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Article: Mitochondrial Melatonin: Beneficial Effects in Protecting against Heart Failure.

Reiter, Russel J / Sharma, Ramaswamy / Chuffa, Luiz Gustavo de Almeida / Simko, Fedor / Dominguez-Rodriguez, Alberto

2024 Volume 14, Issue 1

Abstract: Cardiovascular disease is the cause of physical infirmity and thousands of deaths annually. Typically, during heart failure, cardiomyocyte mitochondria falter in terms of energy production and metabolic processing. Additionally, inflammation and the ... ...

Abstract	Cardiovascular disease is the cause of physical infirmity and thousands of deaths annually. Typically, during heart failure, cardiomyocyte mitochondria falter in terms of energy production and metabolic processing. Additionally, inflammation and the accumulation of non-contractile fibrous tissue contribute to cardiac malfunction. Melatonin, an endogenously produced molecule, experimentally reduces the initiation and progression of atherosclerotic lesions, which are often the basis of coronary artery disease. The current review critically analyzes published data related to the experimental use of melatonin to forestall coronary artery pathologies. Collectively, these studies document melatonin's anti-atherosclerotic actions in reducing LDL oxidation and triglyceride levels, lowering endothelial malfunction, limiting adhesion molecule formation, preventing macrophage polarization to the M1 pro-inflammatory phenotype, changing cellular metabolism, scavenging destructive reactive oxygen species, preventing the proliferation and invasion of arterial smooth muscle cells into the lesioned area, restricting the ingrowth of blood vessels from the vasa vasorum, and solidifying the plaque cap to reduce the chance of its rupture. Diabetic hyperglycemia, which aggravates atherosclerotic plaque formation, is also inhibited by melatonin supplementation in experimental animals. The potential value of non-toxic melatonin as a possible inhibitor of cardiac pathology in humans should be seriously considered by performing clinical trials using this multifunctional molecule.
Language	English
Publishing date	2024-01-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life14010088
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Article ; Online: Maternal protein restriction affects the differentiation of cells in the epididymal epithelium lining of 44-day-old rats.

Colonheze, Fábio / Cavariani, Marilia Martins / Schimming, Bruno Cesar / de Mello Santos, Talita / Chuffa, Luiz Gustavo de Almeida / Domeniconi, Raquel Fantin

Biology open

2024

Abstract: Maternal protein restriction delays the differentiation of epididymal mesenchymal cells in newborn rats. However, it's unclear if this delay persists until the full differentiation of the epididymal epithelium at 44 days postnatal. Thus, this study aimed ...

Abstract	Maternal protein restriction delays the differentiation of epididymal mesenchymal cells in newborn rats. However, it's unclear if this delay persists until the full differentiation of the epididymal epithelium at 44 days postnatal. Thus, this study aimed to assess the impact of maternal protein reduction on 44-day-old rats' epididymal epithelium differentiation, following up on the observed delay in newborn animals. Pregnant rats were randomly divided into groups receiving normal-protein (NP - 17% protein) or low-protein (LP - 6% protein) diets during gestation and lactation. On postnatal day (PDN) 44, male offspring were euthanized, and the epididymis (NP n=10, LP n=10) was processed according to immunohistochemical techniques for the detection of aquaporin 9 (AQP9), KI-67, TP63, and ATPase. LP rats showed: a decrease in the intensity of the AQP9 reaction, an increase in cellular proliferation in the initial segment and corpus of the epididymis, an increase in basal cells in the caput and corpus epididymis, and an increase in ATPase-positive clear cells in the cauda region. These findings demonstrate that maternal protein restriction impacts cell differentiation in the epididymal epithelium of 44-day-old rats, persisting even with a normal-protein diet after weaning.
Language	English
Publishing date	2024-02-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2632264-X
ISSN	2046-6390 ; 2046-6390
ISSN (online)	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.060080
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Article: Decoding Hidden Messengers: Proteomic Profiling of Exosomes in Mammary Cancer Research.

Novais, Adriana Alonso / Tamarindo, Guilherme Henrique / Chuffa, Luiz Gustavo de Almeida / Zuccari, Debora Aparecida Pires de Campos

Biomedicines

2023 Volume 11, Issue 10

Abstract: Cancer is a complex and heterogeneous disease, influenced by various factors that affect its progression and response to treatment. Although a histopathological diagnosis is crucial for identifying and classifying cancer, it may not accurately predict ... ...

Abstract	Cancer is a complex and heterogeneous disease, influenced by various factors that affect its progression and response to treatment. Although a histopathological diagnosis is crucial for identifying and classifying cancer, it may not accurately predict the disease's development and evolution in all cases. To address this limitation, liquid biopsy has emerged as a valuable tool, enabling a more precise and non-invasive analysis of cancer. Liquid biopsy can detect tumor DNA fragments, circulating tumor cells, and exosomes released by cancer cells into the bloodstream. Exosomes attracted significant attention in cancer research because of their specific protein composition, which can provide valuable insights into the disease. The protein profile of exosomes often differs from that of normal cells, reflecting the unique molecular characteristics of cancer. Analyzing these proteins can help identify cancer-associated markers that play important roles in tumor progression, invasion, and metastasis. Ongoing research and clinical validation are essential to advance and effectively utilize protein biomarkers in cancer. Nevertheless, their potential to improve diagnosis and treatment is highly promising. This review discusses several exosome proteins of interest in breast cancer, particularly focusing on studies conducted in mammary tissue and cell lines in humans and experimental animals. Unfortunately, studies conducted in canine species are scarce. This emphasis sheds light on the limited research available in this field. In addition, we present a curated selection of studies that explored exosomal proteins as potential biomarkers, aiming to achieve benefits in breast cancer diagnosis, prognosis, monitoring, and treatment.
Language	English
Publishing date	2023-10-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11102839
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Article ; Online: Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm.

Reiter, Russel J / Sharma, Ramaswamy / Cucielo, Maira Smaniotto / Tan, Dun Xian / Rosales-Corral, Sergio / Gancitano, Giuseppe / de Almeida Chuffa, Luiz Gustavo

Cellular and molecular life sciences : CMLS

2023 Volume 80, Issue 4, Page(s) 88

Abstract: The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal ... ...

Abstract	The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal fluid (CSF)-filled perivascular spaces and classic lymph vessels in the dural covering of the brain and spinal cord that functionally cooperate to remove toxic and non-functional trash from the brain. These two components functioning together are referred to as the glymphatic system. We propose that the high levels of melatonin secreted by the pineal gland directly into the CSF play a role in flushing pathological molecules such as amyloid-β peptide (Aβ) from the brain via this network. Melatonin is a sleep-promoting agent, with waste clearance from the CNS being highest especially during slow wave sleep. Melatonin is also a potent and versatile antioxidant that prevents neural accumulation of oxidatively-damaged molecules which contribute to neurological decline. Due to its feedback actions on the suprachiasmatic nucleus, CSF melatonin rhythm functions to maintain optimal circadian rhythmicity, which is also critical for preserving neurocognitive health. Melatonin levels drop dramatically in the frail aged, potentially contributing to neurological failure and dementia. Melatonin supplementation in animal models of Alzheimer's disease (AD) defers Aβ accumulation, enhances its clearance from the CNS, and prolongs animal survival. In AD patients, preliminary data show that melatonin use reduces neurobehavioral signs such as sundowning. Finally, melatonin controls the mitotic activity of neural stem cells in the subventricular zone, suggesting its involvement in neuronal renewal.
MeSH term(s)	Animals ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Melatonin/cerebrospinal fluid ; Sleep ; Glymphatic System ; Aging ; Humans
Chemical Substances	Amyloid beta-Peptides ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2023-03-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-023-04736-5
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Article: Potential Protective Role of Melatonin in Benign Mammary Cells Reprogrammed by Extracellular Vesicles from Malignant Cells.

Procópio de Oliveira, Caroline / Frigieri, Barbara Maria / Fukumasu, Heidge / Chuffa, Luiz Gustavo de Almeida / Novais, Adriana Alonso / Zuccari, Debora Aparecida Pires de Campos

Biomedicines

2023 Volume 11, Issue 10

Abstract: 1) Background: Mammary neoplasms in female dogs share many similarities with the same tumor class in humans, rendering these animals a valuable preclinical model for studying novel therapies against breast cancer. The intricate role of extracellular ... ...

Abstract	(1) Background: Mammary neoplasms in female dogs share many similarities with the same tumor class in humans, rendering these animals a valuable preclinical model for studying novel therapies against breast cancer. The intricate role of extracellular vesicles (EVs), particularly exosomes, in breast carcinogenesis, by transferring specific proteins to recipient cells within the tumor microenvironment, underscores their significance. Melatonin, a hormone recognized for its antitumor effects, adds another layer of intrigue. (2) Methods: EVs obtained from the plasma of dogs diagnosed with mammary tumors were co cultivated with the benign epithelial lineage E-20 using DMEM. The experiment comprised four 24 h treatment groups: control, EVs, melatonin, and EVs + melatonin. A series of assays were conducted, including colony formation, proliferation, and cellular migration assessments. Furthermore, we conducted colony formation, proliferation, and cellular migration assays. We performed immunohistochemistry for proteins of the mTOR pathway, including mTOR and AKT. (3) Results: Exosomes alone significantly increased proliferation, migration, and colony formation rates and, upregulated the expression of mTOR and AKT proteins. However, when melatonin was added, a protective effect was observed. (4) Conclusions: These findings contributed to the use of melatonin to modulate EV-mediated signaling in the clinical veterinary oncology of mammary tumors.
Language	English
Publishing date	2023-10-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11102837
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Article: Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue.

Reiter, Russel J / Sharma, Ramaswamy / Romero, Alejandro / Manucha, Walter / Tan, Dun-Xian / Zuccari, Debora Aparecida Pires de Campos / Chuffa, Luiz Gustavo de Almeida

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 3

Abstract: Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent ... ...

Abstract	Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent inability to conceive by women in present-day societies who choose to have children later in life leads to increased frustration. Melatonin is known to have anti-aging properties related to its antioxidant and anti-inflammatory actions. Its higher follicular fluid levels relative to blood concentrations and its likely synthesis in the oocyte, granulosa, and luteal cells suggest that it is optimally positioned to interfere with age-associated deterioration of the ovary. Additionally, the end of the female reproductive span coincides with a significant reduction in endogenous melatonin levels. Thus, the aims are to review the literature indicating melatonin production in mitochondria of oocytes, granulosa cells, and luteal cells, identify the multiple processes underlying changes in the ovary, especially late in the cessation of the reproductive life span, summarize the physiological and molecular actions of melatonin in the maintenance of normal ovaries and in the aging ovaries, and integrate the acquired information into an explanation for considering melatonin in the treatment of age-related infertility. Use of supplemental melatonin may help preserve fertility later in life and alleviate frustration in women delaying childbearing age, reduce the necessity of in vitro fertilization-embryo transfer (IVF-ET) procedures, and help solve the progressively increasing problem of non-aging-related infertility in women throughout their reproductive life span. While additional research is needed to fully understand the effects of melatonin supplementation on potentially enhancing fertility, studies published to date suggest it may be a promising option for those struggling with infertility.
Language	English
Publishing date	2023-03-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12030695
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Article ; Online: Protein restriction during puberty alters nutritional parameters and affects ovarian and uterine histomorphometry in adulthood in rats.

de Morais Oliveira, Diego Augusto / Lupi, Luiz Antonio / Silveira, Henrique Spaulonci / de Almeida Chuffa, Luiz Gustavo

International journal of experimental pathology

2021 Volume 102, Issue 2, Page(s) 93–104

Abstract: In a large part of the population inefficient ingestion of proteins, whether for cultural, aesthetic or economic reasons, is a global concern. Low-protein diets can cause severe functional complications, mainly during the development and maturation of ... ...

Abstract	In a large part of the population inefficient ingestion of proteins, whether for cultural, aesthetic or economic reasons, is a global concern. Low-protein diets can cause severe functional complications, mainly during the development and maturation of organs and systems, including the female reproductive system. The present study investigated the effect of nutritional protein restriction during puberty on the oestrous cycle and expression of sex steroid receptors (AR, ERα e ERβ) in ovarian and uterine tissues of adult rats. Protein restriction promoted lower body weight gain, feed efficiency and higher caloric intake. There was an increase in the oestrus phase arrest without changing the total length of the oestrous cycle. The consumption of low-protein diet also reduced the thickness of the uterine endometrium (uterine epithelium and endometrial stroma) in addition to increasing the number of primary and atretic follicles in the ovaries. Furthermore, the low-protein diet reduced the levels of androgen receptor (AR) and increased the oestrogen receptor β (ERβ) in the ovary, while no significant changes were observed in the uterus. Our study reinforces the importance of adequate protein intake during puberty, since physiological changes in this developmental period interfere with the histomorphometry of the ovaries and uteri, possibly resulting in impaired folliculogenesis and fertility in the reproductive period.
MeSH term(s)	Animals ; Estrous Cycle/physiology ; Female ; Ovary/metabolism ; Ovary/pathology ; Protein Deficiency/metabolism ; Protein Deficiency/pathology ; Protein Deficiency/physiopathology ; Rats ; Rats, Inbred F344 ; Sexual Maturation/physiology ; Uterus/metabolism ; Uterus/pathology
Language	English
Publishing date	2021-03-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1016006-1
ISSN	1365-2613 ; 0958-4625 ; 0007-1021 ; 0959-9673
ISSN (online)	1365-2613
ISSN	0958-4625 ; 0007-1021 ; 0959-9673
DOI	10.1111/iep.12388
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Article ; Online: Melatonin synthesis in and uptake by mitochondria: implications for diseased cells with dysfunctional mitochondria.

Reiter, Russel J / Sharma, Ramaswamy / Pires de Campos Zuccari, Debora Aparecida / de Almeida Chuffa, Luiz Gustavo / Manucha, Walter / Rodriguez, Carmen

Future medicinal chemistry

2021 Volume 13, Issue 4, Page(s) 335–339

MeSH term(s)	Acetyl Coenzyme A/metabolism ; Humans ; Melatonin/biosynthesis ; Mitochondria/metabolism ; Oxidative Phosphorylation ; Pyruvate Dehydrogenase Complex/metabolism
Chemical Substances	Pyruvate Dehydrogenase Complex ; Acetyl Coenzyme A (72-89-9) ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2021-01-05
Publishing country	England
Document type	Editorial
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc-2020-0326
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Article ; Online: Melatonin: A mitochondrial resident with a diverse skill set.

Reiter, Russel J / Sharma, Ramaswamy / Rosales-Corral, Sergio / de Campos Zuccari, Debora Aparecida Pires / de Almeida Chuffa, Luiz Gustavo

Life sciences

2022 Volume 301, Page(s) 120612

Abstract: Melatonin is an ancient molecule that originated in bacteria. When these prokaryotes were phagocytized by early eukaryotes, they eventually developed into mitochondria and chloroplasts. These new organelles retained the melatonin synthetic capacity of ... ...

Abstract	Melatonin is an ancient molecule that originated in bacteria. When these prokaryotes were phagocytized by early eukaryotes, they eventually developed into mitochondria and chloroplasts. These new organelles retained the melatonin synthetic capacity of their forerunners such that all present-day animal and plant cells may produce melatonin in their mitochondria and chloroplasts. Melatonin concentrations are higher in mitochondria than in other subcellular compartments. Isolated mouse oocyte mitochondria form melatonin when they are incubated with serotonin, a necessary precursor. Oocyte mitochondria subsequently give rise to these organelles in all adult vertebrate cells where they continue to synthesize melatonin. The enzymes that convert serotonin to melatonin, i.e., arylalkylamine-N-acetyltransferase (AANAT) and acetylserotonin-O-methyltransferase, have been identified in brain mitochondria which, when incubated with serotonin, also form melatonin. Melatonin is a potent antioxidant and anti-cancer agent and is optimally positioned in mitochondria to aid in the maintenance of oxidative homeostasis and to reduce cancer cell transformation. Melatonin stimulates the transfer of mitochondria from healthy cells to damaged cells via tunneling nanotubes. Melatonin also regulates the major NAD
MeSH term(s)	Acetylserotonin O-Methyltransferase ; Animals ; Arylalkylamine N-Acetyltransferase ; Melatonin/pharmacology ; Mice ; Mitochondria ; Serotonin
Chemical Substances	Serotonin (333DO1RDJY) ; Acetylserotonin O-Methyltransferase (EC 2.1.1.4) ; Arylalkylamine N-Acetyltransferase (EC 2.3.1.87) ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2022-05-04
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2022.120612
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Article ; Online: Exosomes and Melatonin: Where Their Destinies Intersect.

Novais, Adriana Alonso / Chuffa, Luiz Gustavo de Almeida / Zuccari, Débora Aparecida Pires de Campos / Reiter, Russel J

Frontiers in immunology

2021 Volume 12, Page(s) 692022

Abstract: Cell-to-cell communication is a broad and complex process associated with regular stimuli to maintain healthy cell interactions. One of the agents capable of cellular communication is known as an exosome, a subset of extracellular vesicles (EVs) released ...

Abstract	Cell-to-cell communication is a broad and complex process associated with regular stimuli to maintain healthy cell interactions. One of the agents capable of cellular communication is known as an exosome, a subset of extracellular vesicles (EVs) released by the cell membrane. The exosome contains a wide range of functional proteins, mRNAs and miRNAs, which have the potential to interact with healthy or diseased cells in the body. On the other hand, melatonin also acts as a cellular communicator, produced and released by the pineal gland in a circadian way and also, non-circadian melatonin is derived from the mitochondria of all normal cells. In addition to exhibiting antioxidant, anti-inflammatory, anti-tumor and anti-aging activities, melatonin has recently been studied by its influence on exosomes. This review summarizes the relationship between exosomes and melatonin in various pathological processes. There is robust evidence that their combination ameliorates inflammation, ischemia-reperfusion injury, hepatic metabolic disturbance, cancer immunosuppression status, degenerative processes like chronic kidney disease, vascular calcification, ageing, ischemic brain injury, neurodegenerative diseases, obesity, colitis, wound healing and even embryonic development. Association of exosomes and melatonin represent a promising therapeutic tool, capable of interfering with basic molecular processes, such as oxidative stress and the inflammatory cascade, which support many pathophysiological aspects of diseases.
MeSH term(s)	Animals ; Brain Diseases/therapy ; Colitis/therapy ; Exosomes/metabolism ; Humans ; Kidney Diseases/therapy ; Liver Diseases/therapy ; Melatonin/metabolism ; Neoplasms/therapy ; Neurodegenerative Diseases/therapy ; Obesity/therapy ; Reperfusion Injury/therapy ; Wound Healing
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2021-06-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.692022
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