36 research outputs found
Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells
Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have
evolved as regulators of important signaling pathways. In this context, tumor cells have an altered
redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS
levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death.
Melatonin is of particular importance in the development of innovative cancer treatments due to
its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant
molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its
use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of
action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic
clinical applications.MCIN/AEI, SpainEuropean Commission SAF2017-85903-P
ID2020-115112RB-I00Consejeria de Innovacion, Ciencia y Empresa
Junta de Andalucia P07-CTS-03135
P10-CTS-5784
CTS-101University of Granada, Spain UCE-PP2017-05Spanish Governmen
Patient-derived tumor models in cancer research: Evaluation of the oncostatic effects of melatonin
MCIN/AEI/10.13039/
501100011033/The
European Regional Development Fund (B-CTS-071-UGR18)University of Granada (Grant “UNETE,” UCEPP2017-
05), SpainUnión Europea “NextGenerationEU”/ PRTR (PID2020-115112RB- I00; SAF2017-85903-P)Consejería de Economía , Innovación, Ciencia y Empleo, Junta de Andalucía (P18- RT-32222)Ministerio de Educación Cultura y Deporte, Spai
Role of c-miR-21, c-miR-126, Redox Status, and Inflammatory Conditions as Potential Predictors of Vascular Damage in T2DM Patients
The development of type 2 diabetes mellitus (T2DM) vascular complications (VCs) is
associated with oxidative stress and chronic inflammation and can result in endothelial dysfunctions.
Circulating microRNAs play an important role in epigenetic regulation of the etiology of T2DM. We
studied 30 healthy volunteers, 26 T2DM patients with no complications, and 26 T2DM patients with
VCs, to look for new biomarkers indicating a risk of developing VCs in T2DM patients. Peripheral
blood samples were used to determine redox state, by measuring the endogenous antioxidant
defense system (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione
peroxidase, GPx; and glucose-6-phosphate dehydrogenase, G6DP) and markers of oxidative damage
(advanced oxidation protein products, AOPP; lipid peroxidation, LPO). Additionally, inflammatory
marker levels (IL-1, IL-6, IL-18, and TNF- ), c-miR-21, and c-miR-126 expression were analyzed.
T2DM patients showed the highest oxidative damage with increased GSSG/GSH ratios, LPO, and
AOPP levels. In both diabetic groups, we found that diminished SOD activity was accompanied by
increased CAT and decreased GRd and G6PD activities. Diabetic patients presented with increased
relative expression of c-miR-21 and decreased relative expression of c-miR-126. Overall, c-miR-21,
SOD, CAT, and IL-6 had high predictive values for diabetes diagnoses. Finally, our data demonstrated
that IL-6 exhibited predictive value for VC development in the studied population. Moreover, c-miR-
21 and c-miR-126, along with GPx and AOPP levels, should be considered possible markers for VC
development in future studies.University of GranadaEugenio Rodriguez Pascual Foundation ERP-2021CIBERfes (ISCIII, Spain) CB16-10-0023
Shared gene expression signatures between visceral adipose and skeletal muscle tissues are associated with cardiometabolic traits in children with obesity
Obesity in children is related to the development of cardiometabolic complications later in life, where
molecular changes of visceral adipose tissue (VAT) and skeletal muscle tissue (SMT) have been proven to
be fundamental. The aim of this study is to unveil the gene expression architecture of both tissues in a cohort
of Spanish boys with obesity, using a clustering method known as weighted gene co-expression network
analysis. For this purpose, we have followed a multi-objective analytic pipeline consisting of three main
approaches; identification of gene co-expression clusters associated with childhood obesity, individually in
VAT and SMT (intra-tissue, approach I); identification of gene co-expression clusters associated with obesitymetabolic
alterations, individually in VAT and SMT (intra-tissue, approach II); and identification of gene
co-expression clusters associated with obesity-metabolic alterations simultaneously in VAT and SMT (intertissue,
approach III). In both tissues, we identified independent and inter-tissue gene co-expression signatures
associated with obesity and cardiovascular risk, some of which exceeded multiple-test correction filters. In these
signatures, we could identify some central hub genes (e.g., NDUFB8, GUCY1B1, KCNMA1, NPR2, PPP3CC)
participating in relevant metabolic pathways exceeding multiple-testing correction filters. We identified the
central hub genes PIK3R2, PPP3C and PTPN5 associated with MAPK signaling and insulin resistance terms. This
is the first time that these genes have been associated with childhood obesity in both tissues. Therefore, they
could be potential novel molecular targets for drugs and health interventions, opening new lines of research on
the personalized care in this pathology. This work generates interesting hypotheses about the transcriptomics
alterations underlying metabolic health alterations in obesity in the pediatric populationERDF/Health Institute Carlos
III (grant numbers PI20/00711 and PI20/00563)ERDF/Regional Government of Andalusia/Ministry of Economic Transformation,
Industry, Knowledge and Universities (grant numbers P18-
RT-2248 and B-CTS-536-UGR20
Oral Mucositis: Melatonin Gel an Effective New Treatment
The current treatment for cervico-facial cancer involves radio and/or chemotherapy. Unfortunately, cancer therapies can lead to local and systemic complications such as mucositis, which is the most common dose-dependent complication in the oral cavity and gastrointestinal tract. Mucositis can cause a considerably reduced quality of life in cancer patients already suffering from physical and psychological exhaustion. However, the role of melatonin in the treatment of mucositis has recently been investigated, and offers an effective alternative therapy in the prevention and/or management of radio and/or chemotherapy-induced mucositis. This review focuses on the pathobiology and management of mucositis in order to improve the quality of cancer patients’ lives.Part of this study was partially funded by the following grants: SAF2009-14037 from the Spanish Ministry of Economy and Competitivity (MINECO), CB/10/00238 from the Carlos III Health Institute, GREIB.PT_2010_04 from the CEIBiotic Program of the University of Granada, Spain, and CTS-101 from the Innovation, Science, and Business Council, Junta de Andalucía, Spain
The Relationship between Clock Genes, Sirtuin 1, and Mitochondrial Activity in Head and Neck Squamous Cell Cancer: Effects of Melatonin Treatment
This study was funded by grants from MCIN/AEI/10.13039/501100011033/y financiado
por la Unión Europea “NextGenerationEU”/PRTR (PID2020-115112RB-I00; SAF2017-85903-P);
the Consejería de Universidad, Investigación e Inovación (CTS-101: Comunicación Intercelular);
FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento/Proyecto ((P18-RT-32222); the
European Regional Development Fund (B-CTS-071-UGR18); the Instituto de Salud Carlos III (Spain)
through the grant CB/10/00238 (co-funded by the European Regional Development Fund/European
Social Fund “Investing in your future”); and the University of Granada (Grant “UNETE,” UCEPP2017-
05), Spain. J. F. and L. M. are recipients of FPU fellowships from the Ministerio de Educación
Cultura y Deporte, Spain, and Y. R.-C. is the recipient of a PFIS fellowship from the Instituto de Salud
Carlos IIISupplementary Materials: The following supporting information can be downloaded at:
https://www.mdpi.com/article/10.3390/ijms241915030/s1.The circadian clock is a regulatory system, with a periodicity of approximately 24 h,
which generates rhythmic changes in many physiological processes, including mitochondrial activity.
Increasing evidence links chronodisruption with aberrant functionality in clock gene expression,
resulting in multiple diseases such as cancer. Melatonin, whose production and secretion oscillates
according to the light–dark cycle, is the principal regulator of clock gene expression. In addition,
the oncostatic effects of melatonin correlate with an increase in mitochondrial activity. However, the
direct links between circadian clock gene expression, mitochondrial activity, and the antiproliferative
effects of melatonin in cancers, including head and neck squamous cell carcinoma (HNSCC), remain
largely unknown. In this study, we analyzed the effects of melatonin on HNSCC cell lines (Cal-27
and SCC9), which were treated with 500 and 1000 M melatonin. We found that the antiproliferative
effect of melatonin is not mediated by the Bmal1 clock gene. Additionally, high doses of melatonin
were observed to result in resynchronization of oscillatory circadian rhythm genes (Per2 and Sirt1).
Surprisingly, the resynchronizing effect of melatonin on Per2 and Sirt1 did not produce alterations in
the oscillation of mitochondrial respiratory activity. These results increase our understanding of the
possible antiproliferative mechanisms in melatonin in the treatment of head and neck squamous cell
carcinoma and suggest that its antiproliferative effects are independent of clock genes but are directly
related to mitochondrial activity.MCIN/AEI/10.13039/501100011033Unión Europea “NextGenerationEU”/PRTR (PID2020-115112RB-I00; SAF2017-85903-P)Consejería de Universidad, Investigación e Inovación (CTS-101: Comunicación Intercelular)FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento/Proyecto ((P18-RT-32222)European Regional Development Fund (B-CTS-071-UGR18)Instituto de Salud Carlos III (Spain) through the grant CB/10/00238 (co-funded by the European Regional Development Fund/European Social Fund “Investing in your future”)University of Granada (Grant “UNETE,” UCEPP2017- 05)FPU fellowships from the Ministerio de Educación Cultura y DeportePFIS fellowship from the Instituto de Salud Carlos II
Protective Effects of Melatonin on the Skin: Future Perspectives
When exposed to hostile environments such as radiation, physical injuries, chemicals,
pollution, and microorganisms, the skin requires protective chemical molecules and pathways.
Melatonin, a highly conserved ancient molecule, plays a crucial role in the maintenance of skin.
As human skin has functional melatonin receptors and also acts as a complete system that is capable of
producing and regulating melatonin synthesis, melatonin is a promising candidate for its maintenance
and protection. Below, we review the studies of new metabolic pathways involved in the protective
functions of melatonin in dermal cells. We also discuss the advantages of the topical use of melatonin
for therapeutic purposes and skin protection. In our view, endogenous intracutaneous melatonin
production, together with topically-applied exogenous melatonin and its metabolites, represent two
of the most potent defense systems against external damage to the skin.Part of this review was co-funded by the Spanish Ministry of the Economy and Competitiveness,
the FEDER Regional Development Fund (nos. SAF2013-49019 and SAF2017-85903), the Charles III Institute
(no. CB/10/00238), and the Economy, Innovation, Science and Employment Council of the Junta de Andalucía
(CTS-101). JF and LM are FPU (Professional University formation) Fellows of the Spanish Ministry of Education,
Culture and Sport
Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress
Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have
oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo
applications. Consequently, an alternative administration route is needed to improve bioavailability and
establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived
tumor models has transformed the field of drug research because they reflect the heterogeneity of patient
tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors
and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both
xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of
melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived
xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions
on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral
injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patientderived
xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-
27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting
mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients
to establish a proper clinical melatonin treatment.European Regional Development Fund (B‐CTS‐071-UGR18)Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (P18-RT‐32222)Ministerio de Ciencia e Innovación/AEI: Agencia Estatal de Investigación/10.13039/501100011033Unión Europea “NextGenerationEU”/ PRTR (SAF2017-85903‐P; PID2020-115112RB‐I00)University of Granada (Grant “UNETE,” UCE‐PP2017-05)Ministerio de Educación Cultura y Deporte, Spai
Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy
Age and age-dependent inflammation are two main risk factors for cardiovascular diseases.
Aging can also affect clock gene-related impairments such as chronodisruption and has been linked
to a decline in melatonin synthesis and aggravation of the NF- B/NLRP3 innate immune response
known as inflammaging. The molecular drivers of these mechanisms remain unknown. This study
investigated the impact of aging and NLRP3 expression on the cardiac circadian system, and the
actions of melatonin as a potential therapy to restore daily rhythms by mitigating inflammaging. We
analyzed the circadian expression and rhythmicity of clock genes in heart tissue of wild-type and
NLRP3-knockout mice at 3, 12, and 24 months of age, with and without melatonin treatment. Our
results support that aging, NLRP3 inflammasome, and melatonin affected the cardiac clock genes
expression, except for Rev-erba, which was not influenced by genotype. Aging caused small phase
changes in Clock, loss of rhythmicity in Per2 and Rora, and mesor dampening of Clock, Bmal1, and
Per2. NLRP3 inflammasome influenced the acrophase of Clock, Per2, and Rora. Melatonin restored the
acrophase and the rhythm of clock genes affected by age or NLRP3 activation. The administration of
melatonin re-established murine cardiac homeostasis by reversing age-associated chronodisruption.
Altogether, these results highlight new findings about the effects aging and NLRP3 inflammasome
have on clock genes in cardiac tissue, pointing to continuous melatonin as a promising therapy to
placate inflammaging and restore circadian rhythm in heart muscle. Additionally, light microscopy
analysis showed age-related morphological impairments in cardiomyocytes, which were less severe
in mice lacking NLRP3. Melatonin supplementation preserved the structure of cardiac muscle fibers
in all experimental groups.Instituto de Salud Carlos III (Ministerio de Economia y Competitividad, Spain) (European Regional Development Fund/European Social Fund "Investing in your future") PI13-981
PI16-00519
PI19-01372
CB16-10-00238
CB16/10/00239Junta de Andalucia CTS-101Spanish Governmen
Melatonin Targets Metabolism in Head and Neck Cancer Cells by Regulating Mitochondrial Structure and Function
This study was funded by grants from the Ministerio de Economia, Industria y Competitividad
y por el Fondo de Desarrollo Regional FEDER, Spain nº SAF2013-49019, SAF2017-85903-P,
and from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P07- CTS- 03135,
P10- CTS- 5784, and CTS- 101), Spain. J.F. and L.M. have FPU fellowships from the Ministerio de
Educación Cultura y Deporte, Spain. C.R.S. was a schorlarship holder from the Plan Propio de
Investigación of the University of Granada.We wish to thank Michael O’Shea for proofreading the paper.Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin's oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 mu M of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin's oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.Ministerio de Economia, Industria y Competitividad y por el Fondo de Desarrollo Regional FEDER, Spain
SAF2013-49019
SAF2017-85903-PJunta de Andalucia
P07-CTS-03135
P10-CTS-5784
CTS-101Ministerio de Educacion Cultura y Deporte, SpainPlan Propio de Investigacion of the University of Granad