Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review.

The purpose of this systematic review is to provide an overview of the existing knowledge on the therapeutic potential of melatonin to counteract the undesirable effects of chemotherapy in breast cancer patients. To this aim, we summarized and critically reviewed preclinical- and clinical-related evidence according to the PRISMA guidelines. Additionally, we developed an extrapolation of melatonin doses in animal studies to the human equivalent doses (HEDs) for randomized clinical trials (RCTs) with breast cancer patients. For the revision, 341 primary records were screened, which were reduced to 8 selected RCTs that met the inclusion criteria. We assembled the evidence drawn from these studies by analyzing the remaining gaps and treatment efficacy and suggested future translational research and clinical trials. Overall, the selected RCTs allow us to conclude that melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients. Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates. Accordingly, this systematic review leads us to draw attention to the need for more RCTs to provide a comprehensive view of the promising actions of melatonin in breast cancer and, given the safety profile of this molecule, adequate translational doses should be established in further RCTs.

Potential of melatonin to reverse epigenetic aberrations in oral cancer: new findings.

It is now an accepted principle that epigenetic alterations cause cellular dyshomeostasis and functional changes, both of which are essential for the initiation and completion of the tumor cycle. Oral carcinogenesis is no exception in this regard, as most of the tumors in the different subsites of the oral cavity arise from the cross-reaction between (epi)genetic inheritance and the huge challenge of environmental stressors. Currently, the biochemical machinery is put at the service of the tumor program, halting the cell cycle, triggering uncontrolled proliferation, driving angiogenesis and resistance to apoptosis, until the archetypes of the tumor phenotype are reached. Melatonin has the ability to dynamically affect the epigenetic code. It has become accepted that melatonin can reverse (epi)genetic aberrations present in oral and other cancers, suggesting the possibility of enhancing the oncostatic capacity of standard multimodal treatments by incorporating this indolamine as an adjuvant. First steps in this direction confirm the potential of melatonin as a countermeasure to mitigate the detrimental side effects of conventional first-line radiochemotherapy. This single effect could produce synergies of extraordinary clinical importance, allowing doses to be increased and treatments not to be interrupted, ultimately improving patients' quality of life and prognosis. Motivated by the urgency of improving the medical management of oral cancer, many authors advocate moving from in vitro and preclinical research, where the bulk of melatonin cancer research is concentrated, to systematic randomized clinical trials on large cohorts. Recognizing the challenge to improve the clinical management of cancer, our motivation is to encourage comprehensive and robust research to reveal the clinical potential of melatonin in oral cancer control. To improve the outcome and quality of life of patients with oral cancer, here we provide the latest evidence of the oncolytic activity that melatonin can achieve by manipulating epigenetic patterns in oronasopharyngeal tissue.

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy.

Viral infections constitute a tectonic convulsion in the normophysiology of the hosts. The current coronavirus disease 2019 (COVID-19) pandemic is not an exception, and therefore the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, like any other invading microbe, enacts a generalized immune response once the virus contacts the body. Melatonin is a systemic dealer that does not overlook any homeostasis disturbance, which consequently brings into play its cooperative triad, antioxidant, anti-inflammatory, and immune-stimulant backbone, to stop the infective cycle of SARS-CoV-2 or any other endogenous or exogenous threat. In COVID-19, the corporal propagation of SARS-CoV-2 involves an exacerbated oxidative activity and therefore the overproduction of great amounts of reactive oxygen and nitrogen species (RONS). The endorsement of melatonin as a possible protective agent against the current pandemic is indirectly supported by its widely demonstrated beneficial role in preclinical and clinical studies of other respiratory diseases. In addition, focusing the therapeutic action on strengthening the host protection responses in critical phases of the infective cycle makes it likely that multi-tasking melatonin will provide multi-protection, maintaining its efficacy against the virus variants that are already emerging and will emerge as long as SARS-CoV-2 continues to circulate among us.

Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics.

The wide variety of epigenetic controls available is rapidly expanding the knowledge of molecular biology even overflowing it. At the same time, it can illuminate unsuspected ways of understanding the etiology of cancer. New emerging therapeutic horizons, then, promise to overcome the current antitumor strategies need. The translational utility of this complexity is particularly welcome in oral cancer (OC), in which natural history is alarmingly disappointing due to the invasive and mutilating surgery, the high relapsing rate, the poor quality of life and the reduced survival after diagnosis. Melatonin activates protective receptor-dependent and receptor-independent processes that prevent tissue cancerisation and inhibit progressive tumor malignancy and metastasis. Related evidence has shown that melatonin pleiotropy encompasses gene expression regulation through all the three best-characterized epigenetic mechanisms: DNA methylation, chromatin modification, and non-coding RNA. OC has received less attention than other cancers despite prognosis is usually negative and there are no significant therapy improvements recorded in the past decade. However, a large research effort is being carried out to elucidate how melatonin´s machinery can prevent epigenetic insults that lead to cancer. In the light of recent findings, a comprehensive examination of biochemistry through which melatonin may reverse epigenetic aberrations in OC is an extraordinary opportunity to take a step forward in the clinical management of patients.

Supramolecular Interactions Modulating Electrical Conductivity and Nanoprocessing of Copper-Iodine Double-Chain Coordination Polymers.

Two coordination polymers (CPs), based on Cu(I)-I double zig-zag chains bearing isonicotinic acid or 3-chloroisonicotinic acid as terminal ligands with molecular recognition capabilities, have been synthesized and fully characterized. Both compounds present extended networks with supramolecular interactions directed by the formation of H-bonds between the complementary carboxylic groups, giving supramolecular sheets. The chloro substituent allows establishing additional Cl···Cl supramolecular interactions that reinforce the stability of the supramolecular sheets. These CPs are semiconductor materials; however, the presence of chlorine produces slight changes in the I-Cu-I chains, generating a worse overlap in the Cu-I orbitals, thus determining a decrease in its electrical conductivity value. These experimental results have also been corroborated by theoretical calculations using the study of the morphology of the density of states and 3D orbital isodensities, which determine that conductivity is mostly produced through the Cu-I skeleton and is less efficient in the case of the chloro derivative compound. A fast and efficient bottom-up approach based on the self-assembly of the initial building blocks and the low solutibility of these CPs has proved very useful for the production of nanostructures.

Melatonin as a versatile molecule to design novel multitarget hybrids against neurodegeneration.

Melatonin is an indoleamine produced mainly in the pineal gland. The natural decline of melatonin levels with aging strongly contributes to the development of neurodegenerative disorders. Pleiotropic actions displayed by melatonin prevent several processes involved in neurodegeneration such as neuroinflammation, oxidative stress, excitotoxicity and/or apoptosis. This review focuses on a number of melatonin hybrids resulting from the juxtaposition of tacrine, berberine, tamoxifen, curcumin, N,N-dibenzyl(N-methyl)amine, among others, with potential therapeutic effects for the treatment of neurodegenerative diseases.

New melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection.

BACKGROUND: Neurodegenerative diseases share many pathological pathways, such as abnormal protein aggregation, mitochondrial dysfunction, extensive oxidative stress and neuroinflammation. Cells have an intrinsic mechanism of protection, the Nrf2 transcriptional factor, known as the master regulator of redox homeostasis. RESULTS: Based on the common features of these diseases we have designed a multi-target hybrid structure derived from melatonin and ethyl cinnamate. The obtained derivatives were Nrf2 inducers and potent-free radical scavengers. These new compounds showed a very interesting neuroprotective profile in several in vitro models of oxidative stress, Alzheimer's disease and brain ischemia. CONCLUSION: We have designed a new hybrid structure with complementary activities. We have identified compound 5h as an interesting Nrf2 inducer, very potent antioxidant and neuroprotectant.

Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models.

Stopping the ischemic cascade by targeting its components is a potential strategy for acute ischemic stroke treatment. During ischemia and especially over reperfusion, oxidative stress plays a major role in causing neuronal cell death. Melatonin has been previously reported to provide neuroprotective effects in in vivo models of stroke by a mechanism that implicates melatonin receptors. In this context, this study was planned to test the potential neuroprotective effects of the novel melatonin MT1/MT2 receptor agonist, Neu-P11, against brain ischemia in in vitro and in vivo models, and to elucidate its underlying mechanism of action. Neu-P11 proved to be a good antioxidant, to protect against glutamate-induced excitotoxicity and oxygen and glucose deprivation in hippocampal slices, and to reduce infarct volume in an in vivo stroke model. Regarding its mechanism of action, the protective effect of Neu-P11 was reverted by luzindole (melatonin receptor antagonist), AG490 (JAK2 inhibitor), LY294002 (PI3/AKT inhibitor) and PD98059 (MEK/ERK1/2 inhibitor). In conclusion, Neu-P11 affords neuroprotection against brain ischemia in in vitro and in vivo models by activating a pro-survival signaling pathway that involves melatonin receptors, JAK/STAT, PI3K/Akt and MEK/ERK1/2.

Poststress treatment with PNU282987 can rescue SH-SY5Y cells undergoing apoptosis via α7 nicotinic receptors linked to a Jak2/Akt/HO-1 signaling pathway.

Most neuroprotection studies with nicotinic agonists have shown efficacy when given before the stressor. Here we have investigated whether the α7 nicotinic acetylcholine receptor (nAChR) agonist PNU282987 can prevent cell death once the cells have already undergone an oxidative stress. The combination of rotenone (30 µM) plus oligomycin A (10 µM) (rot/oligo) has been used as an in vitro model of mitochondrial ROS production. SH-SY5Y cells incubated with rot/oligo for 8h and left for another 16 h in MEM/F-12 experienced 30% apoptotic cell death. Under these experimental conditions, PNU282987 administered after rot/oligo (PST/PNU) prevented cell death in a concentration-dependent manner. Co-incubation of PNU282987 with 100 nM methyllycaconitine (a selective α7 nAChR antagonist), 10 µM mecamylamine (a nonselective nAChR antagonist), 3 µM LY294002 (a PI3K inhibitor), or 10 µM AG490 (a Jak2 inhibitor) prevented the protection afforded by PST/PNU. Moreover, the increase in ROS, active caspase-3, and apoptosis caused by rot/oligo was also prevented by PST/PNU. Furthermore, PNU282987 increased the expression of heme oxygenase-1 (HO-1), a critical cell defense enzyme against oxidative stress; this increase was prevented by AG490 or LY294002. The HO-1 inhibitor Sn(IV) protoporphyrin-IX also inhibited the PST/PNU protecting effects. These results suggest that activation of α7 nAChR linked to the Jak2/PI3K/Akt cascade induces the antioxidant enzyme HO-1 to provide neuroprotection.