Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

Melatonin targeting non-coding RNAs in cancer: Focus on mechanisms and potential therapeutic targets.

Despite, melatonin is mainly known as a regulatory factor for circadian rhythm, its notable role in other fundamental biological processes, such as redox homeostasis and programmed cell death, has been found. In this line, a growing body of evidence indicated that melatonin could apply an inhibitory effect on the tumorigenic processes. Hence, melatonin might be considered an efficient adjuvant agent for cancer treatment. Besides, the physiological and pathological functions of non-coding RNAs (ncRNAs) in various disease, particularly cancers, have been expanded over the past two decades. It is well-established that ncRNAs can modulate the gene expression at various levels. Thereby, ncRNAs can regulate the numerous biological processes, including cell proliferation, cell metabolism, apoptosis, and cell cycle. Recently, targeting the ncRNAs expression provides a novel insight in the therapeutic approaches for cancer treatment. Moreover, accumulating investigations have revealed that melatonin could impact the expression of different ncRNAs in a multiple disorders, including cancer. Therefore, in the precent study, we discuss the potential roles of melatonin in modulating the expression of ncRNAs and the related molecular pathways in different types of cancer. Also, we highlighted its importance in therapeutic application and translational medicine in cancer treatment.

Melatonin and 5-fluorouracil combination chemotherapy: opportunities and efficacy in cancer therapy.

Combined chemotherapy is a treatment method based on the simultaneous use of two or more therapeutic agents; it is frequently necessary to produce a more effective treatment for cancer patients. Such combined treatments often improve the outcomes over that of the monotherapy approach, as the drugs synergistically target critical cell signaling pathways or work independently at different oncostatic sites. A better prognosis has been reported in patients treated with combination therapy than in patients treated with single drug chemotherapy. In recent decades, 5-fluorouracil (5-FU) has become one of the most widely used chemotherapy agents in cancer treatment. This medication, which is soluble in water, is used as the first line of anti-neoplastic agent in the treatment of several cancer types including breast, head and neck, stomach and colon cancer. Within the last three decades, many studies have investigated melatonin as an anti-cancer agent; this molecule exhibits various functions in controlling the behavior of cancer cells, such as inhibiting cell growth, inducing apoptosis, and inhibiting invasion. The aim of this review is to comprehensively evaluate the role of melatonin as a complementary agent with 5-FU-based chemotherapy for cancers. Additionally, we identify the potential common signaling pathways by which melatonin and 5-FU interact to enhance the efficacy of the combined therapy. Video abstract.

Targeting Glioma Cells with Nutraceuticals: Therapeutic Effects Based on Molecular Mechanisms, New Evidence and Perspectives.

Gliomas are the most common malignant cancers of the brain that have unregulated proliferation and are known as highly invasive tumors. Hence, their relapse rate is high, and the prognosis is low. Despite remarkable advances in neuroimaging, neurosurgery, and radiation therapy, they, especially glioblastoma, are highly resistant to treatments, including radiotherapy, surgery, and temozolomide chemotherapy. The average survival rate for patients with malignant glioma is still less than two years. Accordingly, the search for new treatment options has recently become an urgent need. Today, a number of nutraceuticals have been considered because of their special role in inhibiting the angiogenic process, metastasis, and apoptosis, resulting in the inhibition of tumor growth, including glioma. Nutraceuticals can disrupt cancer cells by affecting different pathways. In fact, these compounds can reduce the growth of cancer cells, inhibit their proliferation and angiogenesis, as well as induce apoptosis in these cells and play an important role in various stages of treatment. One of the key targets of nutraceuticals may be to regulate cellular signaling pathways, such as PI3K/Akt/mTORC1, JAK/STAT, and GSK-3, or to exert their effects through other mechanisms, such as cytokine receptors and inflammatory pathways, reactive oxygen species, and miRNAs. This review refers to the results of recent studies and target molecules as well as signaling pathways affected by some nutraceuticals in glioma cells. These studies indicated that clinical trials are imminent and new approaches can be beneficial for patients.

Carnitine and chromium co-supplementation affects mental health, hormonal, inflammatory, genetic, and oxidative stress parameters in women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to evaluate the effect of the co-administration of carnitine and chromium on mental health, hormonal, inflammatory and genetic parameters in women with PCOS. METHODS: This randomized, double-blinded, placebo-controlled clinical trial was conducted on 54 subjects, aged 18-40 years old. Subjects were randomly allocated to take either 1000 mg/d carnitine plus 200 µg/d chromium as chromium picolinate (n = 26) or placebo (n = 27) for 12 weeks. RESULTS: Carnitine and chromium co-supplementation, compared with the placebo, significantly improved beck depression inventory (ß - 0.84; 95% CI, -1.51, -0.17; p = 0.01), general health questionnaire scores (ß - 1.13; 95% CI, -2.13, -0.14; p = 0.02) and depression anxiety and stress scale scores (ß - 0.96; 95% CI, -0.78, -0.14; p = 0.02). Participants who received carnitine plus chromium supplements had significantly lower total testosterone (ß - 0.15 ng/mL; 95% CI, -0.24, -0.06; p = 0.002), hirsutism (ß - 0.48; 95% CI, -0.91, -0.06; p = 0.02), high-sensitivity C-reactive protein (hs-CRP) (ß - 1.02 mg/L; 95% CI, -1.79, -0.25; p = 0.01), and malondialdehyde (MDA) levels (ß - 0.38 µmol/L; 95% CI, -0.56, -0.20; p < 0.001), and higher total antioxidant capacity (TAC) levels (ß 107.18 mmol/L; 95% CI, 44.24, 170.12; p = 0.001) compared with the placebo. Moreover, carnitine and chromium co-supplementation upregulated gene expression of interleukin-6 (IL-6) (p = 0.02) and tumor necrosis factor alpha (TNF-α) (p = 0.02) compared with the placebo. CONCLUSION: Overall, the co-administration of carnitine and chromium for 12 weeks to women with PCOS had beneficial effects on mental health parameters, serum total testosterone, mF-G scores, hs-CRP, TAC and MDA levels, and gene expression of IL-6 and TNF-α.

The effects of omega-3 fatty acids and vitamin E co-supplementation on gene expression related to inflammation, insulin and lipid in patients with Parkinson's disease: A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This study was conducted to evaluate the effects of omega-3 fatty acids and vitamin E co-supplementation on gene expression related to inflammation, insulin and lipid in subjects with Parkinson's disease (PD). PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed in 40 subjects with PD. Participants were randomly allocated into two groups to take either 1000 mg/day of omega-3 fatty acids from flaxseed oil plus 400 IU/day of vitamin E supplements or placebo (n = 20 each group) for 12 weeks. Gene expression related to inflammation, insulin and lipid were quantified in peripheral blood mononuclear cells (PBMC) of PD patients with RT-PCR method. RESULTS: After the 12-week intervention, compared with the placebo, omega-3 fatty acids and vitamin E co-supplementation downregulated gene expression of tumor necrosis factor alpha (TNF-α) (P = 0.002) in PBMC of subjects with PD. In addition, omega-3 fatty acids and vitamin E co-supplementation upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.03), and downregulated oxidized low-density lipoprotein receptor (LDLR) (P = 0.002) in PBMC of subjects with PD compared with the placebo. We did not observe any significant effect of omega-3 fatty acids and vitamin E co-supplementation on gene expression of interleukin-1 (IL-1) and IL-8 in PBMC of patients with PD. CONCLUSIONS: Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks in PD patients significantly improved gene expression of TNF-α, PPAR-γ and LDLR, but did not affect IL-1 and IL-8.

The Effects of Vitamin D Supplementation on Biomarkers of Inflammation and Oxidative Stress Among Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The current systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of vitamin D supplementation on biomarkers of inflammation and oxidative stress among women with polycystic ovary syndrome (PCOS). Cochrane library, Embase, PubMed, and Web of Science database were searched to identify related randomized-controlled articles (RCTs) published up to November 2017. Two researchers assessed study eligibility, extracted data, and evaluated risk of bias of included RCTs, independently. To check heterogeneity Q-test and I2 statistics were used. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as summary effect size. Seven RCTs were included into our meta-analysis. The findings showed that vitamin D supplementation in women with PCOS significantly decreased high-sensitivity C-reactive protein (hs-CRP) (SMD -1.03; 95% CI, -1.58, -0.49; p <0.001) and malondialdehyde (MDA) (SMD -1.64, 95% CI -2.26 to -1.02, p <0.001), and significantly increased total antioxidant capacity (TAC) levels (SMD 0.86, 95% CI 0.08 to 1.64, p=0.03). Vitamin D supplementation had no significant effect on nitric oxide (NO) (SMD 0.11, 95% CI -0.44 to 0.66, p=0.69) and total glutathione (GSH) levels (SMD 0.54, 95% CI -0.20 to 1.28, p=0.15). Overall, the current meta-analysis demonstrated that vitamin D supplementation to women with PCOS resulted in an improvement in hs-CRP, MDA and TAC, but did not affect NO and GSH levels.

The Influences of Chromium Supplementation on Glycemic Control, Markers of Cardio-Metabolic Risk, and Oxidative Stress in Infertile Polycystic ovary Syndrome Women Candidate for In vitro Fertilization: a Randomized, Double-Blind, Placebo-Controlled Trial.

This study was carried out to investigate the effects of chromium intake on glycemic control, markers of cardio-metabolic risk, and oxidative stress in infertile polycystic ovary syndrome (PCOS) women candidate for in vitro fertilization (IVF). This randomized double-blind, placebo-controlled trial was done among 40 subjects with infertile PCOS candidate for IVF, aged 18-40 years old. Individuals were randomly allocated into two groups to take either 200 µg/day of chromium (n = 20) or placebo (n = 20) for 8 weeks. Biochemical parameters were assessed at baseline and at end-of-trial. Compared with the placebo, taking chromium supplements led to significant reductions in fasting plasma glucose (- 2.3 ± 5.7 vs. + 0.9 ± 3.1 mg/dL, P = 0.03), insulin levels (- 1.4 ± 2.1 vs. + 0.4 ± 1.7 µIU/mL, P = 0.004), homeostatic model of assessment for insulin resistance (- 0.3 ± 0.5 vs. + 0.1 ± 0.4, P = 0.005), and a significant increase in quantitative insulin sensitivity check index (+ 0.004 ± 0.008 vs. - 0.001 ± 0.008, P = 0.03). In addition, chromium supplementation significantly decreased serum triglycerides (- 19.2 ± 33.8 vs. + 8.3 ± 21.7 mg/dL, P = 0.004), VLDL- (- 3.8 ± 6.8 vs. + 1.7 ± 4.3 mg/dL, P = 0.004) and total cholesterol concentrations (- 15.3 ± 26.2 vs. - 0.6 ± 15.9 mg/dL, P = 0.03) compared with the placebo. Additionally, taking chromium supplements was associated with a significant increase in plasma total antioxidant capacity (+ 153.9 ± 46.1 vs. - 7.8 ± 43.9 mmol/L, P < 0.001) and a significant reduction in malondialdehyde values (-0.3 ± 0.3 vs. + 0.1 ± 0.2 µmol/L, P = 0.001) compared with the placebo. Overall, our study supported that chromium administration for 8 weeks to infertile PCOS women candidate for IVF had beneficial impacts on glycemic control, few variables of cardio-metabolic risk, and oxidative stress.

Magnesium supplementation affects gene expression related to insulin and lipid in patients with gestational diabetes.

Magnesium is known to exert several beneficial effects, including antiglycemic and antilipidemic properties. The aim of this study was to evaluate the effects of magnesium supplementation on gene expression related to insulin and lipid metabolism in women with gestational diabetes (GDM) who were not on oral hypoglycemic agents. This randomized double-blind, placebo-controlled trial was conducted among 40 patients diagnosed with GDM, aged 18-40 years. Participants were randomly allocated into two groups to take either 250 mg/day of magnesium supplements in the form of magnesium oxide (n = 20) or placebo (n = 20) for 6 weeks. Gene expression related to insulin and lipid metabolism was assessed in peripheral blood mononuclear cells (PBMCs) of women with GDM using RT-PCR method. Compared with the placebo, magnesium supplementation to women with GDM resulted in a significant decrease in levels of fasting plasma glucose (FPG) (-9.7 ± 5.6 vs. -0.1 ± 8.5 mg/dL, P<0.001). Quantitative results of RT-PCR demonstrated that compared with the placebo, magnesium supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.003) and glucose transporter 1 (GLUT-1) (P = 0.004) and downregulated gene expression of oxidized low-density lipoprotein receptor (LDLR) (P = 0.001) in PBMCs of women with GDM. In addition, a trend toward a greater decrease in gene expression of lipoprotein (a) [LP(a)] was observed in the patients belonging to magnesium group compared to placebo group (P = 0.08). Overall, magnesium supplementation for 6 weeks in women with GDM significantly improved FPG levels, and gene expression of PPAR-γ, GLUT-1, and LDLR.