Melatonin, aging, and COVID-19: Could melatonin be beneficial for COVID-19 treatment in the elderly?

The aim of this review is to summarize current studies on the relationship between melatonin and aging. Nowadays, age-related diseases come into prominence, and identifying age-related changes and developing proper therapeutic approaches are counted as some of the major issues regarding community health. Melatonin is the main hormone of the pineal gland. Melatonin is known to influence many biological processes in the body, including circadian rhythms, the immune system, and neuroendocrine and cardiovascular functions.Melatoninrhythms also reflect the biological process of aging. Aging is an extremely complex and multifactorial process. Melatonin levels decline considerably with aging and its decline is associated with several age-related diseases. Aging is closely associated with oxidative damage and mitochondrial dysfunction. Free radical reactions initiated by the mitochondria constitute the inherent aging process. Melatonin plays a pivotal role in preventing age-related oxidative stress. Coronavirus disease 2019 (COVID-19) fatality rates increase with chronic diseases and age, where melatonin levels decrease. For this reason, melatonin supplementation in elderly could be beneficial in COVID-19 treatment. Therefore, studies on the usage of melatonin in COVID-19 treatment are needed.

Vitamin D Levels of Outpatients Admitted to a University Hospital in the Marmara Region of Turkey Over 3 Years.

BACKGROUND: Vitamin D regulates calcium and phosphorus metabolism, and it is essential for bone formation. Several factors can affect vitamin D levels in plasma. In present study we compare vitamin D levels of outpatients, who admit to Maltepe University Hospital between 2011 and 2013 and had vitamin D measurements regarding gender, age, and season. METHODS: Hospital records were evaluated to identify the outpatients with vitamin D levels and their gender, age, and vitamin D levels and the seasons of measurements were recorded. RESULTS: Data of 4860 subjects (74% female) were analyzed and 69.2% were between 18-64 years old. Vitamin D levels were as follows: 43.1% ≤ 10 ng/mL, 31.9% between 10 ng/mL and 20 ng/mL, 16.1% between 20 ng/mL and 30 ng/mL, and only 8.9% ≥ 30 ng/mL. The number of females with vitamin D levels < 10 ng/mL was significantly higher than that of males, while the number of males with vitamin D levels between 10 ng/mL and 20 ng/mL was significantly higher than that of females (P = 0.001) for each of the individuals, 6.2% and 11.1% had sufficient levels in winter and summer, respectively. Overall, it was observed that 6.6% of individuals between 18-44 years old, 8.2% of individuals between 45-64 years old and 10.3% of individuals over 65 years old had vitamin D levels > 30 ng/mL. CONCLUSIONS: The prevalence of vitamin D deficiency in outpatients of Maltepe University Hospital in Marmara region was 75% (< 20 ng/mL).

Evaluation of Sperm DNA Fragmentation via Halosperm Technique and TUNEL Assay Before and After Cryopreservation.

AIM: Human sperm DNA fragmentation is one of the factors suggested for male infertility. The ratio of sperm DNA damage in semen may adversely affect both the fertilization rate and the embryo development of in vitro fertilization/ intracytoplasmic sperm injection cycles. Sperm cryopreservation both increases the success rates in assisted reproductive techniques (ARTs) and contributes to the preservation of fertility before testis surgery, chemotherapy, and radiotherapy. The aim of the current study is to determine sperm DNA fragmentation, following cryopreservation. METHODS: A cross-sectional, observational study was conducted at a university hospital infertility clinic. One hundred (n = 100) volunteer fertile men (ages between 21 and 39 years) with normozoospermic sperm parameters were involved in the current study. Sperm DNA damage was evaluated with the Halosperm technique and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Fresh samples were studied in liquid form. The remaining samples were kept frozen and then thawed after 1 month and reevaluated with the Halosperm technique and TUNEL assay. Results were then compared between the fresh and frozen samples. RESULTS: Sperm DNA fragmentation results with the Halosperm technique both before and after cryopreservation were 25% (5%-65%) and 40% (6%-89%), respectively, with a statistically significant increase (15%; P < .001). Sperm DNA fragmentation results by TUNEL assay before and after cryopreservation were 17% (3%-43%) and 36% (7%-94%), respectively, with a statistically significant increase (19%; P <.001). CONCLUSION: The current data demonstrate increased sperm DNA damage after cryopreservation. Further studies may contribute to development of less harmful techniques and cryoprotectants in order to improve the results of ART.

Protective effect of melatonin and 1,25-dihydroxyvitamin D3 on renal ischemia-reperfusion injury in rats.

Ischemia-reperfusion (I/R) injury induces the generation of reactive oxygen species (ROS) which affect many organs. This study was designed to investigate the roles of melatonin and 1,25-dihydroxyvitamin D3 (VD3) on renal I/R injury. Thirty male Wistar albino rats were divided into five groups: group 1, control; group 2, right nephrectomy (RN) +  I/R in the contralateral kidney; group 3, melatonin + RN + I/R; group 4, VD3 + RN + I/R; and group 5, melatonin + VD3 + RN + I/R. Melatonin (10 mg/kg), VD3 (0.5 µg/kg), and melatonin plus VD3 were injected intraperitoneally for 7 days before renal I/R. After 7 days, right nephrectomy was initially performed and left renal artery was clamped for 45 min. After 45-min reperfusion, the serum and kidney tissue samples were obtained for assays. Melatonin and VD3 had an ameliorative effect on biochemical parameters such as serum creatinine (SCr) and blood urea nitrogen (BUN). Renal tissue malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels, and superoxide dismutase (SOD) activity were determined. Renal I/R decreased the kidney tissue GSH levels and SOD activity and increased the NO levels as compared with control group. However, melatonin and VD3 and melatonin plus VD3 treatment significantly increased the tissue GSH levels and SOD activity and decreased the NO levels compared with those of I/R group. Meanwhile, MDA levels were not different between the control and I/R groups. But, MDA levels decreased in all treated groups compared to I/R and control groups. These data support that melatonin and VD3 have beneficial effects on renal injury.

Comparison of melatonin and ozone in the prevention of reperfusion injury following unilateral testicular torsion in rats.

OBJECTIVE: To compare the efficacy of ozone with melatonin, shown as the most powerful antioxidant in attenuation of testicular ischemia/reperfusion injury, in an experimental rat model of testicular torsion/detorsion. METHODS: Twenty-four male Wistar rats were divided into 4 groups: sham-operated, torsion/detorsion, torsion/detorsion plus melatonin, and torsion/detorsion plus ozone. Melatonin (10 mg/kg) and ozone (4 mg/kg) were intraperitoneally injected daily beginning 15 minutes before detorsion for the following 7 days. At the seventh day, blood and tissue samples were obtained. Johnsen score, malondialdehyde, inhibin B, glutathione plasma total sulfhydryl group (RSH) levels, and total nitric oxide were studied. RESULTS: Torsion/detorsion caused increase in tissue malondialdehyde and total nitric oxide along with a decrease in Johnsen score, tissue and plasma inhibin B, RSH, and glutathione levels. Melatonin prevented the rise in malondialdehyde and total nitric oxide levels and improved Johnsen score, tissue and plasma inhibin B, and tissue glutathione levels, along with a decrease in plasma RSH level. Ozone showed similar results except for the total nitric oxide level. Concomitantly, in contralateral testis, melatonin and ozone induced similar changes for Johnsen score, malondialdehyde, and inhibin B (not significant) and in glutathione (significant). Melatonin decreased the total nitric oxide level in both testes and ozone increased the same parameter. CONCLUSION: On different pathways, ozone was comparable with melatonin in the amelioration of ischemia/reperfusion injury. Protective effects of ozone were associated with nitrous oxide. The potential for ozone as a treatment for torsion/detorsion therefore deserves to be further elucidated.

Melatonin with 1,25-dihydroxyvitamin D3 protects against apoptotic ischemia-reperfusion injury in the rat kidney.

This study was designed to evaluate the preventive role of melatonin (Mel) and 1,25-dihydroxyvitamin D3 (VD3) in biochemical and apoptotic events leading to tissue injury and renal dysfunction after ischemia-reperfusion (I/R). Thirty male Wistar rats were divided into five groups: sham-operated, I/R, Mel + I/R, VD3 + I/R, and Mel + VD3 + I/R. The rats were intraperitoneally administered with Mel (10 mg/kg), VD3 (0.5 µg/kg), or Mel (10 mg/kg) plus VD3 (0.5 µg/kg) each day at 1 week prior to ischemia. Right nephrectomy was initially performed and left renal I/R injury was induced by 45 min of bilateral renal ischemia followed by 45 min of reperfusion. After reperfusion, kidneys and blood were obtained for histopathologic and biochemical evaluation. Mel and VD3 had an ameliorative effect on biochemical parameters such as serum creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and apoptosis (caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining) in the kidneys against renal I/R injury in rats. Additionally, VD3 combined with Mel significantly reduced apoptotic and histological alterations when compared with Mel or VD3 alone. This preventive effect on renal tubular apoptosis was remarkable when Mel was combined with VD3.

Age-related changes in the rat brain mitochondrial antioxidative enzyme ratios: modulation by melatonin.

Oxidative stress is an important factor for aging. The antioxidative enzymes glutathione peroxidase (GPx), glutathione reductase (GRd) and superoxide dismutase (SOD) play a crucial role protecting the organism against the age-dependent oxidative stress. Glutathione (GSH) is present in nearly all living cells. GSH is one of the main antioxidants in the cell and it serves several physiological functions. Our purpose was to evaluate the age-related changes in mitochondrial GPx, GRd and SOD activities, and mitochondrial GSH pool in the brains of young (3 months) and aged rats (24 months). We also investigated whether melatonin administration influences these brain mitochondrial enzyme activities and GSH levels in young and aged rats. The results showed that GPx activity increased with age, whereas melatonin treatment decreased GPx activity in the aged rats at levels similar to those in young and young+melatonin groups. The activities of GRd and SOD, however, did not change with age. But, melatonin treatment increased SOD activity in the aged rats. GSH levels, which also increased with age, were not modified by melatonin treatment. The reduction in the SOD/GPx and GR/GPx ratios with age was prevented by melatonin administration. Together, our results suggest that the age-related oxidative stress in rat brain mitochondria is more apparent when the antioxidant enzyme ratios are analyzed instead of their absolute values. The antioxidative effects of melatonin were also supported by the recovery of the enzyme ratios during aging.

Exercise and melatonin in humans: reciprocal benefits.

The aim of this review is to update the reader as to the association between physical exercise and melatonin, and to clarify how the melatonin rhythm may be affected by different types of exercise. Exercise may act as a zeitgeber, although the effects of exercise on the human circadian system are only now being explored. Depending on the time of the day, on the intensity of light, and on the proximity of the exercise to the onset or decline of the circadian production of melatonin, the consequence of exercise on the melatonin rhythm varies. Moreover, especially strenuous exercise per se induces an increased oxidative stress that in turn may affect melatonin levels in the peripheral circulation because indole is rapidly used to combat free radical damage. On the other hand, melatonin also may influence physical performance, and thus, there are mutually interactions between exercise and melatonin production which may be beneficial.

Is there any correlation among adiponectin levels in serum, tumor tissue and normal tissue of the same patients wih breast cancer?

PURPOSE: Adiponectin is secreted from adipose tissue and is characterized by hyperinsulinemia which is related with obesity. Although serum adiponectin levels in patients with breast cancer have been studied previously, adiponectin levels in the serum, tumor and normal tissue of the same patients have not been simultaneously investigated. The aim of this study was thus to evaluate the relationship among serum, tumor and normal tissue adiponectin levels in patients with breast cancer. METHODS: Fifty-three patients with breast cancer who were operated at the Dr. Lutfi Kirdar Kartal Education and Research Hospital, Department of Surgery, between February 2008 and June 2008, were analyzed. Their serum adiponectin levels, tumor tissue and normal breast tissue adiponectin levels were compared. The correlation between postoperative histopathological parameters, insulin resistance parameters and adiponectin levels was also examined. RESULTS: The mean adiponectin levels in tumor tissue, normal breast tissue and serum were 56 ± 9.6 ng/ml, 56 ± 10 ng/ml and 43.5 ± 3.1 ng/ml, respectively. The serum adiponectin levels were inversely correlated with tumor tissue adiponectin levels (p=0.001, r=-0.43). When tumor tissue adiponectin levels were increased, serum adiponectin levels were decreased. O n the other hand, there was a positive correlation between normal breast tissue adiponectin levels and tumor tissue adiponectin levels (p=0.0001, r= 0.850). The tumor tissue adiponectin level was inversely correlated with tumor stage (p=0.037 , r= -0.29). Moreover, in early-stage and low grade tumors, both tumor tissue and normal tissue adiponectin levels were high compared with those of advanced stage or high grade tumors (p=0.027, r= -0.32 and p=0.004, r= -0.408, respectively). In the subgroup analyses, no significant relationship was found between insulin resistance parameters and adiponectin levels (p>0.05). CONCLUSION: Our results indicate that serum adiponectin levels were inversely correlated with tumor tissue adiponectin levels, but no relationship between normal breast tissue and tumor tissue adiponectin levels was demonstrated. Adiponectin levels in breast tumor tissue increase while serum adiponectin levels decrease. Adiponectin might play an important role in the prevention of tumor progression by decreasing tissue neovascularization.

Age-related changes in tissue and plasma zinc levels: modulation by exogenously administered melatonin.

Melatonin (MEL) is synthesized mainly in the pineal gland and derived from 5-hydroxytryptophan (5-HTP). Zinc (Zn) is one of the most important trace elements in the body. Zn and MEL levels are changed with aging. The aim of this study was to investigate the age-related changes of tissue and plasma Zn levels and effect of MEL administration on these parameters. Male wistar rats received for 3 weeks subcutaneous injection of MEL (10 mg/kg). Kidney and pancreas Zn levels in old rats were significantly lower than middle-aged group. Spleen, small intestine, and plasma Zn levels were not different in middle-aged and old rats. On the other hand, MEL treatment increased Zn levels of small intestine and plasma in middle-aged rats. However, kidney, spleen, and pancreas Zn levels were unaffected by MEL treatment.

Serum levels of nitric oxide end products and interactions with lipoproteins in patients with coronary artery disease.

The purpose of this study was to examine whether the serum levels of nitric oxide end products and the ratio of nitrite to lipoproteins are valid instruments in the clinical follow-up of patients with coronary artery disease. 65 subjects were divided into three groups, including patients with coronary artery disease, silent coronary artery disease and controls. The serum nitrite level and also the ratio of nitrite to high-density lipoprotein were significantly different between the groups. According to the number of obstructed arteries, the serum nitrite level and the ratio of nitrite to high-density lipoprotein were found statistically different between the groups. There was a positive correlation between the serum nitrite level and the ratio of nitrite to high-density lipoprotein and the number of obstructed arteries. In conclusion, the serum nitrite level and ratio of nitrite to high-density lipoprotein may provide a beneficial guide to follow-up the status of patients with coronary artery disease.

NO level and endothelial NO synthase gene polymorphism (Glu298Asp) in the patients with coronary artery disease from the Turkish population.

Nitric oxide is synthesized from L-arginine by endothelial nitric oxide synthase encoded by eNOS gene. This study was performed to investigate the relationship between the serum nitric oxide level and eNOS gene polymorphism in the Turkish population with angiographically diagnosed coronary artery disease (63.47 +/- 9.10 years old, n=250) and control subjects without any history and/or risk factors of coronary artery disease (60.71 +/- 9.14 years old, n=150). Griess assay and PCR-RFLP analysis were used to measure the serum nitric oxide metabolites and genotypes, respectively. It was found that Glu/Glu, Glu/Asp and Asp/Asp genotype frequencies of the eNOS were 49.3%, 41.3% and 9.3% respectively in the control group, and 45.6%, 41.2% and 13.2% in the patient group. Serum nitric oxide levels were (32.56 +/- 17.26) microM in controls and (29.84 +/- 11.88) microM in patients. Neither the frequencies of the Glu298Asp genotypes nor the serum nitricoxide levels showed a significant difference between the groups. There was also no correlation between serum nitric oxide levels and the frequencies of the eNOS genotypes. Result showed that the coronary artery disease of the Turkish population seemed to develop without any alterations in eNOS Glu298Asp genotype frequency and the serum nitric oxide level.

Ratios of homocysteine and nitrite to high-density lipoprotein in coronary artery patients with the different degree of stenosis.

Although the interaction between Hcy, NO(2)(-) and vascular disease has been extensively studied, there are no data verifying their ratios to HDL-C in coronary artery disease (CAD). We examined whether Hcy/HDL-C and NO(2)(-)/HDL-C ratios correlated with the degree of stenosis in CAD. Also, TC/HDL-C and LDL-C/HDL-C ratios were evaluated in the same individuals. Seventy subjects were divided into three groups according to coronary angiography findings: >50% stenosis (n=35, years: 50.9+/-3.4; Group 1), 5-50% stenosis (n=20, years: 50.6+/-3.8; Group 2), <5% narrowing (n=15, years: 49.0+/-3.2; control group). Hcy/HDL-C, NO(2)(-)/HDL-C, TC/HDL-C and LDL-C/HDL-C were statistically higher in both Group 1 patients (p=0.001, for all ratios) and Group 2 patients (p=0.001, p=0.001, p=0.03, 0.041, respectively) with respect to controls. The values were correlated with the degree of stenosis in the different significance levels (r=0.496, p=0.001; r=0.384, p=0.004; r=0.334, p=0.012; r=0.321, p=0.016, respectively). In patients with >50% stenosis, NO(2)(-)/HDL-C was only shown to change significantly in relation to obstructive artery number (p=0.026) and also showed a positive correlation (r=0.379, p=0.032). In conclusion, Hcy/HDL-C and NO(2)(-)/HDL-C appear to be more indicative than TC/HDL-C and LDL-C/HDL-C in the evaluation of CAD patients regarding the degree of stenosis. However, only NO(2)(-)/HDL evaluation seems to be a reliable indicator in the patients with heavy stenosis of CAD. Further studies are needed to confirm the results of present study.

L-arginine and mitomycin C-induced nitric oxide release and apoptosis in human lymphocytes.

Nitric oxide (NO) is a free radical that is produced by a number of mammalian cell types from L-arginine and a critical mediator that acts in many tissues to regulate a diverse range of physiological processes. The major metabolic end product for NO is nitrate (NO(3)) and nitrite (NO(2)), which are stable metabolites within tissue, plasma, and urine. Measurements of nitrate and nitrite values reveal alterations in NO production. Endogenously generated or exogenously applied NO causes DNA cleavage by endonuclease activation. We investigated the effect of L-arginine and mitomycin C (MMC) on cultured lymphocytes of healthy individuals. We observed chromosome breaks, apoptotic cells and increased NO levels after L-arginine and MMC addition. In conclusion, our results confirmed that NO may be the cause of apoptotic cell death in L-arginine added lymphocyte culture.

Nitric oxide production in newborns under phototherapy.

Nitrogen monoxide (NO) is a potent endogenous vasodilator and is involved in cytotoxicity, neurotransmission, and immunological defense mechanisms. Phototherapy has long been known to change the distribution of blood flow throughout the body in newborn infants. The objective of this study was to investigate the effect of phototherapy on NO production in otherwise healthy newborns. Urinary NO levels were measured before and 6 h after phototherapy by a chemiluminescence method using Sievers NOA. Ten newborns (gestational age, 36.4 +/- 3.9 weeks; birth weight, 2863 +/- 677.44 g; postnatal age, 5.1 +/- 2.72 days) were started on phototherapy according to AAP guidelines and urine for NO measurement was collected prior to therapy and 6 h after the commencement of treatment. Urinary NO levels measured during phototherapy were significantly higher (108.8+/-50.69 micromol/mmol creatinine) than the levels measured before phototherapy (73.13+/-34.15 micromol/mmol creatinine; P < 0.05). These results suggest that newborns receiving phototherapy might have increased NO production, which might result in hemodynamic changes. However, further studies on the effects of phototherapy on NO and photorelaxation are needed before reaching firm conclusions.

Cerebrospinal fluid levels of nitric oxide and nitrotyrosine in neonates with mild hypoxic-ischemic encephalopathy.

The objective of this study was to determine the role of cerebral nitric oxide and its powerful oxidant peroxynitrite following mild birth asphyxia. The cerebrospinal fluid levels of nitric oxide and 3-nitrotyrosine as a marker for peroxynitrite are measured in neonates with mild hypoxic-ischemic encephalopathy. Based on the classification of Sarnat and Sarnat, term neonates with mild hypoxic-ischemic encephalopathy and neurologically normal neonates suspected of sepsis were taken as the control group. Nitric oxide measurements were done by chemiluminescence, and nitrotyrosine measurements were made by high-performance liquid chromatography. The Mann Whitney U-test was used, and a Pvalue < .05 was considered significant. Eleven patients with grade 1 hypoxic-ischemic encephalopathy and nine controls were included. The gestational age and birthweights were similar in both groups. Neither of the cerebrospinal fluid levels of nitric oxide (8.60 +/- 0.49 micromol/L) and nitrotyrosine (0.45 +/- 0.33 micromol/L) of the neonates with hypoxic-ischemic encephalopathy showed significant differences from that of the means of nitric oxide (8.66 +/- 1.07 micromol/L) and nitrotyrosine levels (0.25 +/- 0.13 micromol/L) of the controls. These data suggest that the oxidative stress is not overexpressed to lead nitric oxide and peroxynitrite to play a pathologic role in the early phase of mild hypoxic-ischemic encephalopathy of the newborn.

Prognostic role of serum vascular endothelial growth factor, basic fibroblast growth factor and nitric oxide in patients with colorectal carcinoma.

Recently, angiogenesis has gained an increasing interest as a prognostic factor in a variety of solid tumours. In this study we aimed to assess the prognostic role of serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF) and nitric oxide (NO) levels in patients with colorectal carcinoma (CRC).A total of 52 consecutive colorectal cancer patients with stage I to IV disease was included. In addition to routine laboratory and staging procedures, serum VEGF, b-FGF levels, and nitrate levels as a surrogate marker for in-vivo NO production were assayed. Serum VEGF concentrations, adjusted to the platelet count were found to be a significant factor for overall survival in univariate analysis (P=0.033). A new angiogenic index (AI), derived from serum VEGF and nitrate concentrations, was established. AI is the only independent prognostic factor of survival in all patients (P=0.008, Cox regression analysis). Likewise, AI is also significant prognostic factor for disease-free survival (DFS) in patients with operable CRC (P=0.032, Cox regression analysis). In conclusion, serum VEGF and NO levels have prognostic role in patients with CRC and the new angiogenesis index using the serum levels of the factors seem to be useful.