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Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
Putatively adaptive copies of the THRB gene region, as well as PPARA and EPAS1 identified in Tibetans (Simonson et al. 2010), show relationships with hemoglobin concentration in Amhara Ethiopians (Scheinfeldt et al. 2012). EDNRB (endothelial receptor B), previously reported as a top selection candidate in Andeans (Bigham et al. 2010), is also reported in Amhara Ethiopians, and knockdown of this gene increases hypoxia tolerance in mice (Udpa et al. 2014). The gene family member EDNRA is also a top candidate gene in Tibetans (Simonson et al. 2010). BHLHE41, although not associated with hemoglobin, is a key HIF pathway gene and top selection candidate in Amhara, Oromo, and Tigray Ethiopians (Huerta-Sánchez et al. 2013). In addition to these hypoxia-associated genes, three others (VAV3, which encodes vav guanine nucleotide exchange factor 3, and RORA that encodes the RAR-related orphan receptor A) are reported as top candidates in Amhara Ethiopians (Scheinfeldt et al. 2012). Whole-genome sequence analyses indicate three genes contained within the same region of chromosome 19 identified as adaptive targets in Oromo and Simen Ethiopians, CIC, LIPE, and PAFAH1B3 (that encode capicua transcriptional repressor, lipase E hormone-sensitive type, and platelet- activating factor acetylhydrolase 1b catalytic subunit 2, respectively) have orthologs in Drosophila that afford tolerance to hypoxia (Udpa et al. 2014).
Testosterone signaling in spermatogenesis, male fertility and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Arijit Chakraborty, Vertika Singh, Kiran Singh, Rajender Singh
Melatonin is an indoleamine, which is a major secretory product of the pineal gland. It regulates the circadian cycle and acts as a cytokine, neuromodulator and biological response modifier. This hormone functions as a regulator of the reproductive physiology in response to environmental light in seasonally dependent mammals. It displays both hydrophilic and lipophilic properties and can enter testicular cells by crossing the blood-testis barrier. Multiple studies have demonstrated the localization of melatonin receptors on the reproductive system with primary target sites on the testis, epididymis, vas deferens, prostate and ovary. Melatonin is also suggested to regulate the timing for the release of hormones in the female reproductive system. It can act through several receptors such as melatonin receptor 1 (MT1), melatonin receptor 2 (MT2) and retinoid acid receptor–related orphan receptor A (RORα) (28). MT1 and MT2 interact with G-protein to regulate testosterone synthesis by modulating cAMP signal transduction (29). Research suggests that RORα directly activates the aromatase to accelerate the conversion of androgens into estrogens (30).
The Pineal Gland Energy Transducer
Published in Len Wisneski, The Scientific Basis of Integrative Health, 2017
There is also a nuclear-signaling pathway for melatonin, but it does not appear to be as sensitive as the membrane-signaling pathways. Nuclear receptors in humans include RZR/RORα and RZRβ (Wiesenberg et al., 1995). The RZR/RORα receptors are found both in the brain and the peripheral nervous system (Wiesenberg et al., 1995). There is evidence that these are the receptors predominantly involved in immune modulation. However, Mel1a receptors also have been found on lymphocytes, so obviously membrane receptors are involved in the peripheral system as well (Carlberg, 2000). When melatonin appears in concentrations higher than that provided by membrane or nuclear binding, it has a free radical scavenging function. We will review this and other immune-related topics in the section “Melatonin and the Immune and Stress Systems.”
Circadian rhythms of risk factors and management in atherosclerotic and hypertensive vascular disease: Modern chronobiological perspectives of an ancient disease
Published in Chronobiology International, 2023
Yong-Jian Geng, Michael H. Smolensky, Oliver Sum-Ping, Ramon Hermida, Richard J. Castriotta
During the development of atherosclerosis, cholesterol is converted by oxidation into oxysterols, which behave as high-affinity endogenous ROR modulators or ligands. Oxysterol ligands bind directly to the RORα/γ LBD and act as inverse agonists by modulating the interaction of co-regulators. RORs are evolutionarily related to retinoic acid receptors, which are regulated by circadian rhythms or the day-night or light-dark 24 h cycle, and mediate a broad range of nuclear factor activation or suppression, particularly via BMAL1–CLOCK interaction (Figure 2). Interestingly, all-trans retinoic acids recognize the LBD of RORβ, but not the LBD of RORα/γ, suggesting subtype specificity. The first synthetic ligand and inverse agonist identified for RORα/γ is the liver X receptor agonist T0901317 (Kumar et al. 2010). Subsequently, a series of RORα/γ agonists or inverse agonists were developed, as reviewed in detail elsewhere (Kojetin and Burris 2014). In recent years, Chen et al. identified the natural polymethoxylated flavone nobiletin to be an enhancer of the circadian amplitude of molecular rhythms by acting on RORs (Chen et al. 2012; He et al. 2016). The cluster of differentiation-1d (CD1d) recognizes and internalizes pro-atherogenic lipids, such as oxysterols, which subsequently activate nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ) (Rosales et al. 2015). PPAR-γ is involved in CLOCK:BMAL1 chromatin recruitment and cyclic activation of surrogate pathways in response to nutrient challenges (Eckel-Mahan et al. 2013).
Network of co-expressed circadian genes, childhood maltreatment and sleep quality in bipolar disorders
Published in Chronobiology International, 2021
D. Grillault Laroche, E. Curis, F. Bellivier, C. Nepost, G. Gross, B. Etain, C. Marie-Claire
The chronobiological models of BD postulate that biological abnormalities within the circadian system lead to alterations of sleep and circadian rhythms, then impact the neurotransmission in the central nervous system and, therefore, increase the likelihood of experiencing mood episodes. Several reviews of the literature have suggested that genetic variants of circadian genes are associated with an increased vulnerability to develop BD (Landgraf et al. 2014; Takaesu 2018). Some studies have also suggested that some of these variants, for example, in RORA, TIMELESS, or ASMT, are associated with alterations of circadian or sleep parameters (Etain et al. 2012, 2014). Beyond the genetic sequence of circadian genes, environmental factors may also contribute to alterations in the functioning of the biological clock through modifications of methylation and/or expression of circadian genes. Among these environmental factors, childhood maltreatment (CM) has been suggested to impact several biological systems, including the biological clock, pathways of inflammation, neuroplasticity, and HPA (hypothalamic-pituitary-adrenal) axis (Aas et al. 2016; Grillault Laroche et al. 2020).
Repercussions of hypo and hyperthyroidism on the heart circadian clock
Published in Chronobiology International, 2018
Rodrigo A. Peliciari-Garcia, Paula Bargi-Souza, Martin E Young, Maria Tereza Nunes
Recently, our group has investigated the acute (<24 h) effects of T3 on the rodent heart circadian clock. In the earlier study, a suggestion of direct T3 action on Rora and/or Per2 was raised due to rapid alterations in these genes (Peliciari-Garcia et al., 2016). T3 exerts its transcriptional actions through interaction with THR, a ligand-regulated transcription factor, which binds to the thyroid-hormone response element (TRE) present in target genes, mainly as a heterodimer with other nuclear receptors (e.g., retinoid X receptor; RXR). These proteins, along with Rora, belong to the nuclear receptor superfamily. It is noteworthy that these nuclear receptors can undergo reversible covalent modification (in addition to ligand binding), thus impacting activity. For example, Rora is phosphorylated by Ca2+/calmodulin-dependent protein kinases (CaMKs), which increases T3-induced transcription of target genes (Kuno-Murata et al., 2000).