PMID: 

Fitoterapia. 2020 Mar 14:104553. Epub 2020 Mar 14. PMID: 32184097

Abstract Title: 

Cannabidiol exerts protective effects in an in vitro model of Parkinson's disease activating AKT/mTOR pathway.

Abstract: 

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of the nigrostriatal dopaminergic pathway with loss of substantia nigra pars compacta neurons and dopamine depletion. Various natural compounds showed protective actions against PD. In this work, the protective effects of cannabidiol (CBD), obtained from Cannabis sativa, were evaluated in retinoic acid differentiated SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP), an in vitro PD model. In order to evaluate which receptor is involved in CBD actions CB1, CB2 and TRPV1 receptor antagonists were used. CBD counteracted the loss of cell viability caused by MPP, reducing apoptosis as demonstrated by the reduction of Bax and caspase 3. Moreover, CBD reduced the nuclear levels of PARP-1. The protective effects of CBD seem to be mediated by the activation of ERK and AKT/mTOR pathways. The treatment with AKT1/2 inhibitor and the mTOR inhibitor rapamycin abolished CBD protective effects. The CBD-induced ERK activation may be mediated by CBD interaction with CB2 and TRPV1. We also investigated the protein levels of the autophagic proteins LC3 and beclin 1. CBD reduced the MPP-induced increase of LC3 by CB2 and TRPV1 receptors. These data suggested the involvement of ERK in the modulation of autophagy. However, beclin 1 levels were not modified neither by MPPnor by CBD. These results indicated that CBD may exert preventive and protective actions in PD.

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PMID: 

World J Diabetes. 2020 Mar 15 ;11(3):52-65. PMID: 32180894

Abstract Title: 

Vitamin C ameliorated cardiac autonomic neuropathy in type 2 diabetic rats.

Abstract: 

BACKGROUND: Vitamin C (VC) is a common antioxidant with cell protection potentials. However, its possible protective effect on cardiac autonomic nerves from diabetic induced insults is yet to be explored.AIM: To investigate the effects of VC on diabetic cardiac autonomic neuropathy.METHODS: Thirty male Wistar rats were equally grouped into control, diabetic and diabetic + VC. Type 2 diabetes was induced with fructose diet and alloxan. VC (1 g/kg) was administered for 4 wkoral canula. Blood pressure and heart rate were measured non-invasively using tail flick blood pressure monitor. Spectral analysis of heart rate variability (HRV) was used to assess cardiac autonomic neuropathy. Blood was collected from the ocular sinus for biochemical analysis. Urethane (1 g/kg-ip) was used for anaesthesia prior to HRV and cervical dislocation to harvest hearts. Intracardiac autonomic nerve was assessed using tyrosine hydroxylase immunohistochemistry on fixed heart sections.RESULTS: Results were analysed using ANOVA atαUnlike VC and control groups, diabetic rats showed significantly (

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PMID: 

Cancers (Basel). 2020 Mar 14 ;12(3). Epub 2020 Mar 14. PMID: 32183295

Abstract Title: 

Vitamin C Restricts the Emergence of Acquired Resistance to EGFR-Targeted Therapies in Colorectal Cancer.

Abstract: 

The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents are often vulnerable to alterations in cell metabolism including oxidative stress. Vitamin C (VitC) is an antioxidant agent which can paradoxically trigger oxidative stress at pharmacological dose. Here we tested the hypothesis that VitC in combination with cetuximab could restrain the emergence of secondary resistance to EGFR blockade in CRCwild-type models. We found that addition of VitC to cetuximab impairs the emergence of drug persisters, limits the growth of CRC organoids, and significantly delays acquired resistance in CRC patient-derived xenografts. Mechanistically, proteomic and metabolic flux analysis shows that cetuximab blunts carbohydrate metabolism by blocking glucose uptake and glycolysis, beyond promoting slow but progressive ROS production. In parallel, VitC disrupts iron homeostasis and further increases ROS levels ultimately leading to ferroptosis. Combination of VitC and cetuximab orchestrates a synthetic lethal metabolic cell death program triggered by ATP depletion and oxidative stress, which effectively limits the emergence of acquired resistance to anti-EGFR antibodies. Considering that high-dose VitC is known to be safe in cancer patients, our findings might have clinical impact on CRC patients treated with anti-EGFR therapies.

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PMID: 

Endocr Metab Immune Disord Drug Targets. 2019 Oct 9. Epub 2019 Oct 9. PMID: 32138638

Abstract Title: 

Dietary melatonin protects against behavioural, metabolic, oxidative, and organ morphological changes in mice that are fed high-fat, high-sugar diet.

Abstract: 

BACKGROUND: Metabolic syndrome is a complex pattern of disorders which occur jointly and is associated with increased risk of cardiovascular and cerebrovascular disease. Therefore the need for more-efficient options of treatment has become imperative.OBJECTIVE: This study examined the effect of dietary-melatonin in the management of behavioural, metabolic, antioxidant and organ changes due to high-fat/high-sugar (HFHS) diet- induced metabolic syndrome in mice.METHODOLOGY: Mice were randomly-assigned into five groups of ten animals each. Groups were normal control [fed standard diet (SD)], HFHS control, and 3 groups of melatonin incorporated into HFHS at 2.5, 5 and 10 mg/kg of feed. Mice were fed for seven weeks, and body weight was assessed weekly. Open-field behaviours, radial-arm and Y-maze spatial memory were scored at the end of the experimental period. Twenty-four hours after the last behavioural test, blood was taken for estimation of blood glucose levels after an overnight fast. Animals were then euthanised, and blood was taken for estimation of plasma insulin, leptin and adiponectin levels, and serum lipid profile. The liver, kidneys and brain were excised and processed for general histology, while homogenates of the liver and whole brain were used to assess oxidative stress parameters.RESULTS: Results showed that dietary melatonin (compared to HFHS diet) was associated with a decrease in body weight, food intake and novelty-induced behaviours; and an increase in spatial-working memory scores. A decrease in glucose, insulin, leptin and malondialdehyde levels; and an increase in adiponectin levels and superoxide dismutase activity were also observed. Histomorphological/histomorphometric examination revealed evidence of organ injury with HFHS diet, and varying degrees of amelioration with melatonin- supplemented diet.CONCLUSION: In conclusion, dietary melatonin supplementation may have beneficial effects in the management of metabolic syndrome.

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PMID: 

Int J Dermatol. 2020 Mar 5. Epub 2020 Mar 5. PMID: 32141063

Abstract Title: 

Melatonin and oxidative stress in melasma – an unexplored territory; a prospective study.

Abstract: 

BACKGROUND: Melasma, an acquired disorder of hyperpigmentation, is the most common pigmentary disorder in India. Many factors are implicated in the pathogenesis, and recently the role of oxidative damage including melatonin has been postulated. This study was undertaken to evaluate the role of oxidative stress and serum melatonin in pathogenesis of melasma.METHODS: Seventy-five patients with melasma and an equal number of age and sex-matched controls were included in the study. Clinical characteristics were noted, and baseline severity assessment using modified Melasma Area and Severity Index (MASI) was done in all patients. Serum melatonin, catalase, protein carbonyl, and nitric oxide levels were measured and compared between cases and controls.RESULTS: The serum levels of melatonin and catalase were significantly lower among the cases as compared to controls, while the serum levels of protein carbonyl and nitric oxide were significantly higher in cases compared to controls. There was no statistically significant correlation between these markers of oxidative stress and severity of the disease.CONCLUSIONS: Oxidative stress is increased in patients with melasma compared to the control group in this study. A state of melatonin deficit also exists in patients with melasma. No correlation between the oxidative stress and severity of the disease was found. Further and larger studies including therapeutic trials with powerful antioxidants are warranted.

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PMID: 

J Thorac Dis. 2020 Feb ;12(Suppl 1):S54-S65. PMID: 32148926

Abstract Title: 

Melatonin for the treatment of sepsis: the scientific rationale.

Abstract: 

Sepsis affects 30 million people worldwide, leading to 6 million deaths every year (WHO), and despite decades of research, novel initiatives are drastically needed. According to the current literature, oxidative imbalance and mitochondrial dysfunction are common features of septic patients that can cause multiorgan failure and death. Melatonin, alongside its traditionally accepted role as the master hormonal regulator of the circadian rhythm, is a promising adjunctive drug for sepsis through its anti-inflammatory, antiapoptotic and powerful antioxidant properties. Several animal models of sepsis have demonstrated that melatonin can prevent multiorgan dysfunction and improve survival through restoring mitochondrial electron transport chain (ETC) function, inhibiting nitric oxide synthesis and reducing cytokine production. The purpose of this article is to review the current evidence for the role of melatonin in sepsis, review its pharmacokinetic profile and virtual absence of side effects. While clinical data is limited, we propose the adjunctive use of melatonin is patients with severe sepsis and septic shock.

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PMID: 

Antioxidants (Basel). 2020 Mar 6 ;9(3). Epub 2020 Mar 6. PMID: 32155702

Abstract Title: 

Melatonin Mitigates Chilling-Induced Oxidative Stress and Photosynthesis Inhibition in Tomato Plants.

Abstract: 

Melatonin has been demonstrated to play a variety of roles in plants. Of particular importance is its role as a potent antioxidative agent. In the present study, we generated melatonin-deficient tomato plants using virus-induced gene silencing (VIGS) approach and melatonin-rich tomato plants by foliar application of melatonin. These tomato plants were used to assess the effect of melatonin on chilling-induced oxidative stress and chilling-induced photosynthesis inhibition. We found that melatonin deficiency increased accumulation of reactive oxygen species (ROS) and aggravated lipid peroxidation in chilling-stressed tomato leaves, while exogenous application of melatonin had the opposite effect. Under chilling stress, melatonin-deficient tomato plants showed impaired antioxidant capacity as evidenced by lower activities of antioxidant enzymes and decreased rations of reduced glutathione (GSH)/oxidized glutathione (GSSG) and reduced ascorbate (AsA)/oxidized ascorbate (DHA), compared with melatonin-rich tomato plants. Furthermore, suppression of melatonin biosynthesis led to more photosynthesis inhibition under the chilling condition and compromised the capability of subsequent photosynthesis recovery in tomato plants. In addition, melatonin-deficient tomato plants displayed less activity of an important Calvin-Benson cycle enzyme sedoheptulose-1,7-bisphosphatase (SBPase) than melatonin-rich tomato plants under chilling stress. Collectively, our data indicate that melatonin is critical for antioxidant capacity and redox balance and is in favor of photosynthesis in tomato plants under chilling stress.

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PMID: 

Food Chem. 2020 Feb 5 ;319:126360. Epub 2020 Feb 5. PMID: 32151896

Abstract Title: 

Melatonin triggers metabolic and gene expression changes leading to improved quality traits of two sweet cherry cultivars during cold storage.

Abstract: 

Sweet cherry is a valuable non-climacteric fruit with elevated phytonutrients, whose fruit quality attributes are prone to rapid deterioration after harvest, especially peel damage and water loss of stem. Here the metabolic and transcriptional response of exogenous melatonin was assessed in two commercial cultivars of sweet cherry (Santina and Royal Rainier) during cold storage. Gene expression profiling revealed that cuticle composition and water movement may underlie the effect of melatonin in delaying weight loss. An effect of melatonin on total soluble solids and lower respiration rate was observed in both cultivars. Melatonin induces overexpression of genes related to anthocyanin biosynthesis, which correlates with increased anthocyanin levels and changes in skin color (Chroma). Our results indicate that along with modulating antioxidant metabolism, melatonin improves fruit quality traits by triggering a range of metabolic and gene expression changes, which ultimately contribute to extend sweet cherry postharvest storability.

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PMID: 

Eur J Pharmacol. 2020 Mar 4 ;876:173055. Epub 2020 Mar 4. PMID: 32145324

Abstract Title: 

The effects of cannabinoids on glioblastoma growth: A systematic review with meta-analysis of animal model studies.

Abstract: 

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant brain tumour, with a poor prognosis despite available surgical and radio-chemotherapy, rising the necessity for searching alternative therapies. Several preclinical studies evaluating the efficacy of cannabinoids in animal models of GBM have been described, but the diversity of experimental conditions and of outcomes hindered definitive conclusions about cannabinoids efficacy. A search in different databases (Pubmed, Web of Science, Scopus and SciELO) was conducted during June 2019 to systematically identify publications evaluating the effects of cannabinoids in murine xenografts models of GBM. The tumour volume and number of animals were extracted, and a random effects meta-analysis of these results was performed to estimate the efficacy of cannabinoids. The impact of different experimental factors and publication bias on the efficacy of cannabinoids was also assessed. Nine publications, which satisfied the inclusion criteria, were identified and subdivided in 22 studies involving 301 animals. Overall, cannabinoid therapy reduced the fold of increase in tumour volume in animal models of GBM, when compared with untreated controls. The overall weighted standardized difference in means (WSDM) for the effect of cannabinoids was -1.399 (95% CI: -1.900 to -0.898; P-value

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PMID: 

Histol Histopathol. 2020 Mar 10:18212. Epub 2020 Mar 10. PMID: 32154907

Abstract Title: 

Melatonin and cannabinoids: mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases.

Abstract: 

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.

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