Search

Introduction: The reproductive system is tightly regulated by environmental and physiological signals. Melatonin, known as the hormone of darkness, plays a crucial role in regulating both the circadian and reproductive systems in mammals. Hypothyroidism is a key endocrine disorder that harms the reproductive system. Despite many studies on melatonin's effects on the reproductive system, there is conflicting information regarding melatonin synthesis modulation in hypothyroidism. The objective of this study was to investigate the modulation of plasma melatonin levels and gene expression of Aanat and Asmt in the pineal gland and gonads of rats with hypothyroidism at different times of the day. Methods: Female and male Wistar rats were divided into control and hypothyroid groups. Hypothyroidism was induced using propylthiouracil (PTU) for 15 days, rats were euthanized six hours after lights on (ZT6), before lights off (ZT11.5), and six hours after lights off (ZT18). Free thyroxine (FT4) and melatonin were quantified in plasma, and gene expressions of melatonin synthesizing enzymes (Aanat and Asmt) were measured in pineal and sexual organs (testis and ovary). Also, morphological analysis was performed in sexual organs. Results: The results reveal some disparities between the sexes. Hypothyroidism reduced antral and primary follicles in the ovary, and reduced the weight of testis, epididymis, and prostate. In relation to gene expression, we observed a reduction in Aanat expression in the pineal gland during the light phase (ZT6), and in males, this reduction occurred during the dark phase (ZT18). Regarding Asmt expression, there was a decrease in females also during the dark phase (ZT18). In the gonads, there was an increase in expression in both sexes at ZT11.5. Additionally, it was interesting to observe the association between FT4 levels and Asmt expression in the gonads. Conclusions: This study showed that acute hypothyroidism can affect components of the melatonergic system in gonads, particularly gene expression of melatonin synthesis enzymes (Aanat and Asmt) contributing to changes in reproduction organs during disease progression. These findings enhance our understanding of melatonin synthesis in the reproductive system during hypothyroidism, showing distinct responses in male and female rats, and suggest that hypothyroidism affects the circadian rhythmicity of melatonin synthesis in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Coralsnakes (Micrurus spp.) are the only elapids found throughout the Americas. They are recognized for their highly neurotoxic venom, which is comprised of a wide variety of toxins, including the stable, low-mass toxins known as three-finger toxins (3FTx). Due to difficulties in venom extraction and availability, research on coralsnake venoms is still very limited when compared to that of other Elapidae snakes like cobras, kraits, and mambas. In this study, two previously described 3FTx from the venom of M. corallinus, NXH1 (3SOC1_MICCO), and NXH8 (3NO48_MICCO) were characterized. Using in silico, in vitro, and ex vivo experiments, the biological activities of these toxins were predicted and evaluated. The results showed that only NXH8 was capable of binding to skeletal muscle cells and modulating the activity of nAChRs in nerve–diaphragm preparations. These effects were antagonized by anti-rNXH8 or antielapidic sera. Sequence analysis revealed that the NXH1 toxin possesses eight cysteine residues and four disulfide bonds, while the NXH8 toxin has a primary structure similar to that of non-conventional 3FTx, with an additional disulfide bond on the first loop. These findings add more information related to the structural diversity present within the 3FTx class, while expanding our understanding of the mechanisms of the toxicity of this coralsnake venom and opening new perspectives for developing more effective therapeutic interventions. [ABSTRACT FROM AUTHOR]

Immune‐pineal axis activation is part of the assembly of immune responses. Proinflammatory cytokines inhibit the pineal synthesis of melatonin while inducing it in macrophages by mechanisms dependent on nuclear factor‐κB (NF‐κB) activation. Cytokines activating the Janus kinase/signal transducer and activator of transcription (STAT) pathways, such as interferon‐gamma (IFN‐γ) and interleukin‐10 (IL‐10), modulate melatonin synthesis in the pineal, bone marrow (BM), and spleen. The stimulatory effect of IFN‐γ upon the pineal gland depends on STAT1/NF‐κB interaction, but the mechanisms controlling IL‐10 effects on melatonin synthesis remain unclear. Here, we evaluated the role of STAT3 and NF‐κB activation by IL‐10 upon the melatonin synthesis of rats' pineal gland, BM, spleen, and peritoneal cells. The results show that IL‐10‐induced interaction of (p)STAT3 with specific NF‐κB dimmers leads to different cell effects. IL‐10 increases the pineal's acetylserotonin O‐methyltransferase (ASMT), N‐acetylserotonin, and melatonin content via nuclear translocation of NF‐κB/STAT3. In BM, the nuclear translocation of STAT3/p65‐NF‐κB complexes increases ASMT expression and melatonin content. Increased pSTAT3/p65‐NF‐κB nuclear translocation in the spleen enhances phosphorylated serotonin N‐acetyltransferase ((p)SNAT) expression and melatonin content. Conversely, in peritoneal cells, IL‐10 leads to NF‐κB p50/p50 inhibitory dimmer nuclear translocation, decreasing (p)SNAT expression and melatonin content. In conclusion, IL‐10's effects on melatonin production depend on the NF‐κB subunits interacting with (p)STAT3. Thus, variations of IL‐10 levels and downstream pathways during immune responses might be critical regulatory factors adjusting pineal and extra‐pineal synthesis of melatonin. [ABSTRACT FROM AUTHOR]

Chronic inflammatory diseases are triggered by causal stimuli that might occur long before the appearance of the symptoms. Increasing evidence suggests that these stimuli are necessary but not always sufficient to induce the diseases. The murine model of type II collagen emulsified in Freund's incomplete adjuvant (collagen‐induced arthritis) to induce rheumatoid arthritis (RA) follows this pattern as some animals do not develop the chronically inflamed phenotype. Considering that in the immune–pineal axis (IPA) theory adrenal–pineal cross‐talk adjusts early phases of inflammatory processes, we investigated whether differences in IPA activation could explain why some animals are resistant (RES) while others develop RA. We observed a similar increase in 6‐sulfatoxymelatonin (aMT6s) excretion from day 3 to 13 in both RES and RA animals, followed by a significant decrease in RA animals. This pattern of aMT6s excretion positively correlated with plasma corticosterone (CORT) in RES animals. Additionally, RA animals presented a lower aMT6s/CORT ratio than saline‐injected or RES animals. Plasmatic levels of tumour necrosis factor were similar in both groups, but interleukin (IL)‐1β and monocyte chemotactic protein 1 (MCP‐1) levels were lower in RES compared to RA animals. IL‐2 and IL‐4 were decreased in RES animals compared to saline‐injected animals. The aMT6s/CORT ratio inversely correlated with the paw thickness and the inflammatory score (levels of IL‐1β, MCP‐1, IL‐2 and IL‐4 combined). Thus, adrenocortical–pineal positive interaction is an early defence mechanism for avoiding inflammatory chronification. Key points: Immune–pineal axis imbalance is observed in early‐phase rheumatoid arthritis development.Only resistant animals present a positive association between adrenal and pineal hormones.The 6‐sulfatoxymelatonin/corticosterone ratio is decreased in animals that develop rheumatoid arthritis.The inflammatory score combining the levels of nocturnal interleukin (IL)‐1β, monocyte chemotactic protein 1, IL‐2 and IL‐4 presents a very strong positive correlation with the size of inflammatory lesion.The 6‐sulfatoxymelatonin/corticosterone ratio presents a strong negative correlation with the inflammatory score and paw oedema size. [ABSTRACT FROM AUTHOR]

Increased plasma glucocorticoids (corticosterone – CORT, in amphibians) and melatonin (MEL) are associated with the daily activity phase and with environmental darkness, respectively. Besides, CORT and MEL also play pivotal immunomodulatory roles in several vertebrates. Herein we described the daily profile of plasma MEL and CORT for Rhinella icterica toads in captivity. Thereafter, we investigated the effects of lipopolysaccharide (LPS)-induced systemic inflammation on the production of CORT and MEL in the R. icterica. Captive toads showed CORT and MEL diurnal variation typical of nocturnal species, with increased values for CORT at ZT12 (18 h) and MEL peak at ZT18 (24 h). LPS-induced hormonal changes included increased plasma CORT and decreased ocular and plasma MEL when compared to those from toads treated with saline 2 h post-injection. Our results demonstrated the presence of a diurnal CORT and MEL variation in toads. We also showed the crosstalk between CORT and MEL during the toad's systemic inflammation in response to an immune challenge with LPS. Additionally, our results demonstrated that anuran eyes' MEL production might be regulated during the inflammatory processes. [ABSTRACT FROM AUTHOR]