Retinoid X receptors (RXRα, β, and γ) are essential members of the nuclear receptor (NR) superfamily of ligand-dependent transcriptional regulators that bind DNA response elements and control the expression of large gene networks. As obligate heterodimerization partners of many NRs, RXRs are involved in a variety of pathophysiological processes. However, despite this central role in NR signaling, there is still no consensus regarding the precise biological functions of RXRs and the putative role of the endogenous ligands (rexinoids) previously proposed for these receptors. Based on available crystal structures, we introduced a series of amino acid substitutions into the ligand-binding pocket of all three RXR subtypes in order to alter their binding properties. Subsequent characterization using a battery of cell-based and in vitro assays led to the identification of a double mutation abolishing the binding of any ligand while keeping the other receptor functions intact and a triple mutation that selectively impairs interaction with natural rexinoids but not with some synthetic ligands. We also report crystal structures that help understand the specific ligand-binding capabilities of both variants. These RXR variants, either fully disabled for ligand binding or retaining the property of being activated by synthetic compounds, represent unique tools that could be used in future studies to probe the presence of active endogenous rexinoids in tissues/organs and to investigate their role in vivo. Last, we provide data suggesting a possible involvement of fatty acids in the weak interaction of RXRs with corepressors.
Albane le Maire, Martial Rey, Valérie Vivat, Laura Guée, Pauline Blanc, Christian Malosse, Julia Chamot-Rooke, Pierre Germain, and William Bourguet
Abdolreza Esmaeilzadeh, Reza Elahi, Amir Siahmansouri, Armin Jahani Maleki, and Amirhosein Moradi
Coronavirus disease 2019 (COVID-19) is well known for its respiratory complications; however, it can also cause extrapulmonary manifestations, including cardiovascular, thrombotic, renal, gastrointestinal, neurologic, and endocrinological symptoms. Endocrinological complications of COVID-19 are rare but can considerably impact the outcome of the patients. Moreover, preexisting endocrinologic disorders can affect the severity of COVID-19. Thyroid, pancreas, adrenal, neuroendocrine, gonadal, and parathyroid glands are the main endocrinologic organs that can be targeted by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Endocrinological complications of COVID-19 are rare but can significantly deteriorate the patients’ prognosis. Understanding the interaction between COVID-19 and the endocrine system can provide a potential treatment option to improve the outcome of COVID-19. In this article, we aim to review the short-term and long-term organ-based endocrinological complications of COVID-19, the pathophysiology, the influence of each complication on COVID-19 prognosis, and potential therapeutic interventions based on current published data. Moreover, current clinical trials of potential endocrinological interventions to develop therapeutic strategies for COVID-19 have been discussed.
Sangappa B Chadchan, Vertika Singh, and Ramakrishna Kommagani
The gut microbiome is considered an endocrine organ that can influence distant organs and associated biological pathways. Recent advances suggest that gut microbial homeostasis is essential for reproductive health and that perturbations in the gut microbiota can lead to reproductive pathologies. This review provides an updated overview of the relationship between the gut microbiome and female reproductive diseases. Specifically, we highlight the most recent findings on the gut microbiome in gynecological pathologies including polycystic ovarian syndrome, endometriosis, and endometrial cancer. Most studies revealed associations between altered gut microbial compositions and these reproductive diseases, though few have suggested cause–effect relationships. Future studies should focus on determining the molecular mechanisms underlying associations between gut microbiota and reproductive diseases. Understanding this bidirectional relationship could lead to the development of novel and effective strategies to prevent, diagnose, and treat female reproductive organ-related diseases.
Anuradha Mishra, Nirmalya Ganguli, Subeer S Majumdar, and Deepak Modi
Endometrial cancer is the fourth most common malignancy in women and the precursor lesion is endometrial hyperplasia. HOXA10 is a transcription factor that plays key roles in endometrial functions such as the endowment of receptivity, embryo implantation, and trophoblast invasion. Herein, using testicular transgenesis, we developed transgenic mice that expressed a shRNA against HOXA10 and there was a nearly 70% reduction in the expression of HOXA10 in these animals. We observed that downregulation of HOXA10 led to the development of endometrial hyperplasia in the young animals (3 months), and as they aged (>1 year), most animals developed well-differentiated endometrial adenocarcinoma. In the endometrium of animals with reduced HOXA10, there was increased proliferation and elevated levels of ERα and ERβ. In parallel, there was increased expression of Wnt4 and β-Catenin, SOX9, and YAP1. We propose that chronic reduction in HOXA10 expression disrupts multiple pathways in the uterus that aids in the development of endometrial hyperplasia which progresses to endometrial cancer with age.
Kazuma Saito, Kazuhiko Horiguchi, Sayaka Yamada, Battsetseg Buyandalai, Emi Ishida, Shunichi Matsumoto, Satoshi Yoshino, Yasuyo Nakajima, Eijiro Yamada, Tsugumichi Saito, Atsushi Ozawa, Yuki Tajika, Hideo Akiyama, and Masanobu Yamada
Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH−/−) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/− mice born to TRH+/− or TRH−/− dams, and conducted S/M-opsin analysis in TRH+/+ or TRH−/− mice born to TRH+/− dams at P12, P17, and P30. M-opsin expression was lower in TRH+/− mice born to TRH−/− dams than in those born to TRH+/− dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH−/− mice born to TRH+/− dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH−/− mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.
Yi Wang, Qi-Ling Shen, Qi Xin, Bei Sun, Shi Zhang, Qian-Hua Fang, Ying-Xin Shi, Wen-Yan Niu, Jing-Na Lin, and Chun-Jun Li
Medium-chain acyl-CoA dehydrogenase (MCAD) is one of the significant enzymes involved in the β-oxidation of mitochondrial fatty acids. MCAD deficiency affects the β-oxidation of fatty acid and leads to lipid deposition in multiple organs, but little is known about its importance in nonalcoholic steatohepatitis (NASH). Empagliflozin is revealed to effectively improve NASH by increasing research, whereas the specific mechanism still has to be explored. Human liver tissues of patients with or without NASH were obtained for proteomic analysis to screen proteins of interest. db/db mice were given empagliflozin by gavage for 8 weeks. The expression of MCAD and signaling molecules involved in hepatic lipid metabolism was evaluated in human liver, mice and HL7702 cells. We found that the MCAD levels in the liver were significantly reduced in NASH patients compared to patients without NASH. Protein–protein interaction network analysis showed that MCAD was highly correlated with forkhead box A2 (FOXA2) and protein kinase AMP-activated catalytic subunit alpha (PRKAA). AMPK/FOXA2/MCAD signaling pathway was detected to be inhibited in the liver of NASH patients. Decreased expression of MCAD was also observed in the livers of db/db mice and hepatocyte treated with palmitic acid and glucose. Of note, empagliflozin could upregulate MCAD expression by activating AMPK/FOXA2 signaling pathway, reduce lipid deposition and improve NASH in vivo and in vitro. This research demonstrated that MCAD is a key player of hepatic lipid deposition and its targeting partially corrects NASH. MCAD thus may be a potential therapeutic target for the treatment of NASH.
Dongmei Lan, Shengcai Qi, Chao Yao, Xue Li, Haijiang Liu, Dan Wang, and Yan Wang
Quercetin has been shown to have a wide range of beneficial effects, such as anti-inflammation, anti-oxidation and immunomodulation. The study was designed to explore the role and molecular mechanisms of quercetin on the protective effect of bone marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress in vitro. BMSCs were isolated from 4-week-old male Sprague–Dawley rats. Upon H2O2 stimulation in vitro, the effects of quercetin on the proliferation, anti-oxidation and osteogenic differentiation of BMSCs were evaluated by Cell Counting Kit-8, reactive oxygen species analysis, Western blot (WB), real-time PCR (RT-PCR), alkaline phosphatase staining and alizarin red staining. Additionally, ferroptosis-related markers were examined by WB, RT-PCR and Mito-FerroGreen. Finally, PI3K/AKT/mTOR signaling pathway was explored in these processes. We found that quercetin significantly maintained BMSCs viability upon H2O2 stimulation. Quercetin upregulated protein (ALP, OPN and RUNX2) and mRNA (Alp, Opn, Ocn and Runx2) levels of osteogenic markers, downregulated ROS levels and upregulated antioxidative gene expressions (Nrf2, Cat, Sod-1 and Sod-2) compared with the H2O2 group. The ferroptosis in BMSCs was activated after H2O2 stimulation, and the phosphorylation level of PI3K, AKT and mTOR was upregulated in H2O2-stimulated BMSCs. More importantly, quercetin inhibited ferroptosis and the phosphorylation level of PI3K, AKT and mTOR were downregulated after quercetin treatment. We conclude that quercetin maintained the viability and the osteoblastic differentiation of BMSCs upon H2O2 stimulation, potentially via ferroptosis inhibition by PI3K/AKT/mTOR pathway.
Aprajita S Yadav, Nina Isoherranen, and Katya B Rubinow
Vitamin A (retinol) is an essential, fat-soluble vitamin that plays critical roles in embryonic development, vision, immunity, and reproduction. Severe vitamin A deficiency results in profound embryonic dysgenesis, blindness, and infertility. The roles of bioactive vitamin A metabolites in regulating cell proliferation, cellular differentiation, and immune cell function form the basis of their clinical use in the treatment of dermatologic conditions and hematologic malignancies. Increasingly, vitamin A also has been recognized to play important roles in cardiometabolic health, including the regulation of adipogenesis, energy partitioning, and lipoprotein metabolism. While these roles are strongly supported by animal and in vitro studies, they remain poorly understood in human physiology and disease. This review briefly introduces vitamin A biology and presents the key preclinical data that have generated interest in vitamin A as a mediator of cardiometabolic health. The review also summarizes clinical studies performed to date, highlighting the limitations of many of these studies and the ongoing controversies in the field. Finally, additional perspectives are suggested that may help position vitamin A metabolism within a broader biological context and thereby contribute to enhanced understanding of vitamin A’s complex roles in clinical cardiometabolic disease.
Rebecca K Davidson, Staci A Weaver, Nolan Casey, Sukrati Kanojia, Elise Hogarth, Rebecca Schneider Aguirre, Emily K Sims, Carmella Evans-Molina, and Jason M Spaeth
Type 2 diabetes (T2D) is associated with loss of transcription factors (TFs) from a subset of failing β-cells. Among these TFs is Pdx1, which controls the expression of numerous genes involved in maintaining β-cell function and identity. Pdx1 activity is modulated by transcriptional coregulators and has recently been shown, through an unbiased screen, to interact with the Chd4 ATPase subunit of the nucleosome remodeling and deacetylase complex. Chd4 contributes to the maintenance of cellular identity and functional status of numerous different cell types. Here, we demonstrated that Pdx1 dynamically interacts with Chd4 under physiological and stimulatory conditions within islet β-cells and established a fundamental role for Chd4 in regulating insulin secretion and modulating numerous Pdx1-bound genes in vitro, including the MafA TF, where we discovered Chd4 is bound to the MafA region 3 enhancer. Furthermore, we found that Pdx1:Chd4 interactions are significantly compromised in islet β-cells under metabolically induced stress in vivo and in human donor tissues with T2D. Our findings establish a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes in vitro, and disruption of Pdx1:Chd4 interactions coincides with β-cell dysfunction associated with T2D.
Rohita Rangu, Pandora L Wander, Breanne M Barrow, and Sakeneh Zraika
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Following initial infection of airway epithelia, SARS-CoV-2 invades a wide range of cells in multiple organs, including pancreatic islet cells. Diabetes is now recognised as a risk factor for severe COVID-19 outcomes, including hospitalisation and death. Additionally, COVID-19 is associated with a higher risk of new-onset diabetes and metabolic complications of diabetes. One mechanism by which these deleterious outcomes may occur is via the destruction of insulin-producing islet β cells, either directly by SARS-CoV-2 entry into β cells or indirectly due to inflammation and fibrosis in the surrounding microenvironment. While the canonical pathway of viral entry via angiotensin-converting enzyme 2 (ACE2) has been established as a major route of SARS-CoV-2 infection in the lung, it may not be solely responsible for viral entry into the endocrine pancreas. This is likely due to the divergent expression of viral entry factors among different tissues. For example, expression of ACE2 has not been unequivocally demonstrated in β cells. Thus, it is important to understand how other proteins known to be highly expressed in pancreatic endocrine cells may be involved in SARS-CoV-2 entry, with the view that these could be targeted to prevent the demise of the β cell in COVID-19. To that end, this review discusses alternate receptors of SARS-CoV-2 (CD147 and GRP78), as well as mediators (furin, TMPRSS2, cathepsin L, ADAM17, neuropilin-1, and heparan sulphate) that may facilitate SARS-CoV-2 entry into pancreatic islets independent of or in conjunction with ACE2.
