-inflammatory and antioxidative actions at the mitochondrial level due to the strategic functions of this organelle. The aim of this review is to summarize the most recent advances in the study of neuroinflammation and neurodegeneration associated with age and to consider the use of new mitochondrial therapeutic targets related to the endocannabinoid system and the pineal gland.

Chronic inflammation is a pathologic feature of neurodegeneration and aging; however, the mechanism regulating this process is not understood. Melatonin, an endogenous free radical scavenger synthesized by neuronal mitochondria, decreases with aging and neurodegeneration. We proposed that insufficient melatonin levels impair mitochondrial homeostasis resulting in mitochondrial DNA (mtDNA) release, activation of cytosolic DNA mediated inflammatory response in neurons. We found increased mitochondrial oxidative stress and decreased mitochondrial membrane potential with higher mitochondrial DNA (mtDNA) release in brain and primary cerebro-cortical neurons of melatonin deficient aralkylamine N-acetyltransferase (AANAT) knockout mice. Cytosolic mtDNA activated the cGAS/STING/IRF3 pathway, stimulating inflammatory cytokine generation. We found that Huntington's disease mice increased mtDNA release, cGAS activation, and inflammation, all inhibited by exogenous melatonin. Thus, we demonstrated that cytosolic mtDNA activated the inflammatory response in aging and neurodegeneration, a process modulated by melatonin. Furthermore, our data suggest that AANAT knockout mice are a model of accelerated aging.

This study tested the ergogenic effects of acute administration of melatonin on exhaustive exercise (tlim) at the anaerobic threshold intensity (iAnT) during periods of lower (L) and higher (H) spontaneous physical activity in swimming rats. Additionally, we evaluated the time of day effect on aerobic exercise tolerance. The periods of L and H were determined gravimetrically. All animals were subjected to an incremental test to determine the iAnT. Melatonin was administered (10 mg.kg(-1), intraperitoneal) and after 30 min, the rats were subjected to tlim during the L (LM) or H (HM) period. Control groups were called LC and HC. The criterion of significance was 5%. Melatonin enhanced tlim by 169% during H (HC=72 min; HM=194 min; P<0.01; ES=1.23) and by 90% during L (LC=31 min vs. LM=59 min; P=0.39; ES=1.18), demonstrating a significant effect on tlim (F=10.35; P<0.01) and a strong effect size (ES). Additionally, tlim was higher during H (F=14.24; P<0.01). Melatonin is a reasonable ergogenic aid, particularly during the wakefulness period, and the exercise tolerance is dependent on the time of day for swimming rats.

INTRODUCTION:Oxidative stress has been considered to play a primary role in the pathogenesis of stress-induced gastric damage. The aim of this study was to investigate the effects of melatonin, ascorbic acid andβ-carotene on stress-induced gastric mucosal damage.

MATERIAL AND METHODS:Fifty-six male Wistar albino rats were divided into control, stress, stress + standard diet, stress + saline, stress + melatonin, stress + ascorbic acid and stress +β-carotene groups. The rats from stress groups were exposed to starvation, immobilization and cold by immobilizing for 8 h at +4°C following 72-hour food restriction. Following stress application, melatonin, ascorbic acid and β-carotene were administered for 7 days. Specimens of gastric tissue were prepared for microscopic and biochemical examinations.

RESULTS:Mean histopathological damage scores and mean tissue malondialdehyde levels were significantly decreased but mean tissue glutathione levels and glutathione peroxidase and superoxide dismutase activities were increased in treatment groups vs. stress groups in general. Mean histopathological damage scores of the stress + Mel group was lower than those of stress + D, stress + S, stress +β-car (p<0.05) and stress + Asc groups (p<0.005). Additionally, mean tissue catalase activity of the stress + Mel group was higher than that of stress + S (p<0.005), stress + D (p<0.05) and stress +β-car groups (p<0.05).

CONCLUSIONS:Melatonin is more effective than ascorbic acid andβ-carotene in improvement of gastric damage induced by intensive stress. We suggest that as well as the direct antioxidant and free radical scavenging potency of melatonin, its indirect effect via the brain-gut axis might account for its greater beneficial action against stress-induced gastric damage.

Muscle injury occurs due to trauma, strenuous exercise or sports activities; most people affected are athletes. Ineffectively treated muscle injury can negatively affect sports careers and quality of life after retirement from sports. Reports have indicated that the current therapeutic management of muscle injury, particularly anti-inflammatory drugs, are not necessarily effective. Therefore, better therapies are required. Accumulating evidence has demonstrated melatonin's potent antioxidant and anti-inflammatory actions against musclepathology in sarcopenia or atrophy in systemic disease. However, the underlying mechanisms for the protective effect of melatonin in the context of trauma/strenuous exercise are multifactorial and not well described. This paper reviews data on melatonin's impact on muscle injury and findings that points toward the mechanisms through which melatonin achieves muscle protection. The general concept described in this review is that melatonin inhibits NFκB, reduces cytokine expression, increases Akt that downregulates the ratio of MAFBX and MURF-1 in order to limit the extent of muscle injury andpromote muscle recovery post-injury. The work discussed in this review supports the notion that melatonin may be considered a possible therapy against trauma/sports related muscle injury. Inclusion of melatonin as a therapy in sports medicine could therefore provide a better treatment option for injured athletes and sports individuals.

Venezuelan equine encephalitis (VEE) virus causes an acute central nervous system infection in human and animals. Melatonin (MLT), minocycline (MIN) and ascorbic acid (AA) have been shown to have antiviral activities in experimental infections; however, the mechanisms involved are poorly studied. Therefore, the aim of this study was to determine the effects of those compounds on the viral titers, NO production and lipid peroxidation in the brain of mice and neuroblastoma cultures infected by VEE virus. Infected mouse (10 LD50) were treated with MLT (500μg /kg bw), MIN (50mg /kg bw) or AA (50mg /kg bwl). Infected neuroblastoma cultures (MOI: 1); MLT: 0.5, 1, 5mM, MIN: 0.1, 0.2, 2μM or AA: 25, 50, 75μM. Brains were obtained at days 1, 3 and 5. In addition, survival rate of infected treated mice was also analyzed. Viral replication was determinedby the plaque formation technique. NO and lipid peroxidation were measured by Griess' reaction and thiobarbituric acid assay respectively. Increased viral replication, NO production and lipid peroxidation were observed in both, infected brain and neuroblastoma cell cultures compared with uninfectedcontrols. Those effects were diminished by the studied treatments. In addition, increased survival rate (50%) in treated infected animals compared with untreated infected mice (0%) was found. MLT, MIN and AA have an antiviral effect involving their anti-oxidant properties, and suggesting a potentialuse of these compounds for human VEE virus infection.

BACKGROUND:The aging process is not univocal, both body and brain age. Neurological disorders are a major cause of disability and death worldwide. According to the Global Burden of Disease Study 2015, neurological diseases are the second most common cause of death and 16.8% of total deaths are caused by neurological diseases worldwide. Neurological disease deaths have risen 36% worldwide in 25 years. Melatonin is a neuroregulator hormone that has free radical scavenger, strong antioxidant, anti-inflammatory, and immunosuppressive actions. These major properties of melatonin can play an important role in the pathophysiological mechanisms of neurological diseases. In addition, melatonin is necessary for circadian rhythm. Studies have shown that melatonin levels are low in people with neurological diseases. Both preventive and therapeutic effects of melatonin are known for many diseases, including neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headache, etc.). Based on all these reasons, clinical trials of melatonin were performed and successful results were declared.

CONCLUSIONS:In this review, biological and chemical knowledge of melatonin, its experimental effects, and the clinical impact on patients with neurological disorders were described. According to all of the beneficial results obtained from experimental and clinical trials, melatonin may have a prophylactic and therapeutic effect on neurological diseases. Strong collaboration between neurologists and health service policy makers is needed to encourage use of melatonin in the patients suffering from neurological diseases. Melatonin may be the solution we have been looking for.

Mitochondria play a central role in the cell physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis and apoptosis control. Simultaneously mitochondria are the main producer and target of ROS and with the result, multiple mitochondrial diseases are related to ROS induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Among these, neurodegenerative diseases such as Alzheimer´s disease (AD), Parkinson´s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington´s disease (HD) and aging are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergeticfunction. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. Keeping these functions into consideration, this article was framed to review the protective role of melatonin with mechanistic insights against mitochondrial diseases, and may suggest the new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights have also been discussed.

OBJECTIVE:Critical macromolecules such as DNA maybe damaged by free radicals that are generated from the interaction of ionizing radiation with biological systems. Melatonin and vitamin C have been shown to be direct free radical scavengers. The aim of this study was to investigate the in vivo/in vitro radioprotective effects of melatonin and vitamin C separately and combined against genotoxicity induced by 6 MV x-ray irradiation in human cultured blood lymphocytes.

MATERIALS AND METHODS:In this experimental study, fifteen volunteers were divided into three groups of melatonin, vitamin C and melatonin plus vitamin C treatment. Peripheral blood samples were collected from each group before, and 1, 2 and 3 hours after melatonin and vitamin C administration (separately and combined). The blood samples were then irradiated with 200 cGy of 6 MV x-ray. In order to characterize chromosomal aberrations, the lymphocyte samples were cultured with mitogenic stimulus on cytokinesisblocked binucleated cells.

RESULTS:The samples collected 1hour after melatonin and vitamin C (separately and combined) ingestion exhibited a significant decrease in the incidence of micronuclei compared with their control group (P<0.05). The maximum synergic protection and reduction in frequency of micronuclei (57%) was observed 1 hour after vitamin C and melatonin administration combined.

CONCLUSION:We conclude that simultaneous administration of melatonin and vitamin C as radioprotector substances before irradiation may reduce genotoxicity caused by x-ray irradiation.

Nephrotoxicity induced by chlorpyrifos-ethyl (CE) and ameliorating effects of melatonin and vitamin E plus vitamin C were evaluated in rats exposed to CE. Experimental groups were as follows: control (C), CE treated (CE), vitamin E plus vitamin C treated (Vit), melatonin treated (Mel), vitamin E plus vitamin C plus CE treated (Vit+CE), and melatonin plus CE treated (Mel+CE). The rats in the CE, Vit+CE and Mel+CE groups were administered orally with CE in two equal doses of 41 mg/kg body weight (0.25 LD50). Melatonin and vitamins E and C were administrated intramuscularly at the doses of 10, 150 and 200 mg/kg, respectively. The levels of thiobarbituric acid reactive substance (TBARS) and antioxidant potential (AOP), and the activities of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) were studied in the homogenates of kidney tissue. There were no significant differences in the activities of SOD and CAT between the experimental groups. The level of TBARS increased significantly (P<0.05) while AOP decreased significantly (P<0.05) in the CE group compared with the C group. GSH-Px activity was significantly (P<0.05) lower in the CE group and higher in the melatonin group than the control group. Histopathological changes were found in the kidney tissue of rats treated with CE. These were infiltration in mononuclear cells at perivascular and peritubular areas, hydropic degenerations in tubule epithelium and glomerular sclerosis. The severity of the lesions was reduced by administration of vitamins and melatonin. These results suggest that CE increases lipid peroxidation and decreases AOP by increasing oxidative stress, and that high doses of melatonin and a combination of vitamin E plus vitamin C considerably reduce the toxic effect of CE on kidney tissue of rats.

Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets, a large number of studies has investigated the possible BP lowering effect of different dietary supplements and nutraceuticals, the most part of them being antioxidant agents with a high tolerability and safety profile. In particular relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of the above discussed products. Moreover further clinical research is advisable to identify between the available active nutraceuticals those with the best cost-effectiveness and risk-benefit ratio for a large use in general population with low-added cardiovascular risk related to uncomplicated hypertension.

Alendronate causes serious gastrointestinal adverse effects. We aimed to investigate if free radicals have any role in the damage induced by alendronate and if melatonin or omeprazole is protective against this damage. Rats were administered 20 mg/kg alendronate by gavage for 4 days, either alone or following treatment with melatonin or omeprazole. On the last day, following drug administration, pilor ligation was performed, and 2 hr later rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation, and myeloperoxidase and glutathione levels, as well as the histologic appearance of the stomach tissues, were determined. Chronic oral administration of alendronate induced significant gastric damage, increasing lipid peroxidation and myeloperoxidase activity, while tissue glutathione levels decreased. Treatment with omeprazole or melatonin prevented this damage as well as the changes in biochemical parameters, and melatonin appeared to be more efficient than omeprazole in protecting the mucosa. Intraperitoneal administration of alendronate did not cause much gastric irritation. Findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect and that melatonin and omeprazole are protective against this damage due to their antioxidant properties.