The reproductive rhythm undergoes several changes during the evolution of mammals to adapt to local environmental changes. Although the critical roles of melatonin (MLT) in the formation of reproductive rhythm have been well established, the genetic basis for the changes of reproductive rhythm remains uncertain. Here, we constructed the phylogenetic trees of 13 melatonin synthesis, metabolism and receptor genes, estimated their divergence times, and calculated their selection pressures. Then, we evaluated the effect of positively selected and functionally related mutations on protein activity. Our results showed that there were significant positive selection sites in the three major genes, including tryptophan hydroxylase 1 (TPH1), tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) that are involved in melatonin synthesis, metabolism and function. At the protein level, amino acids at the 442nd site of TPH1 protein and the 194th, 286th, 315th and 404th sites of IDO1 protein were under positive selection, and the variants of the amino acid in these sites might lead to the changes in protein function. Remarkably, the 442nd site of these positive selection sites is in the tetramerization domain of TPH1 protein, and it is proline or leucine. At this site, 89.5% of the amino acid of non-seasonal reproducing mammals was proline, while that of 88.9% of seasonal reproducing mammals was leucine. This variation of the amino acid was derived from the T/C polymorphism at the 1325th site of the TPH1 gene coding sequence, which significantly altered the TPH1 activity (p < 0.01). Interestingly, the predicted age of the allele C in the mammalian genome appeared about 126.6 million years ago, and allele T appeared about 212.6 million years ago, indicating that the evolution of the TPH1 gene was affected by the two mammalian split events and the K-T extinction event. In conclusion, the T/C polymorphism at the 1325th site in the TPH1 gene coding sequence altered TPH1 activity, suggesting that this polymorphism is consistent with the reproductive rhythm of mammals. Full article

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. Full article

Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate. Full article