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Ovarian cancer (OC) adjusts energy metabolism in favor of its progression and dissemination. Because melatonin (Mel) has antitumor actions, we investigated its impact on energy metabolism and kinase signaling in OC cells (SKOV-3 and CAISMOV-24). Cells were divided into control and Mel-treated groups, in the presence or absence of the antagonist luzindole. There was a decrease in the levels of HIF-1α, G6PDH, GAPDH, PDH, and CS after Mel treatment even in the presence of luzindole in both OC cells. Mel treatment also reduced the activity of OC-related enzymes including PFK-1, G6PDH, LDH, CS, and GS whereas PDH activity was increased. Lactate and glutamine levels dropped after Mel treatment. Mel further promoted a reduction in the concentrations of CREB, JNK, NF-kB, p-38, ERK1/2, AKT, P70S6K, and STAT in both cell lines. Mel reverses Warburg-type metabolism and possibly reduces glutaminolysis, thereby attenuating various oncogenic molecules associated with OC progression and invasion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

(Background). Canine mammary tumors (CMTs) have emerged as an important model for understanding pathophysiological aspects of human disease. Liquid biopsy (LB), which relies on blood-borne biomarkers and offers minimal invasiveness, holds promise for reflecting the disease status of patients. Small extracellular vesicles (SEVs) and their protein cargo have recently gained attention as potential tools for disease screening and monitoring. (Objectives). This study aimed to isolate SEVs from canine patients and analyze their proteomic profile to assess their diagnostic and prognostic potential. (Methods). Plasma samples were collected from female dogs grouped into CMT (malignant and benign), healthy controls, relapse, and remission groups. SEVs were isolated and characterized using ultracentrifugation (UC), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Proteomic analysis of circulating SEVs was conducted using liquid chromatography-mass spectrometry (LC-MS). (Results). While no significant differences were observed in the concentration and size of exosomes among the studied groups, proteomic profiling revealed important variations. Mass spectrometry identified exclusive proteins that could serve as potential biomarkers for mammary cancer. These included Inter-alpha-trypsin inhibitor heavy chain (ITIH2 and ITI4), phosphopyruvate hydratase or alpha enolase (ENO1), eukaryotic translation elongation factor 2 (eEF2), actin (ACTB), transthyretin (TTR), beta-2-glycoprotein 1 (APOH) and gelsolin (GSN) found in female dogs with malignant tumors. Additionally, vitamin D-binding protein (VDBP), also known as group-specific component (GC), was identified as a protein present during remission. (Conclusions). The results underscore the potential of proteins found in SEVs as valuable biomarkers in CMTs. Despite the lack of differences in vesicle concentration and size between the groups, the analysis of protein content revealed promising markers with potential applications in CMT diagnosis and monitoring. These findings suggest a novel approach in the development of more precise and effective diagnostic tools for this challenging clinical condition.

The percentage of the total amount of melatonin produced in vertebrates that comes from the pineal is small (likely <5%) but, nevertheless, functionally highly noteworthy. The significance of pineal melatonin is that it is secreted cyclically such that it has a critical function in influencing not only the suprachiasmatic nucleus but clock genes that reside in perhaps every cell throughout the organism. Extrapineal melatonin, which may be synthesized in the mitochondria of all other cells in much larger amounts than that in the pineal gland has a different function than that derived from the pineal gland. Its synthesis is not circadian and it is not directly impacted by the photoperiodic environment. Also, melatonin from the extrapineal sites is not normally secreted into the blood stream; rather, it acts locally in its cell of synthesis or, possibly via paracrine mechanisms, on immediately adjacent cells. The functions of extrapineal melatonin include central roles in maintaining molecular and redox homeostasis and actions in resisting pathological processes due to its ability to directly or indirectly detoxify free radicals. The vast majority of organisms that exist on Earth lack a pineal gland so pineal-derived melatonin is unique to vertebrates. Evidence suggests that all invertebrates, protists and plants synthesized melatonin and they have no pineal homolog; thus, the production of melatonin by extrapineal cells in vertebrates should not be unexpected. While the factors that control pineal melatonin synthesis are well documented, the processes that regulate extrapineal melatonin production are undefined., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin, herein referred to as Source #1, is the pineal gland. In this organ, melatonin production is circadian with maximal synthesis and release into the blood and cerebrospinal fluid occurring during the night. Of the total amount of melatonin produced in mammals, we speculate that less than 5% is synthesized by the pineal gland. The melatonin rhythm has the primary function of influencing the circadian clock at the level of the suprachiasmatic nucleus (the CSF melatonin) and the clockwork in all peripheral organs (the blood melatonin) via receptor-mediated actions. A second source of melatonin (Source # 2) is from multiple tissues throughout the body, probably being synthesized in the mitochondria of these cells. This constitutes the bulk of the melatonin produced in mammals and is concerned with metabolic regulation. This review emphasizes the action of melatonin from peripheral sources in determining re-dox homeostasis, but it has other critical metabolic effects as well. Extrapineal melatonin synthesis does not exhibit a circadian rhythm and it is not released into the blood but acts locally in its cell of origin and possibly in a paracrine matter on adjacent cells. The factors that control/influence melatonin synthesis at extrapineal sites are unknown. We propose that the concentration of melatonin in these cells is determined by the subcellular redox state and that melatonin synthesis may be inducible under stressful conditions as in plant cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Reiter, Sharma, Tan, Chuffa, da Silva, Slominski, Steinbrink and Kleszczynski.)

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., (© 2024. Published by The Company of Biologists Ltd.)

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.

In addition to its highly aggressive nature and late diagnosis, hepatocellular carcinoma (HCC) does not respond effectively to available chemotherapeutic agents. The search is on for an ideal and effective compound with low cost and minimal side effects that can be used as an adjunct to chemotherapeutic regimens. One of the mechanisms involved in the pathology of HCC is the oxidative stress, which plays a critical role in tumor survival and dissemination. Our group has already demonstrated the antitumor potential of melatonin against HuH 7.5 cells. In the present study, we focused on the effects of melatonin on oxidative stress parameters and their consequences on cell metabolism. HuH 7.5 cells were treated with 2 and 4 mM of melatonin for 24 and 48 h. Oxidative stress biomarkers, antioxidant enzyme, mitochondrial membrane potential, formation of lipid bodies and autophagic vacuoles, cell cycle progression, cell death rate and ultrastructural cell alterations were evaluated. The treatment with melatonin increased oxidative stress biomarkers and reduced antioxidant enzyme activities of HuH 7.5 cells. Additionally, melatonin treatment damaged the mitochondrial membrane and increased lipid bodies and autophagic vacuole formation. Melatonin triggered cell cycle arrest and induced cell death by apoptosis. Our results indicate that the treatment of HuH 7.5 cells with melatonin impaired antioxidant defense systems, inhibited cell cycle progression, and caused metabolic stress, culminating in tumor cell death., Competing Interests: Declaration of Competing Interest All co-authors have contributed substantially to conducting the underlying research and drafting this manuscript.The authors of this manuscript declare that they have no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

(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.

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.

Canine mammary tumors (CMTs) are among the most common diseases in female dogs and share similarities with human breast cancer, which makes these animals a model for comparative oncology studies. In these tumors, metabolic reprogramming is known as a hallmark of carcinogenesis whereby cells undergo adjustments to meet the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as a therapeutic strategy, which has mostly been tested in human clinical trials but is poorly explored in CMTs. In this dedicated review, we compiled the metabolic changes described for CMTs, emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial functions. We observed key factors associated with the presence and aggressiveness of CMTs, such as an increase in glucose uptake followed by enhanced anaerobic glycolysis via the upregulation of glycolytic enzymes, changes in glutamine catabolism due to the overexpression of glutaminases, increased fatty acid oxidation, and distinct effects depending on lipid saturation, in addition to mitochondrial DNA, which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Background: Ovarian cancer is a highly aggressive disease that is frequently diagnosed in advanced stages. Melatonin, with its numerous antitumor properties, holds great promise in cancer treatment. Herein, we investigated the effects of melatonin on apoptosis, cell migration, and kinase levels in human ovarian carcinoma SKOV-3 cells and determined whether these effects are mediated by the activation of the MT1 receptor., Methods: SKOV-3 cells were exposed to different concentrations of melatonin based on the presence of MT1 receptor, and we also performed specific silencing of the melatonin receptor gene MTNR1A., Results: Our findings revealed that melatonin reduced cell viability as shown by the MTT assay, and flow cytometry analysis showed increased rates of apoptosis and necrosis in all melatonin-treated cells. Melatonin significantly decreased the migratory and invasive capacities of the cells. Propidium iodide labeling indicated that melatonin induced cell cycle arrest by reducing DNA content in the S and G2/M phases in SKOV-3 cells. Additionally, the levels of AKT, ERK1/2, JNK, CREB, p70S6K, STAT3/5, and p38 MAP kinase involved in cell survival, proliferation, motility, and stress responses were depressed by melatonin and further reduced after MT1 knockdown. These molecules were found to be associated with lower overall survival in ovarian cancer patients., Conclusions: Melatonin had obvious oncostatic actions on ovarian cancer cells, and MT1 receptor knockdown intensified its antitumor effect. The inhibition of the MT1 receptor resulted in a substantial reduction in the migratory and invasive capacities of the cells, suggesting its potential as a therapeutic target for the treatment of ovarian cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Aims: Breast cancer (BC) presents high mortality rate and about 25-46 % have mutation in the PIK3CA gene. Alpelisib is a PI3K inhibitor that acts on p110α, which is a subunit of the PI3K protein. The melatonin shown important anti-neoplastic effects and may increase the effectiveness of chemotherapy. This study evaluated the synergistic action of Alpelisib and Melatonin in BC lines carrying the H1047R mutation in PIK3CA, relative to the cellular dynamics and the PI3K/AKT/mTOR pathway., Main Methods: MDA-MB-468 (triple-ernegative), MDA-MB-453 (H1047R PIK3CA, HER2+) and T-47D cells (H1047R PIK3CA, ER+/PR+) were divided into four treatment groups: control; Melatonin (1 mM); Alpelisib (1 μM); and Alpelisib (1 μM) + Melatonin (1 mM). Cell viability and migration were investigated using the MTT assay and Transwell assay, respectively. Protein expression of PI3K, p-AKT, mTOR, HIF-1α, and caspase-3, was verified using immunocytochemistry., Key Findings: MTT assay revealed that MDA-MB-453 and T-47D showed reduction in cell viability in all groups, especially in the MDA-MB-453 treated with Melatonin + Alpelisib. MDA-MB-468 presents reduction in cell migration only with Melatonin, while in the lines with mutation, the treatment of Melatonin + Alpelisib caused inhibition of cell migration. PI3K, p-AKT, mTOR and HIF-1α were inhibited after treatment with Melatonin + Alpelisib in MDA-MB-453 and T-47D lines. The expression of caspase-3 increased in all groups in MDA-MB-453 and T-47D cells, being the increase more pronounced in the Melatonin + Alpelisib group., Significance: These results indicate that the combined use of Melatonin and Alpelisib may be more effective in inhibiting BC in women carrying the PIK3CA gene mutation than either treatment alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

Purpose of Review: This review summarizes the involvement of inflammaging in vascular damage with focus on the epigenetic mechanisms by which inflammaging-induced hypertension is triggered., Recent Findings: Inflammaging in hypertension is a complex condition associated with the production of inflammatory mediators by the immune cells, enhancement of oxidative stress, and tissue remodeling in vascular smooth muscle cells and endothelial cells. Cellular processes are numerous, including inflammasome assembly and cell senescence which may involve mitochondrial dysfunction, autophagy, DNA damage response, dysbiosis, and many others. More recently, a series of noncoding RNAs, mainly microRNAs, have been described as possessing epigenetic actions on the regulation of inflammasome-related hypertension, emerging as a promising therapeutic strategy. Although there are a variety of pharmacological agents that effectively regulate inflammaging-related hypertension, a deeper understanding of the epigenetic events behind the control of vessel deterioration is needed for the treatment or even to prevent the disease onset., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolic dysregulation as a reflection of specific metabolite production and its utilization is a common feature of many human neoplasms. Melatonin, an indoleamine that is highly available during darkness, has a variety of metabolic functions in solid tumors. Because plasma metabolites undergo circadian changes, we investigated the role of melatonin on the profile of amino acids (AAs), biogenic amines, carnitines, sphingolipids, and hexoses present in the plasma of mice bearing xenograft triple negative breast cancer (MDA-MB-231 cells) over 24 h. Plasma concentrations of nine AAs were reduced by melatonin, especially during the light phase, with a profile closer to that of non-breast cancer (BC) animals. With respect to acylcarnitine levels, melatonin reduced 12 out of 24 molecules in BC-bearing animals compared to their controls, especially at 06:00 h and 15:00 h. Importantly, melatonin reduced the concentrations of asymmetric dimethylarginine, carnosine, histamine, kynurenine, methionine sulfoxide, putrescine, spermidine, spermine, and symmetric dimethylarginine, which are associated with the BC metabolite sets. Melatonin also led to reduced levels of sphingomyelins and hexoses, which showed distinct daily variations over 24 h. These results highlight the role of melatonin in controlling the levels of plasma metabolites in human BC xenografts, which may impact cancer bioenergetics, in addition to emphasizing the need for a more accurate examination of its metabolomic changes at different time points.

Nutrition is an environmental factor able to activate physiological interactions between fetus and mother. Maternal protein restriction is able to alter sperm parameters associated with epididymal functions. Since correct development and functioning of the epididymides are fundamental for mammalian reproductive success, this study investigated the effects of maternal protein restriction on epididymal morphology and morphometry in rat offspring as well as on the expression of Src, Cldn-1, AR, ER, aromatase p450, and 5α-reductase in different stages of postnatal epididymal development. For this purpose, pregnant females were allocated to normal-protein (NP-17% protein) and low-protein (LP-6% protein) groups that received specific diets during gestation and lactation. After weaning, male offspring was provided only normal-protein diet until the ages of 21, 44, and 120 days, when they were euthanized and their epididymides collected. Maternal protein restriction decreased genital organs weight as well as crown-rump length and anogenital distance at all ages. Although the low-protein diet did not change the integrity of the epididymal epithelium, we observed decreases in tubular diameter, epithelial height and luminal diameter of the epididymal duct in 21-day-old LP animals. The maternal low-protein diet changed AR, ERα, ERβ, Src 416, and Src 527 expression in offspring epididymides in an age-dependent manner. Finally, maternal protein restriction increased Cldn-1 expression throughout the epididymides at all analyzed ages. Although some of these changes did not remain until adulthood, the insufficient supply of proteins in early life altered the structure and functioning of the epididymis in important periods of postnatal development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cavariani, de Mello Santos, Chuffa, Pinheiro, Scarano and Domeniconi.)

Mammary tumours (MT) are one of the most prevalent malignancies in female dogs and women. Currently, molecular analyzes have shown that each tumour type presents its own genetic signature. In this context, liquid biopsy allows a comprehensive genetic characterisation of the tumour, enabling early diagnosis and personalised treatment of patients. In women, deleterious mutations inherited in BRCA2 gene are associated with an increased risk of breast cancer, resistance to therapies and worse prognosis. In female dogs, there are many divergent data on the involvement of BRCA2 gene with mammary carcinogenesis and what its pathogenic potential is. Therefore, the objective was to identify BRCA2 gene variants in 20 plasma DNA samples, from 10 newly diagnosed dogs with mammary cancer (RD), five control (CTR) and five mastectomized patients. Eleven single nucleotide polymorphisms (SNPs) were detected, most of them in the exon 11 and two indels (deletion/insertion) in the BRCA2 gene. However, there was no statistically significant difference in the SNPs/indels detected between the groups. In addition, only one SNP (p.T1425P) and one deletion (p.L2307del) were considered deleterious using in silico computational models. Interestingly, most common variants were present in the plasma of all groups, except for the Ile2614Thr, Ile2614Val, Thr1425Pro and p.L2307del variants. Thus, we observed that SNPs are common in the BRCA2 gene of female dogs with MT, with a similar condition identified in women with breast cancer. Liquid biopsy approach in dogs with MT is useful for genetic and therapeutic proposals., (© 2021 John Wiley & Sons Ltd.)

Vascular inflammation is one of the main activating stimuli of cardiovascular disease and its uncontrolled development may worsen the progression and prognosis of these pathologies. Therefore, the search for new therapeutic options to treat this condition is undoubtedly needed. In this regard, it may be better to repurpose endogenous anti-inflammatory compounds already known, in addition to synthesizing new compounds for therapeutic purposes. It is well known that vitamin D, anandamide, and melatonin are promising endogenous substances with powerful and wide-spread anti-inflammatory properties. Currently, the epigenetic mechanisms underlying these effects are often unknown. This review summarizes the potential epigenetic mechanisms by which vitamin D, anandamide, and melatonin attenuate vascular inflammation. This information could contribute to the improvement in the therapeutic management of multiple pathologies associated with blood vessel inflammation, through the pharmacological manipulation of new target sites that until now have not been addressed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.

Nile tilapia (Oreochromis niloticus) is a species of worldwide importance for aquaculture. A crossbred lineage was developed through introgressive backcross breeding techniques and combines the high growth performance of the Chitralada (CHIT) lwith attractive reddish color of the Red Stirling (REDS) strains. Since the crossbreed has an unknown genetically improved background, the objective of this work was to characterize expression signatures that portray the advantageous phenotype of the crossbreeds. We characterized the microRNA transcriptome by high throughput sequencing (RNA-seq) and the proteome through mass spectrometry (ESI-Q-TOF-MS) and applied bioinformatics for the comparative analysis of such molecular data on the three strains. Crossbreed expressed a distinct set of miRNAs and proteins compared to the parents. They comprised several microRNAs regulate traits of economic interest. Proteomic profiles revealed differences between parental and crossbreed in expression of proteins associated with glycolisis. Distinctive miRNA and protein signatures contribute to the phenotype of crossbreed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Breast cancer (BC) is the malignant neoplasm with the highest mortality rate in women and female dogs are good models to study BC., Objective: We investigated the efficacy of liquid biopsy to detect gene mutations in the diagnosis and follow-up of women and female dogs with BC., Materials and Methods: In this study, 57 and 37 BC samples were collected from women and female dogs, respectively. After core biopsy and plasma samples were collected, the DNA and ctDNA of the tumor fragments and plasma were processed for next generation sequencing (NGS) assay. After preprocessing of the data, they were submitted to the Genome Analysis ToolKit (GATK)., Results: In women, 1788 variants were identified in tumor fragments and 221 variants in plasma; 66 variants were simultaneously detected in tumors and plasma. Conversely, in female dogs, 1430 variants were found in plasma and 695 variants in tumor fragments; 59 variants were simultaneously identified in tumors and plasma. The most frequently mutated genes in the tumor fragments of women were USH2A , ATM , and IGF2R ; in female dogs, they were USH2A , BRCA2 , and RRM2 . Plasma of women showed the most frequent genetic variations in the MAP3K1, BRCA1, and GRB7 genes, whereas plasma from female dogs had variations in the NF1 , ERBB2 , and KRT17 genes. Mutations in the AKT1 , PIK3CA , and BRIP genes were associated with tumor recurrence, with a highly pathogenic variant in PIK3CA being particularly prominent. We also detected a gain-of-function mutation in the GRB7 , MAP3K1 , and MLH1 genes., Conclusion: Liquid biopsy is useful to identify specific genetic variations at the beginning of BC manifestation and may be accompanied over the entire follow-up period, thereby supporting the clinicians in refining interventions.

This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes., (Copyright © 2021. Published by Elsevier Inc.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Novais, Chuffa, Zuccari and Reiter.)

The use of nanosized particles has emerged to facilitate selective applications in medicine. Drug-delivery systems represent novel opportunities to provide stricter, focused, and fine-tuned therapy, enhancing the therapeutic efficacy of chemical agents at the molecular level while reducing their toxic effects. Melatonin ( N -acetyl-5-methoxytriptamine) is a small indoleamine secreted essentially by the pineal gland during darkness, but also produced by most cells in a non-circadian manner from which it is not released into the blood. Although the therapeutic promise of melatonin is indisputable, aspects regarding optimal dosage, biotransformation and metabolism, route and time of administration, and targeted therapy remain to be examined for proper treatment results. Recently, prolonged release of melatonin has shown greater efficacy and safety when combined with a nanostructured formulation. This review summarizes the role of melatonin incorporated into different nanocarriers (e.g., lipid-based vesicles, polymeric vesicles, non-ionic surfactant-based vesicles, charge carriers in graphene, electro spun nanofibers, silica-based carriers, metallic and non-metallic nanocomposites) as drug delivery system platforms or multilevel determinations in various in vivo and in vitro experimental conditions. Melatonin incorporated into nanosized materials exhibits superior effectiveness in multiple diseases and pathological processes than does free melatonin; thus, such information has functional significance for clinical intervention.

Alcoholic injury can alter the hormonal signaling pathway and lead to glucose and lipid metabolism disorders. In this study, we investigated whether the strength training could exert protective effects against the alterations caused by ethanol consumption on prostatic metabolism. A UChB, ethanol-preferring rats were used in this study. Strength training was conducted for 3 days per week for 13 weeks, rats performed jumps in water carrying a weight load strapped to their chests as part of a strength training protocol. The reduced alcohol consumption by strength training was accompanied by increased glucose, serum lipid profile, total protein levels, and reduced hormonal levels. The results of protein expression of prostatic tissues in the ethanol- and strength training-treated groups indicated that "steroidal hormone receptors," "fatty acid translocation," and "cell regulation" were significantly different between ethanol- and strength training-treated groups. Taken together, these findings show that strength training effectively ameliorated prostatic injuries in alcoholic rats at least partially by acting on lipids receptors and steroidal hormone receptors pathway, suggesting the strength training as a potential novel therapeutic strategy for treating prostate injuries caused by ethanol., (© 2020 Wiley Periodicals LLC.)

Melatonin is a ubiquitous molecule with a broad spectrum of functions including widespread anti-cancer activities. Identifying how melatonin intervenes in complex molecular signaling at the gene level is essential to guide proper therapies. Using meta-analysis approach, herein we examined the role of melatonin in regulating the expression of 46 microRNAs (miRNAs) and their target genes in breast, oral, gastric, colorectal, and prostate cancers, and glioblastoma. The deregulated miRNA-associated target genes revealed their involvement in the regulation of cellular proliferation, differentiation, apoptosis, senescence, and autophagy. Melatonin changes the expression of miRNA-associated genes in breast, gastric, and oral cancers. These genes are associated with cellular senescence, the hedgehog signaling pathway, cell proliferation, p53 signaling, and the hippo signaling pathway. Conversely, colorectal and prostate cancers as well as glioblastoma and oral carcinoma present a clear pattern of less pronounced changes in the expression of miRNA-associated genes. Most notably, colorectal cancer displayed a unique molecular change in response to melatonin. Considering breast cancer network complexity, we compared the genes found during the meta-analysis with RNA-Seq data from breast cancer-bearing mice treated with melatonin. Mechanistically, melatonin upregulated genes associated with immune responses and apoptotic processes, whereas it downregulated genes involved in cellular aggressiveness/metastasis (eg, mitosis, telomerase activity, and angiogenesis). We further characterized the expression profile of our gene subsets with human breast cancer and found eight upregulated genes and 16 downregulated genes that were appositively correlated with melatonin. Our results pose a multi-dimension network of tumor-associated genes regulated by miRNAs potentially targeted by melatonin., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nandrolone decanoate (ND) is an anabolic-androgenic steroid, and its indiscriminate use leads to subclinical alterations in the hypothalamic-pituitary-gonadal axis and androgen-dependent organs., Objectives: To evaluate the effects of ND, either alone or in combination with resistance exercise (RE), on the levels of sex hormones, converting enzymes, and steroid receptors and the morphology of the ventral prostate (VP) in adult and aged rats., Methods: Forty Sprague-Dawley adult and aged rats were divided into four groups each, sedentary and trained with and without ND. The groups received treatments over 8 weeks. Adult animals were sacrificed immediately following treatment completion, while the aged groups were left untreated until 300 days of age., Results: Adult and aged animals showed reductions in testosterone levels following the different treatments, and 17β-estradiol levels were decreased in the ND-treated groups. The level of 5α-reductase type 2 (5αR2) and aromatase was increased significantly in the prostates of adult animals that performed RE. However, aromatase levels were decreased in the prostates of aged animals that performed RE and were treated with ND, while 5αR2 levels were reduced in aged animals that performed RE without ND treatment. When sex receptors levels were examined, the aged and trained animals presented low androgen receptor (AR) levels. Estrogen receptors (ERs) levels were increased in the prostates of adult animals that received ND. ERβ levels were reduced after treatments in aged animals. The heights of the prostatic epithelium were reduced in all adult treated animals, coinciding with increases in PCNA and PAR4 levels., Discussion: ND and RE alter the levels of hormone, converting enzymes, and sex steroid receptors and the morphology of the VP. These effects were observed in both adult and aged rats., Conclusion: ND, either with or without RE, during post-puberty stage is able to interfere with the morphophysiology of the prostate., (© 2019 American Society of Andrology and European Academy of Andrology.)

The development of the endometrium is a cyclic event tightly regulated by hormones and growth factors to coordinate the menstrual cycle while promoting a suitable microenvironment for embryo implantation during the "receptivity window". Many women experience uterine failures that hamper the success of conception, such as endometrium thickness, endometriosis, luteal phase defects, endometrial polyps, adenomyosis, viral infection, and even endometrial cancer; most of these disturbances involve changes in endocrine components or cell damage. The emerging evidence has proven that circadian rhythm deregulation followed by low circulating melatonin is associated with low implantation rates and difficulties to maintain pregnancy. Given that melatonin is a circadian-regulating hormone also involved in the maintenance of uterine homeostasis through regulation of numerous pathways associated with uterine receptivity and gestation, the success of female reproduction may be dependent on the levels and activity of uterine and placental melatonin. Based on the fact that irregular production of maternal and placental melatonin is related to recurrent spontaneous abortion and maternal/fetal disturbances, melatonin replacement may offer an excellent opportunity to restore normal physiological function of the affected tissues. By alleviating oxidative damage in the placenta, melatonin favors nutrient transfer and improves vascular dynamics at the uterine-placental interface. This review focuses on the main in vivo and in vitro functions of melatonin on uterine physiological processes, such as decidualization and implantation, and also on the feto - maternal tissues, and reviews how exogenous melatonin functions from a mechanistic standpoint to preserve the organ health. New insights on the potential signaling pathways whereby melatonin resists preeclampsia and endometriosis are further emphasized in this review., Competing Interests: Authors declare no conflict of interest.

Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment.

To investigate the potential role of immunotherapies in the cellular and molecular mechanisms associated with ovarian cancer (OC), we applied a comparative proteomic toll using protein identification combined with mass spectrometry. Herein, the effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) were tested alone or in combination in human SKOV-3 cells. The doses and period were defined based on a previous study, which showed that 25 μg/mL P-MAPA and 1 ng/mL IL-12 are sufficient to reduce cell metabolism after 48 h. Indeed, among 2,881 proteins modulated by the treatments, 532 of them were strictly concordant and common. P-MAPA therapy upregulated proteins involved in tight junction, focal adhesion, ribosome constitution, GTP hydrolysis, semaphorin interactions, and expression of SLIT and ROBO, whereas it downregulated ERBB4 signaling, toll-like receptor signaling, regulation of NOTCH 4, and the ubiquitin proteasome pathway. In addition, IL-12 therapy led to upregulation of leukocyte migration, tight junction, and cell signaling, while cell communication, cell metabolism, and Wnt signaling were significantly downregulated in OC cells. A clear majority of proteins that were overexpressed by the combination of P-MAPA with IL-12 are involved in tight junction, focal adhesion, DNA methylation, metabolism of RNA, and ribosomal function; only a small number of downregulated proteins were involved in cell signaling, energy and mitochondrial processes, cell oxidation and senescence, and Wnt signaling. These findings suggest that P-MAPA and IL-12 efficiently regulated important proteins associated with OC progression; these altered proteins may represent potential targets for OC treatment in addition to its immunoadjuvant effects., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

The maternal nutritional status is essential to the health and well-being of the fetus. Maternal protein restriction during the perinatal stage causes sperm alterations in the offspring that are associated with epididymal dysfunctions. Vascular endothelial growth factor (VEGF) and its receptor, VEGFr-2, as well as aquaporins (AQPs) are important regulators of angiogenesis and the epididymal microenvironment and are associated with male fertility. We investigated the effects of maternal protein restriction on epididymal angiogenesis and AQP expression in the early stages of postnatal epididymal development. Pregnant rats were divided into two experimental groups that received either a normoprotein (17% protein) or low-protein diet (6% protein) during gestation and lactation. At postnatal day (PND)7 and PND14, male offspring were euthanized, the epididymides were subjected to morphometric and microvascular density analyses and to VEGF-A, VEGF-r2, AQP1 and AQP9 expression analyses. The maternal low-protein diet decreased AQP9 and VEGFr-2 expression, decreased epididymal microvascularity and altered the morphometric features of the epididymal epithelium; no changes in AQP1 expression were observed at the beginning of postnatal epididymal development. Maternal protein restriction alters microvascularization and affects molecules involved in the epidydimal microenvironment, resulting in morphometric alterations related to a delay in the beginning of epididymis postnatal development.

Ovarian cancer (OC) is a highly prevalent gynecological malignancy worldwide. Throughout ovarian carcinogenesis, the crosstalk between cellular components of the microenvironment, including tumor cells and fibroblasts, is proposed to play critical roles in cancer progression. The dysregulation of microRNA expression is also a pronounced feature of the OC. The screening of microRNAs, mainly those involved in OC microenvironment, could have diagnostic and/or therapeutic potential for this malignancy. Thus, we assessed the influence of fibroblasts on microRNA expression and the motility of OC cells. To achieve this goal, SKOV-3 cancer cells were co-cultured with human normal fibroblasts derived from primary culture (FP-96). Cell viability, expression of tumor suppressor microRNAs and oncomiRs by RT-qPCR, cell migration by wound healing assay and analysis of MMP-2 activity by zymography were performed in SKOV-3 cells. Moreover, α-smooth muscle actin (α-SMA) expression was evaluated by Western blot in FP-96 fibroblasts. Notably, the co-culture downregulated the tumor suppressor miR-29b and increased migration of SKOV-3 cells. In addition, co-culture increased the activity of MMP-2, which is a miR-29 target, and accounted for extracellular matrix remodeling and augmented cellular motility. Concomitantly, the co-culture system induced α-SMA expression in FP-96 fibroblasts, the commonly expressed marker in cancer-associated fibroblasts (CAFs). Our findings suggest that the potential crosstalk between OC cells and fibroblasts in tumor microenvironment may play a key role in the progression of OC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alcoholism is a multifactorial disease with high risk for dependence determined by genetic background, environmental factors and neuroadaptations. The excessive consumption of this substance is related to psychiatric problems, epilepsy, cardiovascular disease, cirrhosis and cancers. Caffeine is one of the most popular psychostimulants currently consumed in the world. The combination of ethanol and caffeine ingested by consuming "energy drinks" is becoming increasingly popular among young people. We analyzed the effect of simultaneous consumption of ethanol and caffeine on the serum profile of miRNAs differentially expressed in the ethanol-drinking rat model (UChB strain). Adult rats were divided into three groups ( n = 5 per group): UChB group (rats fed with 1 : 10 (v/v) ethanol ad libitum ); UChB + caffeine group (rats fed with 1 : 10 (v/v) ethanol ad libitum + 3 g L -1 of caffeine); control group (rats drinking water used as the control for UChB). The treatment with caffeine occurred from day 95 to 150 days old, totalizing 55 days of ethanol + caffeine ingestion. The expressions of microRNAs ( miR ) - 9-3p , - 15b-5p , - 16-5p , - 21-5p , - 200a-3p and - 222-3p were detected by Real Time-PCR (RT-PCR). The expressions of miR-9-3p , - 15b-5p , - 16-5p and - 222-3p were upregulated in the UChB group. Conversely, simultaneous ingestion of ethanol and caffeine significantly reversed these expressions to similar levels to control animals, thus emphasizing that caffeine had a protective effect in the presence of ethanol. In addition, miR-21-5p was downregulated with ethanol consumption whereas miR- 222-3p was unchanged. Ethanol and caffeine consumption was capable of altering serum miRNAs, which are potential biomarkers for the systemic effects of these addictive substances., (This journal is © The Royal Society of Chemistry 2019.)

Aims: The present study aimed to verify changes in cerebellar and plasmatic expression of miRNAs after the chronic consumption of ethanol and caffeine in the UChB rat, an experimental model for alcoholism., Material and Methods: Male rats at 5 months of age, were divided into the following groups (n = 10/group): 1. Ethanol (UChB rats receiving 10% ethanol solution and water ad libitum); 2. Ethanol + caffeine (UChB rats receiving 10% ethanol solution + 3g/l caffeine and water ad libitum); 3. Control (rats receiving water ad libitum). The cerebellum and plasma of the animals were collected and processed by RT-PCR for the miRNAs-155-5p, -146a-5p, -126-3p, -132-3p, -339-5p., Key Findings: Ethanol and caffeine were capable of regulating the expression of miRNAs associated with the inflammatory process in the tissue and plasma of the UChB rats. Increased expression of the analyzed miRNAs-155-5p, -146a-5p, -126-3p, -132-3p was observed for the cerebellar tissue in the Ethanol group and reduced expression of them in the Ethanol + caffeine group. In plasma, caffeine significantly elevated the miR-126-3p and miR-132-3p levels and decreased miR-155-5p levels. Ethanol consumption increased miR-146a-5p expression and decreased miR-339-5p levels. In brief, altered plasmatic levels of the miRNAs did not reflect the miRNAs levels found in cerebellar tissue., Significance: Considering the results herein, we concluded that ethanol predisposes to an inflammatory process while caffeine has a neuroprotective effect on the cerebellar tissue., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is an abundant raw material applied in the production of daily necessities, such as food cans, baby bottles, electronic and medical equipment. Phytotherapeutic use of plant preparations has long been known for multiple target medicinal uses. The species Bauhinia forficata is widely used as hypoglycemic, anti-inflammatory, antioxidant, diuretic and hypocholesterolemic agent. The aim of this study was to verify the effects of B. forficata extract in association with BPA exposure on serological parameters, hepatic antioxidant status and glycogen store capacity in Wistar rats. B. forficata was able to reduce BPA-induced glucose levels; it also prevented the early glucose elevation in control and BPA-exposed animals after the glucose provocative test. This effect was related to the hepatic glycogen content; while BPA reduced the hepatic glycogen deposits B. forficata treatment contributed to minimize it. BPA and B. forficata singly caused elevation in triacylglycerol and VLDL levels and reduction in cholesterol and LDL concentrations. BPA increased hepatic malondialdehyde levels and reduced catalase activity, thus inducing liver oxidative stress. Conversely, B. forficata treatment reduced malondialdehyde concentration without interfering with catalase activity; this antioxidant capacity is attributed to the flavonoids content (e.g., kaempferol and myricetin). Based on these results, we demonstrated that B. forficata commercial extract has hypoglycemic and antioxidant properties capable of minimizing the effects of BPA. However, it should be considered that the consumption of herbal commercial extract must be judicious to avoid deleterious health effects.

Ethanol alters motricity, learning, cognition, and cellular metabolism in the cerebellum. The combination of ethanol with caffeine by consuming "energy drinks" is becoming increasingly popular among young people. We analyzed the use of ethanol and caffeine on apoptosis in the cerebellum of UChB rats. The adult rats were divided into three groups (n = 14/group): UChB group: rats fed with 1:10 (v/v) ethanol ad libitum (free choice for water or ethanol) drinking from >1.9 mL of ethanol/kg body weight/day, Control group and UChB/caffeine group (free choice for water or ethanol + caffeine 300 mg/L). The treatments occurred from Day 100 till Day 150, totalizing 50 days of ethanol/caffeine ingestion. Cerebellar sections were subjected to immunohistochemistry and gene expression for Real Time-PCR (RT-PCR) for Caspase-3, XIAP, and insulin-like growth factor 1-receptor (IGF-1R). The results showed a significant increase in the gene expression of Caspase-3 and XIAP in UChB group. On the other hand, the animals of the UChB/caffeine group showed similar results to the Controls. Regarding IGFR-1, there was greater expression in the UChB groups with strong labeling in Purkinje cells. Ethanol produces neuronal and glial neurodegeneration on the cerebellum of UChB rats. The simultaneous ingestion of ethanol and caffeine reversed the ethanol damages acting caffeine with a neuroprotective effect., (© 2018 International Federation for Cell Biology.)

Testosterone is often recommended in the treatment of several aging-related conditions. However, there are still questions about the consequences of this therapy in terms of hormonal and inflammatory parameters that are crucial for prostate homeostasis. Thus, we investigate if the testosterone therapy (TT) modulates the hormone receptors and inflammatory cytokines in the ventral prostate of adult rats. Wistar rats aging 150 days were divided into two experimental groups (n = 10/group): T: received subcutaneous injections of testosterone cypionate (5 mg/kg body weight) diluted in corn oil every other day for 4 weeks; and C: received corn oil as vehicle. Animals were euthanized at 180 days old by decapitation. Blood was collected to obtain hormone and cytokines concentrations. The ventral prostate was dissected and processed for light microscope and molecular analyses. Relative ventral prostate weight and epithelial compartment were increased after TT. The number of intact and degranulated mast cells was reduced in the T group. Plasma testosterone, DHT and intraprostatic testosterone concentrations were higher in the T group. TT leads to an increase in cell proliferation and up-regulation of AR, ERβ, PAR-4, and NRF2. Importantly, plasma concentration and tissue expression of IL-10 and TNF-α were higher after TT. In summary, these results indicate that TT can regulate inflammatory response, with impacts in cytokines and mast cell population, and modulates steroids receptors, important parameters for prostatic homeostasis., (© 2018 International Federation for Cell Biology.)

Anabolic androgenic steroids (AAS) are recommended for therapeutic clinic, but their use has increased in recent decades for aesthetic reasons. No study has evaluated the impact of AAS in the fallopian tube, after treatment and recovery periods. Herein, the aim of study was to investigate the effects of Nandrolone Decanoate (ND), administered in different doses (1.87; 3.75; 7.5 and 15 mg/kg) on the ampulla of the fallopian tube in rats, following post-treatment (PT; 15 consecutive days) and post-recovery (PR; 30 consecutive days) periods. The control group received mineral oil. Estrous cycle was monitored daily during both periods and in sequence the rats (n = 8/group/period) were killed. All ND-treated animals showed estral acyclicity during the PT and PR periods, but the histomorphometric changes in the fallopian tube varied according to the ND dose level. The expression of AR, ERα and ERβ varied in the nucleus and cytoplasm of epithelial cells. No AR expression was observed in the stroma. The muscle cells exhibited variation in immunostaining. In conclusion, ND promoted histomorphometric and immunohistochemical changes in the ampullary portion of the fallopian tube after treatment and recovery periods in a dose-independent manner., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers, and most patients develop chemoresistance after first-line treatments. Despite recent advances, the 5-year relative survival is ~45% for all OC subtypes, and invasive epithelial OC has only a 17% survival rate when diagnosed at a late stage. Identification of new efficacious molecules or biomarkers represents important opportunities in the treatment of OC. The pharmacological and physiological properties of melatonin indicate this agent could be useful against OC progression and metastasis. In normal cells, melatonin has potent antioxidant and anti-apoptotic actions. Conversely, melatonin has pro-oxidant as well as anti-proliferative, anti-angiogenic and immunomodulatory properties in many cancer types including hormone-dependent cancers. Although melatonin receptors have been identified in OC cells, the exact mechanism by which melatonin induces anticancer activities remains incompletely understood. Clinical studies have reported negative correlation between aggressiveness of OC and serum levels of melatonin, reinforcing the idea that melatonin may be a critical factor determining OC development. In vitro and in vivo studies suggest melatonin differentially regulates multiple signaling pathways in OC cells. This focused review explores the potential mechanisms of action of melatonin on cultured OC cells and in experimental models of OC in an attempt to clarify how melatonin modulates the signaling pathways involved in cancer cell apoptosis, survival, inflammation, proliferation and metabolic processes. Based on the evidence presented, we feel that melatonin, as an agent that controls cellular signals associated with malignancy, may be beneficial in combination with other therapeutics for OC treatment., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We described the effects of low- and high-dose ethanol intake on the structure and apoptosis signaling of the uterine endometrium of UChA and UChB rats (animals with voluntary ethanol consumption). Thirty adult female rats, 90 days old, were divided into three groups (n = 10/group): UChA rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking < 1.9 g/kg/day; UChB rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking from 2 to 5 g/kg/day; control rats without ethanol (only water). After 120 days of treatment, rats displaying estrus were euthanized. Uterine epithelial cells of the UCh rats showed dilated cisterns of the rough endoplasmic reticulum, presence of lipid droplets, altered nuclear chromatin, and disrupted mitochondria. The UCh rats exhibited intense atrophied epithelial cells with smaller areas and perimeters of cytoplasm and nuclei. The endometrium of UChA rats showed higher levels of caspase-3 while Xiap and Bcl2 varied from moderate to weak. Both UChA and UChB rats exhibited a stronger immunoreaction to Ki-67 and IGFR-1 on epithelial and stromal cells. Chronic ethanol intake leads to structural and molecular alterations in the uterine endometrium of UCh rats, regardless of low- or high-dose consumption, promoting reproductive disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)