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This review describes the evidence for the potential benefit of vitamin D supplementation in people with respiratory diseases who may have a higher susceptibility to coronavirus disease 2019 (COVID‐19) infection and its consequences. Clinical evidence indicates that vitamin D may reduce the risk of both upper and lower respiratory tract infections and offers benefit particularly in people with vitamin D deficiency. Some evidence exists for a higher incidence of active tuberculosis (TB) in patients who are deficient in vitamin D. An association between low levels of 25(OH)D (the active form of vitamin D) and COVID‐19 severity of illness and mortality has also been reported. In addition, low 25(OH)D levels are associated with poor outcomes in acute respiratory distress syndrome (ARDS). The cytokine storm experienced in severe COVID‐19 infections results from excessive release of pro‐inflammatory cytokines. Due to its immunomodulatory effects, adequate vitamin D levels may cause a decrease in the pro‐inflammatory cytokines and an increase in the anti‐inflammatory cytokines during COVID‐19 infections. Vitamin D deficiency was found in 82.2% of hospitalized COVID‐19 cases and 47.2% of population‐based controls (p

Exhaled breath test is a typical disease monitoring method for replacing of blood and urine samples that may create discomfort for patients. To monitor exhaled breath markers, gas biomedical sensors have undergone rapid progresses for non‐invasive and point‐of‐care diagnostic devices. Among gas sensors, metal oxide‐based biomedical gas sensors have received remarkable attentions owing to their unique properties, such as high sensitivity, simple fabrication, miniaturization, portability, and real‐time monitoring. Herein, we reviewed the recent advances in chemoresistive metal oxide‐based gas sensors with ZnO, SnO2, and In2O3 as sensing materials for monitoring a range of exhaled breath markers (i.e., NO, H2, H2S, acetone, isoprene, and formaldehyde). We focused on the strategies that improve the sensitivity and selectivity of metal oxide‐based gas sensors. The challenges to fabricate a functional gas sensor with high sensing performance along with suggestions are outlined.

Historically, the focus of type II diabetes mellitus (T2DM) research has been on host metabolism and hormone action. However, emerging evidence suggests that the gut microbiome, commensal microbes that colonize the gastrointestinal tract, also play a significant role in T2DM pathogenesis. Specifically, gut microbes metabolize what is available to them through the host diet to produce small molecule metabolites that can have endocrine-like effects on human cells. In fact, the meta-organismal crosstalk between gut microbe-generated metabolites and host receptor systems may represent an untapped therapeutic target for those at risk for or suffering from T2DM. Recent evidence suggests that gut microbe-derived metabolites can impact host adiposity, insulin resistance, and hormone secretion to collectively impact T2DM progression. Here we review the current evidence that structurally diverse gut microbe-derived metabolites, including short chain fatty acids, secondary bile acids, aromatic metabolites, trimethylamine-N-oxide, polyamines, and N-acyl amides, that can engage with host receptors in an endocrine-like manner to promote host metabolic disturbance associated with T2DM. Although these microbe-host signaling circuits are not as well understood as host hormonal signaling, they hold untapped potential as new druggable targets to improve T2DM complications. Whether drugs that selectively target meta-organismal endocrinology will be safe and efficacious in treating T2DM is a key new question in the field of endocrinology. Here we discuss the opportunities and challenges in targeting the gut microbial endocrine organ for the treatment of diabetes and potentially many other diseases where diet-microbe-host interactions play a contributory role.

Organoids are 3-dimensional (3D) structures grown in vitro that emulate the cytoarchitecture and functions of true organs. Therefore, testicular organoids arise as an important model for research on male reproductive biology. These organoids can be generated from different sources of testicular cells, but most studies to date have used immature primary cells for this purpose. The complexity of the mammalian testicular cytoarchitecture and regulation poses a challenge for working with testicular organoids, because, ideally, these 3D models should mimic the organization observed in vivo. In this review, we explore the characteristics of the most important cell types present in the testicular organoid models reported to date and discuss how different factors influence the regulation of these cells inside the organoids and their outcomes. Factors such as the developmental or maturational stage of the Sertoli cells, for example, influence organoid generation and structure, which affect the use of these 3D models for research. Spermatogonial stem cells have been a focus recently, especially in regard to male fertility preservation. The regulation of the spermatogonial stem cell niche inside testicular organoids is discussed in the present review, as this research area may be positively affected by recent progress in organoid generation and tissue engineering. Therefore, the testicular organoid approach is a very promising model for male reproductive biology research, but more studies and improvements are necessary to achieve its full potential.

Thyroid hormone (T3) is critical not only for organ function and metabolism in the adult but also for animal development. This is particularly true during the neonatal period when T3 levels are high in mammals. Many processes during this postembryonic developmental period resemble those during amphibian metamorphosis. Anuran metamorphosis is perhaps the most dramatic developmental process controlled by T3 and affects essentially all organs/tissues, often in an organ autonomous manner. This offers a unique opportunity to study how T3 regulates vertebrate development. Earlier transgenic studies in the pseudo-tetraploid anuran Xenopus laevis revealed that T3 receptors (TRs) are necessary and sufficient for mediating the effects of T3 during metamorphosis. Recent gene knockout studies with gene-editing technologies in the highly related diploid anuran Xenopus tropicalis showed, surprisingly, that TRs are not required for most metamorphic transformations, although tadpoles lacking TRs are stalled at the climax of metamorphosis and eventually die. Analyses of the changes in different organs suggest that removal of TRs enables premature development of many adult tissues, likely due to de-repression of T3-inducible genes, while preventing the degeneration of tadpole-specific tissues, which is possibly responsible for the eventual lethality. Comparison with findings in TR knockout mice suggests both conservation and divergence in TR functions, with the latter likely due to the greatly reduced need, if any, to remove embryo/prenatal-specific tissues during mammalian postembryonic development.

The mammalian oviduct is a dynamic organ where important events such as final maturation of oocytes, transport of gametes, sperm capacitation, fertilization, embryo development, and transport take place. Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), is the rate-limiting enzyme in the production of prostaglandins (PGs) and plays an essential role during early pregnancy, including ovulation, fertilization, implantation, and decidualization. Even though the maternal-embryo communication originates in the oviduct, not many studies have systemically investigated PTGS2 signaling during early development. Most of the studies investigating implantation and decidualization processes in Ptgs2-/- mice employed embryo transfer into the uterus, thereby bypassing the mammalian oviduct. Consequently, an understanding of the mechanistic action as well as the regulation of PTGS2 and derived PGs in oviductal functions is far from complete. In this review, we aim to focus on the importance of PTGS2 and associated PGs signaling in the oviduct particularly in humans, farm animals, and laboratory rodents to provide a broad perspective to guide further research in this field. Specifically, we review the role of PTGS2-derived PGs in fertilization, embryo development, and transport. We focus on the actions of ovarian steroid hormones on PTGS2 regulation in the oviduct. Understanding of cellular PTGS2 function during early embryo development and transport in the oviduct will be an important step toward a better understanding of reproduction and may have potential implication in the assisted reproductive technology.

Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues throughout the body. Three types of deiodinases (D1, D2, and D3) were originally defined based on their biochemical characteristics. Cloning of the first complementary DNAs in the 1990s (Dio1 in rat and dio2 and dio3 in frog) allowed to confirm the existence of 3 distinct enzymes. Over the years, increasing genomic information revealed that deiodinases are present in all chordates, vertebrates, and nonvertebrates and that they can even be found in some mollusks and annelids, pointing to an ancient origin. Research in nonmammalian models has substantially broadened our understanding of deiodinases. In relation to their structure, we discovered for instance that biochemical properties such as inhibition by 6-propyl-2-thiouracil, stimulation by dithiothreitol, and temperature optimum are subject to variation. Data from fish, amphibians, and birds were key in shifting our view on the relative importance of activating and inactivating deiodination pathways and in showing the impact of D2 and D3 not only in local but also whole body T3 availability. They also led to the discovery of new local functions such as the acute reciprocal changes in D2 and D3 in hypothalamic tanycytes upon photostimulation, involved in seasonal rhythmicity. With the present possibilities for rapid and precise gene silencing in any species of interest, comparative research will certainly further contribute to a better understanding of the importance of deiodinases for adequate TH action, also in humans. ispartof: ENDOCRINOLOGY vol:162 issue:6 ispartof: location:United States status: published

Context This mini-review provides an overview of menopausal hormone therapy (HT) and cardiovascular disease (CVD) risk, with a focus on the role of hormone formulation, dose, and route of delivery. Methods This summary is based on authors’ knowledge in the field of menopausal HT and supplemented by a PubMed search using the terms “menopause hormone therapy,” “transdermal,” “estradiol,” “conjugated estrogens,” “bioidentical,” “cardiovascular disease,” “lipoproteins,” “glucose,” “progestogens,” “low dose.” Results Available evidence indicates that oral unopposed estrogens have a favorable effect on lipoprotein levels, glycemia, insulin, and CVD risk; however, the addition of progestogens blunts the lipid-related effects. The progestogen with the smallest attenuating effect is micronized progesterone. Transdermal estrogens have less effect on coagulation, inflammation, and lipids than oral estrogens and observational studies suggest they pose a lower risk of venous thromboembolism and stroke than oral estrogens. Clinical effects of hormones were not consistently dose dependent. Conclusions Although HT continues to have an important role in menopause management, it is not recommended for primary or secondary CVD prevention. Different formulations, doses, and routes of delivery of HT have different effects on cardiometabolic markers and risks of clinical CVD events. However, long-term trials evaluating clinical outcomes with transdermal and other alternate HT regimens are limited.

A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G-protein–coupled receptor GPRC6A to directly regulate glucose and fat metabolism in liver, muscle, and fat, and to stimulate the release of metabolism-regulating hormones, including insulin, fibroblast growth factor 21, glucagon-like peptide 1, testosterone, and interleukin 6. Ocn/GPRC6A activation has also been implicated in cancer progression. GPRC6A is activated by cations, amino acids, and testosterone. The multiligand specificity, the regulation of energy metabolism in diverse tissues, and the coordinated release of metabolically active hormones make the GPRC6A endocrine networks unique. Recently, the significance of Ocn/GPRCA has been questioned. There is a lack of metabolic abnormalities in newly created genetically engineered Ocn- and Gprc6a-deficient mouse models. There are also paradoxical observations that GPRC6A may function as a tumor suppressor. In addition, discordant published studies have cast doubt on the function of the most prevalent uniquely human GPRC6A-KGKY polymorphism. Explanations for these divergent findings are elusive. We provide evidence that the metabolic susceptibility of genetically engineered Ocn- and Gprc6a-deficient mice is influenced by environmental challenges and genetic differences in mouse strains. In addition, the GPRC6A-KGKY polymorphism appears to be a gain-of-function variant. Finally, alternatively spliced isoforms of GPRC6A may alter ligand specificity and signaling that modulate oncogenic effects. Thus, genetic, post-translational and environmental factors likely account for the variable results regarding the functions of GPRC6A in animal models. Pending additional information, GPRC6A should remain a potential therapeutic target for regulating energy and fat metabolism, hormone production, and cancer progression.

The term energy metabolism comprises the entirety of chemical processes associated with uptake, conversion, storage, and breakdown of nutrients. All these must be tightly regulated in time and space to ensure metabolic homeostasis in an environment characterized by cycles such as the succession of day and night. Most organisms evolved endogenous circadian clocks to achieve this goal. In mammals, a ubiquitous network of cellular clocks is coordinated by a pacemaker residing in the hypothalamic suprachiasmatic nucleus. Adipocytes harbor their own circadian clocks, and large aspects of adipose physiology are regulated in a circadian manner through transcriptional regulation of clock-controlled genes. White adipose tissue (WAT) stores energy in the form of triglycerides at times of high energy levels that then serve as fuel in times of need. It also functions as an endocrine organ, releasing factors in a circadian manner to regulate food intake and energy turnover in other tissues. Brown adipose tissue (BAT) produces heat through nonshivering thermogenesis, a process also controlled by the circadian clock. We here review how WAT and BAT contribute to the circadian regulation of energy metabolism. We describe how adipose rhythms are regulated by the interplay of systemic signals and local clocks and summarize how adipose-originating circadian factors feed-back on metabolic homeostasis. The role of adipose tissue in the circadian control of metabolism becomes increasingly clear as circadian disruption leads to alterations in adipose tissue regulation, promoting obesity and its sequelae. Stabilizing adipose tissue rhythms, in turn, may help to combat disrupted energy homeostasis and obesity.

In this minireview, we provide a historical outline of the events that led to the identification and characterization of the deiodinases, the recognition that deiodination plays a major role in thyroid hormone action, and the cloning of the 3 deiodinase genes. The story starts in 1820, when it was first determined that elemental iodine was important for normal thyroid function. Almost 100 years later, it was found that the primary active principle of the gland, T4, contains iodine. Once radioactive iodine became available in the 1940s, it was demonstrated that the metabolism of T4 included deiodination, but at the time it was assumed to be merely a degradative process. However, this view was questioned after the discovery of T3 in 1952. We discuss in some detail the events of the next 20 years, which included some failures followed by the successful demonstration that deiodination is indeed essential to normal thyroid hormone action. Finally, we describe how the 3 deiodinases were identified and characterized and their genes cloned.

Two specialized functions of cholesterol during fetal development include serving as a precursor to androgen synthesis and supporting hedgehog (HH) signaling activity. Androgens are produced by the testes to facilitate masculinization of the fetus. Recent evidence shows that intricate interactions between the HH and androgen signaling pathways are required for optimal male sex differentiation and defects of either can cause birth anomalies indicative of 46,XY male variations of sex development (VSD). Further, perturbations in cholesterol synthesis can cause developmental defects, including VSD, that phenocopy those caused by disrupted androgen or HH signaling, highlighting the functional role of cholesterol in promoting male sex differentiation. In this review, we focus on the role of cholesterol in systemic androgen and local HH signaling events during fetal masculinization and their collective contributions to pediatric VSD.

Treatment for critical illness typically focuses on a patient’s short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut–brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.

The main clinical characteristics of COVID‐19 are respiratory symptoms that can lead to serious cardiovascular damages and severe worsening of other medical conditions. One of the major strategies in preparedness and response to COVID 19 is effective utilization of personal protective equipment (PPE) among which the masks of different kinds are on the top of the list especially for activities in the public places. However, the underlying mechanisms of masks in preventing virus transmission have not been well identified and the current experimental data still show inconsistent outcomes that may mislead the public. For instance, the early understanding of the mask functions was limited especially in the escalating phase of the COVID 19 pandemic, resulting in quite controversial remarks on masks. Although extensive studies in mask functions have been carried out ever since the COVID‐19 outbreaks, most of the investigations appear to have focused on exhalation isolation of individuals who may have been infected with the disease. Less emphasis was laid on inhalation protection from virus transmission, an important aspect that undergirds the public health policies and protective strategies. This review provides the most up‐to‐date information on the transmission modes of COVID‐19 virus in terms of droplets and aerosols. The roles of masks in disease prevention and transmission reduction are evaluated on various types, structures and functions. More important, both aspects of exhalation isolation and inhalation protection are discussed based on virus transmission modes and the effectiveness of different types of masks under varied environmental conditions.

The liver is a “front line” in the homeostatic defenses against variation in nutrient intake. It orchestrates metabolic responses to feeding by secreting factors essential for maintaining metabolic homeostasis, converting carbohydrates to triglycerides for storage, and releasing lipids packaged as lipoproteins for distribution to other tissues. Between meals, it provides fuel to the body by releasing glucose produced from glucogenic precursors and ketones from fatty acids and ketogenic amino acids. Modern diets enriched in sugars and saturated fats increase lipid accumulation in hepatocytes (nonalcoholic fatty liver disease). If untreated, this can progress to liver inflammation (nonalcoholic steatohepatitis), fibrosis, cirrhosis, and hepatocellular carcinoma. Dysregulation of liver metabolism is also relatively common in modern societies. Increased hepatic glucose production underlies fasting hyperglycemia that defines type 2 diabetes, while increased production of atherogenic, large, triglyceride-rich, very low-density lipoproteins raises the risk of cardiovascular disease. Evidence has accrued of a strong connection between meal timing, the liver clock, and metabolic homeostasis. Metabolic programming of the liver transcriptome and posttranslation modifications of proteins is strongly influenced by the daily rhythms in nutrient intake governed by the circadian clock. Importantly, whereas cell-autonomous clocks have been identified in the liver, the complete circadian programing of the liver transcriptome and posttranslational modifications of essential metabolic proteins is strongly dependent on nutrient flux and circadian signals from outside the liver. The purpose of this review is to provide a basic understanding of liver circadian physiology, drawing attention to recent research on the relationships between circadian biology and liver function.

The largest subtype of breast cancer is characterized by the expression and activity of the estrogen receptor alpha (ERalpha/ER). Although several effective therapies have significantly improved survival, the adaptability of cancer cells means that patients frequently stop responding or develop resistance to endocrine treatment. ER does not function in isolation and multiple associating factors have been reported to play a role in regulating the estrogen-driven transcriptional program. This review focuses on the dynamic interplay between some of these factors which co-occupy ER-bound regulatory elements, their contribution to estrogen signaling, and their possible therapeutic applications. Furthermore, the review illustrates how some ER association partners can influence and reprogram the genomic distribution of the estrogen receptor. As this dynamic ER activity enables cancer cell adaptability and impacts the clinical outcome, defining how this plasticity is determined is fundamental to our understanding of the mechanisms of disease progression.

Background The primary role of the International Federation of Clinical Chemistry (IFCC) Committee on Clinical Application of Cardiac Bio-Markers (C-CB) is to provide educational materials about cardiac biomarker use, emphasizing high-sensitivity cardiac troponin assays. Content This mini-review, regarding high-sensitivity cardiac and point-of-care troponin assays, addresses 1) new IFCC C-CB/AACC Academy laboratory practice recommendations; 2) new and updated concepts from the Fourth Universal Definition of Myocardial Infarction; 3) the role of point-of-care assays in practice and research; 4) regulatory challenges concerning point-of-care assays; e) testing in the COVID-19 world. Summary Implementation of high-sensitivity cardiac troponin assays makes a difference now and into the future in clinical practice and research. Providing point-of-care high-sensitivity cardiac troponin assays and optimizing studies to allow clearance of these assays by regulatory agencies, in a timely fashion, may provide improved patient management and outcomes.

The hypothalamus and pituitary have been identified to play essential roles in maintaining homeostasis. Various diseases can disrupt the functions of these systems, which can often result in serious lifelong symptoms. The current treatment for hypopituitarism involves hormone replacement therapy. However, exogenous drug administration cannot mimic the physiological changes that are a result of hormone requirements. Therefore, patients are at a high risk of severe hormone deficiency, including adrenal crisis. Pluripotent stem cells (PSCs) self-proliferate and differentiate into all types of cells. The generation of endocrine tissues from PSCs has been considered as another new treatment for hypopituitarism. Our colleagues established a 3-dimensional (3D) culture method for embryonic stem cells (ESCs). In this culture, the ESC-derived aggregates exhibit self-organization and spontaneous formation of highly ordered patterning. Recent results have shown that strict removal of exogenous patterning factors during early differentiation efficiently induces rostral hypothalamic progenitors from mouse ESCs. These hypothalamic progenitors generate vasopressinergic neurons, which release neuropeptides upon exogenous stimulation. Subsequently, we reported adenohypophysis tissue self-formation in 3D cultures of mouse ESCs. The ESCs were found to differentiate into both nonneural oral ectoderm and hypothalamic neuroectoderm in adjacent layers. Interactions between the 2 tissues appear to be critically important for in vitro induction of a Rathke’s pouch-like developing embryo. Various endocrine cells were differentiated from nonneural ectoderm. The induced corticotrophs efficiently secreted adrenocorticotropic hormone when engrafted in vivo, which rescued hypopituitary hosts. For future regenerative medicine, generation of hypothalamic and pituitary tissues from human PSCs is necessary. We and other groups succeeded in establishing a differentiation method with the use of human PSCs. Researchers could use these methods for models of human diseases to elucidate disease pathology or screen potential therapeutics.

The development and application of quantitative systems pharmacology models in neuroscience have been modest relative to other fields, such as oncology and immunology, which may reflect the complexity of the brain. Technological and methodological advancements have enhanced the quantitative understanding of brain physiology and pathophysiology and the effects of pharmacological interventions. To maximize the knowledge gained from these novel data types, pharmacometrics modelers may need to expand their toolbox to include additional mathematical and statistical frameworks. A session was held at the 10th annual American Conference on Pharmacometrics (ACoP10) to highlight several recent advancements in quantitative and systems neuroscience. In this mini‐review, we provide a brief overview of technological and methodological advancements in the neuroscience therapeutic area that were discussed during the session and how these can be leveraged with quantitative systems pharmacology modeling to enhance our understanding of neurological diseases. Microphysiological systems using human induced pluripotent stem cells (IPSCs), digital biomarkers, and large‐scale imaging offer more clinically relevant experimental datasets, enhanced granularity, and a plethora of data to potentially improve the preclinical‐to‐clinical translation of therapeutics. Network neuroscience methodologies combined with quantitative systems models of neurodegenerative disease could help bridge the gap between cellular and molecular alterations and clinical end points through the integration of information on neural connectomics. Additional topics, such as the neuroimmune system, microbiome, single‐cell transcriptomic technologies, and digital device biomarkers, are discussed in brief.

Pair bonds represent some of the strongest attachments we form as humans. These relationships positively modulate health and well-being. Conversely, the loss of a spouse is an emotionally painful event that leads to numerous deleterious physiological effects, including increased risk for cardiac dysfunction and mental illness. Much of our understanding of the neuroendocrine basis of pair bonding has come from studies of monogamous prairie voles (Microtus ochrogaster), laboratory-amenable rodents that, unlike laboratory mice and rats, form lifelong pair bonds. Specifically, research using prairie voles has delineated a role for multiple neuromodulatory and neuroendocrine systems in the formation and maintenance of pair bonds, including the oxytocinergic, dopaminergic, and opioidergic systems. However, while these studies have contributed to our understanding of selective attachment, few studies have examined how interactions among these 3 systems may be essential for expression of complex social behaviors, such as pair bonding. Therefore, in this review, we focus on how the social neuropeptide, oxytocin, interacts with classical reward system modulators, including dopamine and endogenous opioids, during bond formation and maintenance. We argue that an understanding of these interactions has important clinical implications and is required to understand the evolution and encoding of complex social behaviors more generally. Finally, we provide a brief consideration of future directions, including a discussion of the possible roles that glia, specifically microglia, may have in modulating social behavior by acting as a functional regulator of these 3 neuromodulatory systems.

Endocrine-driven malignancies, including breast and prostate cancer, are among the most common human cancers. The relationship between sex steroid hormones (eg, androgen, estrogen, and progesterone), their cognate receptors, and genomic stability lie at the center of endocrine-driven cancer development, progression, and therapeutic resistance. A variety of direct and indirect mechanisms have been described that link steroid hormone signaling to the loss of genomic integrity that drives early carcinogenesis. These effects are often enriched within endocrine receptor cistromes, accounting for the high proportion of mutations and rearrangements in the region of hormone response elements. In other cases, the effects are generalized and rely on a complex array of genetic, epigenetic, and metabolic interactions. Both androgen and estrogen receptors directly modulate the DNA damage response by trans-activating DNA damage response genes and redirecting the cellular repair machinery in the wake of genotoxic stress. Here we review the key mechanistic underpinnings of the relationship between sex steroid hormone receptors and genomic stability. In addition, we summarize emerging research in this area and discuss important implications for cancer prevention and treatment.

Multicellular organisms have evolved sophisticated mechanisms to recover and maintain original tissue functions following injury. Injury responses require a robust transcriptomic response associated with cellular reprogramming involving complex gene expression programs critical for effective tissue repair following injury. Steroid receptor coactivators (SRCs) are master transcriptional regulators of cell–cell signaling that is integral for embryogenesis, reproduction, normal physiological function, and tissue repair following injury. Effective therapeutic approaches for facilitating improved tissue regeneration and repair will likely involve temporal and combinatorial manipulation of cell-intrinsic and cell-extrinsic factors. Pleiotropic actions of SRCs that are critical for wound healing range from immune regulation and angiogenesis to maintenance of metabolic regulation in diverse organ systems. Recent evidence derived from studies of model organisms during different developmental stages indicates the importance of the interplay of immune cells and stromal cells to wound healing. With SRCs being the master regulators of cell–cell signaling integral to physiologic changes necessary for wound repair, it is becoming clear that therapeutic targeting of SRCs provides a unique opportunity for drug development in wound healing. This review will provide an overview of wound healing–related functions of SRCs with a special focus on cellular and molecular interactions important for limiting tissue damage after injury. Finally, we review recent findings showing stimulation of SRCs following cardiac injury with the SRC small molecule stimulator MCB-613 can promote cardiac protection and inhibit pathologic remodeling after myocardial infarction.

Background Type 2 myocardial infarction (T2MI) is frequently encountered in clinical practice and associated with adverse outcomes. Content T2MI occurs most frequently due to noncoronary etiologies that alter myocardial oxygen supply and/or demand. The diagnosis of T2MI is often confused with acute nonischemic myocardial injury, in part because of difficulties in delineating the nature of symptoms and misunderstandings about disease categorization. The use of objective features of myocardial ischemia using electrocardiographic (ECG) or imaging abnormalities may facilitate more precise T2MI diagnosis. High-sensitivity cardiac troponin (hs-cTn) assays allow rapid MI diagnosis and risk stratification, yet neither maximum nor delta values facilitate differentiation of T2MI from T1MI. Several investigational biomarkers have been evaluated for T2MI, but none have robust data. There is interest in evaluating risk profiles among patients with T2MI. Clinically, the magnitude of maximum and delta cTn values as well as the presence and magnitude of ischemia on ECG or imaging is used to indicate disease severity. Scoring systems such as GRACE, TIMI, and TARRACO have been evaluated, but all have limited to modest performance, with substantial variation in time intervals used for risk-assessment and endpoints used. Summary The diagnosis of T2MI requires biomarker evidence of acute myocardial injury and clear clinical evidence of acute myocardial ischemia without atherothrombosis. T2MIs are most often caused by noncoronary etiologies that alter myocardial oxygen supply and/or demand. They are increasingly encountered in clinical practice and associated with poor short- and long-term outcomes. Clinicians require novel biomarker or imaging approaches to facilitate diagnosis and risk-stratification.

Islet β-cell dysfunction that leads to impaired insulin secretion is a principal source of pathology of diabetes. In type 2 diabetes, this breakdown in β-cell health is associated with compromised islet-enriched transcription factor (TF) activity that disrupts gene expression programs essential for cell function and identity. TF activity is modulated by recruited coregulators that govern activation and/or repression of target gene expression, thereby providing a supporting layer of control. To date, more than 350 coregulators have been discovered that coordinate nucleosome rearrangements, modify histones, and physically bridge general transcriptional machinery to recruited TFs; however, relatively few have been attributed to β-cell function. Here, we will describe recent findings on those coregulators with direct roles in maintaining islet β-cell health and identity and discuss how disruption of coregulator activity is associated with diabetes pathogenesis.

Appropriate food intake requires exquisite coordination between the gut and the brain. Indeed, it has long been known that gastrointestinal signals communicate with the brain to promote or inhibit feeding behavior. Recent advances in the ability to monitor and manipulate neural activity in awake, behaving rodents has facilitated important discoveries about how gut signaling influences neural activity and feeding behavior. This review emphasizes recent studies that have advanced our knowledge of gut–brain signaling and food intake control, with a focus on how gut signaling influences in vivo neural activity in animal models. Moving forward, dissecting the complex pathways and circuits that transmit nutritive signals from the gut to the brain will reveal fundamental principles of energy balance, ultimately enabling new treatment strategies for diseases rooted in body weight control.

The etiology of polycystic ovary syndrome (PCOS) remains unclear, although studies indicate that both genetic and environmental factors contribute to the syndrome. In 2012, Tremellen and Pearce proposed the idea that dysbiosis of the intestinal (gut) microbiome is a causative factor of metabolic and reproductive manifestations of PCOS. In the past 5 years, studies in both humans and rodent models have demonstrated that changes in the taxonomic composition of gut bacteria are associated with PCOS. Studies have also clearly shown that these changes in gut microbiota are associated with PCOS as opposed to obesity, since these changes are observed in women with PCOS that are both of a normal weight or obese, as well as in adolescent girls with PCOS and obesity compared with body mass index- and age-matched females without the disorder. Additionally, studies in both women with PCOS and rodent models of PCOS demonstrated that hyperandrogenism is associated with gut microbial dysbiosis, indicating that androgens may modulate the gut microbial community in females. One study reported that the fecal microbiome transplantation of stool from women with PCOS or exposure to certain bacteria resulted in a PCOS-like phenotype in mice, while other studies showed that exposure to a healthy gut microbiome, pre/probiotics, or specific gut metabolites resulted in protection from developing PCOS-like traits in mice. Altogether, these results suggest that dysbiosis of the gut microbiome may be sufficient to develop PCOS-like symptoms and that modulation of the gut microbiome may be a potential therapeutic target for PCOS.

Puberty is a developmental period characterized by a broad range of physiologic changes necessary for the acquisition of adult sexual and reproductive maturity. These changes mirror complex modifications within the central nervous system, including within the hypothalamus. These modifications result in the maturation of a fully active hypothalamic–pituitary–gonadal (HPG) axis, the neuroendocrine cascade ensuring gonadal activation, sex steroid secretion, and gametogenesis. A complex and finely regulated neural network overseeing the HPG axis, particularly the pubertal reactivation of gonadotropin-releasing hormone (GnRH) secretion, has been progressively unveiled in the last 3 decades. This network includes kisspeptin, neurokinin B, GABAergic, and glutamatergic neurons as well as glial cells. In addition to substantial modifications in the expression of key targets, several changes in neuronal morphology, neural connections, and synapse organization occur to establish mature and coordinated neurohormonal secretion, leading to puberty initiation. The aim of this review is to outline the current knowledge of the major changes that neurons secreting GnRH and their neuronal and glial partners undergo before and after puberty. Emerging mediators upstream of GnRH, uncovered in recent years, are also addressed herein. In addition, the effects of sex steroids, particularly estradiol, on changes in hypothalamic neurodevelopment and plasticity are discussed.

Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of T enanthate (TE) or oral T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how T should be administered and optimal strategies for monitoring therapy once it is initiated. Only TE and T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.

AbstractEstrogen (17β-estradiol or E2) is a crucial regulator of the synthesis and secretion of pituitary reproductive hormones luteinizing hormone, follicle-stimulating hormone, and prolactin. In this review, we summarize the role of estrogen receptors in nonfunctioning pituitary neuroendocrine tumors (NF-Pitnets), focusing on immunoexpression and gonadotroph cell proliferation and apoptosis. Gonadotroph tumors are the most common subtype of NF-Pitnets. Two major estrogen receptor (ER) isoforms expressed in the pituitary are estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Overall, estrogen actions are mostly exerted through the ERα isoform on the pituitary. The G protein–coupled estrogen receptor (GPER) located at the plasma membrane may contribute to nongenomic effects of estrogen. Nuclear immunoreactivity for ERα and ERβ was highest among gonadotroph and null cell tumors. Silent corticotroph tumors are the least immunoreactive for both receptors. A significantly elevated ERα expression was observed in macroadenomas compared with microadenomas. ERα and ERβ may act in opposite directions to regulate the Slug-E-cadherin pathway and to affect invasiveness of NF-Pitnets. In the cellular pathway, ERs regulate estrogen-induced proliferation and differentiation and impact several signaling pathways including the MAPK and PI3K/Akt pathway. Estrogen was the first-discovered inducer of pituitary tumor transforming gene 1 that was abundantly expressed in NF-Pitnets. ERα can be a potential biomarker for predicting tumor size and invasiveness as well as therapeutic target for NF-Pitnets. Selective estrogen receptor modulators or antiestrogen may represent as an alternative choice for the treatment of NF-Pitnets.

The intestinal microbiome is emerging as a critical factor in health and disease. The microbes, although spatially restricted to the gut, are communicating and modulating the function of distant organs such as the brain. Stroke and other neurological disorders are associated with a disrupted microbiota. In turn, stroke-induced dysbiosis has a major impact on the disease outcome by modulating the immune response. In this review, we present current knowledge on the role of the gut microbiome in stroke, one of the most devastating brain disorders worldwide with very limited therapeutic options, and we discuss novel insights into the gut-immune-brain axis after an ischemic insult. Understanding the nature of the gut bacteria-brain crosstalk may lead to microbiome-based therapeutic approaches that can improve patient recovery.

The entire world is suffering from a new type of viral disease, occurred by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). The present article briefly discussed the genome sequencing and interaction of host cells with SARS‐CoV‐2. The influence of pre‐existing diseases such as diabetes, heart disease and age of the patients on COVID‐19 infection is reviewed. The possible treatments of SARS‐CoV‐2 including antiviral drugs, Chinese traditional treatment and plasma therapy are elaborately discussed. The proper vaccine for COVID‐19 is not available till date. However, the trials of pre‐existing antiviral vaccines such as, chloroquine/hydroxychloroquine, remdesivir, ritonavir and lopinavir and their consequences are briefly presented. Further, the importance of new materials and devices for the detection and treatment of COVID‐19 has also been reviewed. The polymerase chain reaction (PCR)‐based, and non‐PCR based devices are used for the detection of COVID‐19 infection. The non‐PCR based devices provide rapid results as compared to PCR based devices.

Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from β- and α-cells, respectively. The historical narrative positions these hormones in opposition, with insulin primarily responsible for glucose-lowering and glucagon-driving elevations in glucose. Recent progress in this area has revealed a more complex relationship between insulin and glucagon, highlighted by data demonstrating that α-cell input is essential for β-cell function and glucose homeostasis. Moreover, the common perception that glucagon levels decrease following a nutrient challenge is largely shaped by the inhibitory effects of glucose administration alone on the α-cell. Largely overlooked is that a mixed nutrient challenge, which is more representative of typical human feeding, actually stimulates glucagon secretion. Thus, postprandial metabolism is associated with elevations, not decreases, in α-cell activity. This review discusses the recent advances in our understanding of how α-cells regulate metabolism, with a particular focus on the postprandial state. We highlight α- to β-cell communication, a term that describes how α-cell input into β-cells is a critical axis that regulates insulin secretion and glucose homeostasis. Finally, we discuss the open questions that have the potential to advance this field and continue to evolve our understanding of the role that α-cells play in postprandial metabolism.

In 1997, the first in vivo bisphenol A (BPA) study by endocrinologists reported that feeding BPA to pregnant mice induced adverse reproductive effects in male offspring at the low dose of 2 µg/kg/day. Since then, thousands of studies have reported adverse effects in animals administered low doses of BPA. Despite more than 100 epidemiological studies suggesting associations between BPA and disease/dysfunction also reported in animal studies, regulatory agencies continue to assert that BPA exposures are safe. To address this disagreement, the CLARITY-BPA study was designed to evaluate traditional endpoints of toxicity and modern hypothesis-driven, disease-relevant outcomes in the same set of animals. A wide range of adverse effects was reported in both the toxicity and the mechanistic endpoints at the lowest dose tested (2.5 µg/kg/day), leading independent experts to call for the lowest observed adverse effect level (LOAEL) to be dropped 20 000-fold from the current outdated LOAEL of 50 000 µg/kg/day. Despite criticism by members of the Endocrine Society that the Food and Drug Administration (FDA)’s assumptions violate basic principles of endocrinology, the FDA rejected all low-dose data as not biologically plausible. Their decisions rely on 4 incorrect assumptions: dose responses must be monotonic, there exists a threshold below which there are no effects, both sexes must respond similarly, and only toxicological guideline studies are valid. This review details more than 20 years of BPA studies and addresses the divide that exists between regulatory approaches and endocrine science. Ultimately, CLARITY-BPA has shed light on why traditional methods of evaluating toxicity are insufficient to evaluate endocrine disrupting chemicals.

Pancreatic islet beta cells (β-cells) synthesize and secrete insulin in response to rising glucose levels and thus are a prime target in both major forms of diabetes. Type 1 diabetes ensues due to autoimmune destruction of β-cells. On the other hand, the prevailing insulin resistance and hyperglycemia in type 2 diabetes (T2D) elicits a compensatory response from β-cells that involves increases in β-cell mass and function. However, the sustained metabolic stress results in β-cell failure, characterized by severe β-cell dysfunction and loss of β-cell mass. Dynamic changes to β-cell mass also occur during pancreatic development that involves extensive growth and morphogenesis. These orchestrated events are triggered by multiple signaling pathways, including those representing the transforming growth factor β (TGF-β) superfamily. TGF-β pathway ligands play important roles during endocrine pancreas development, β-cell proliferation, differentiation, and apoptosis. Furthermore, new findings are suggestive of TGF-β’s role in regulation of adult β-cell mass and function. Collectively, these findings support the therapeutic utility of targeting TGF-β in diabetes. Summarizing the role of the various TGF-β pathway ligands in β-cell development, growth and function in normal physiology, and during diabetes pathogenesis is the topic of this mini-review.

Circadian rhythms are 24-hour biological rhythms within organisms that have developed over evolutionary time due to predefined environmental changes, mainly the light-dark cycle. Interestingly, metabolic tissues, which are largely responsible for establishing diurnal metabolic homeostasis, have been found to express cell-autonomous clocks that are entrained by food intake. Disruption of the circadian system, as seen in individuals who conduct shift work, confers significant risk for the development of metabolic diseases such as type 2 diabetes and obesity. The gastrointestinal (GI) tract is the first point of contact for ingested nutrients and is thus an essential organ system for metabolic control. This review will focus on the circadian function of the GI tract with a particular emphasis on its role in metabolism through regulation of gut hormone release. First, the circadian molecular clock as well as the organization of the mammalian circadian system is introduced. Next, a brief overview of the structure of the gut as well as the circadian regulation of key functions important in establishing metabolic homeostasis is discussed. Particularly, the focus of the review is centered around secretion of gut hormones; however, other functions of the gut such as barrier integrity and intestinal immunity, as well as digestion and absorption, all of which have relevance to metabolic control will be considered. Finally, we provide insight into the effects of circadian disruption on GI function and discuss chronotherapeutic intervention strategies for mitigating associated metabolic dysfunction.

Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Because of the central role of mitochondria in energy production, heme biosynthesis, calcium buffering, steroidogenesis, and apoptosis signaling within cells, understanding the molecular mechanisms behind mitochondrial dysregulation and its potential implications in disease is critical. This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders, focusing on metabolic alterations and reproductive abnormalities. Evidence is presented from studies in different human populations, and rodents with genetic manipulations of pathways known to affect mitochondrial function.

A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.

Highlights • New techniques emerge to study peripheral sensory neurons in iPS-cell derived models. • Genetic pain syndromes, e.g. gain- and loss-of-function mutations in Nav-channels are helpful. • Individualized treatment for neuropathic pain can be identified with iPS-cell derived nociceptors., In this concise Mini-Review we will summarize ongoing developments of new techniques to study physiology and pathophysiology of the peripheral sensory nervous system in human stem cell derived models. We will focus on recent developments of reprogramming somatic cells into induced pluripotent stem cells, neural differentiation towards neuronal progenitors and human sensory neurons. We will sum up the high potential of this new technique for disease modelling of human neuropathies with a focus on genetic pain syndromes, such as gain- and loss-of-function mutations in voltage-gated sodium channels. The stem cell derived human sensory neurons are used for drug testing and we will summarize their usefulness for individualized treatment identification in patients with neuropathic pain. The review will give an outlook on potential application of this technique as companion diagnostics and for personalized medicine.

The majority of breast cancers are diagnosed as estrogen receptor–positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.

It is well known that the neuromodulator adenosine, acting through the adenosine A(1) receptor subtype, can limit or stop seizures. In 2008, adenosine was proposed as a key component of the anticonvulsant mechanism of the ketogenic diet (KD), a very low carbohydrate diet that can be highly effective in drug-refractory epilepsy. In this study, we review the accumulated data on the intersection among adenosine, ketosis, and anticonvulsant/antiepileptogenic effects. In several rodent models of epilepsy and seizures, antiseizure effects of ketogenic treatments (the KD itself, exogenous ketone bodies, medium-chain triglycerides or fatty acids) are reversed by administration of an adenosine A(1) receptor antagonist. In addition, KD treatment elevates extracellular adenosine and tissue adenosine content in brain. Efforts to maintain or mimic a ketogenic milieu in brain slices reveal a state of reduced excitability produced by pre- and postsynaptic adenosine A(1) receptor-based effects. Long-lasting seizure reduction may be due to adenosine-based epigenetic effects. In conclusion, there is accumulating evidence for an adenosinergic anticonvulsant action in the ketogenic state. In some cases, the main trigger is mildly but consistently lowered glucose in the brain. More research is needed to investigate the importance of adenosine in the antiepileptogenic and neuroprotective effects of these treatments. Future research may begin to investigate alternative adenosine-promoting strategies to enhance the KD or to find use as treatments themselves.

Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia,” “diagnosis,” “management,” “guideline,” “consensus,” “genetics,” “screening,” “lipid lowering agents.” The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.

Obesity is associated with increased mortality as a result of several comorbidities which occur in tandem with the obese state. Chronic inflammation is well documented in obesity, and evidence from numerous studies support the notion that the increased inflammation in individuals with obesity accentuates the comorbidities seen in this condition. The remission of comorbidities such as metabolic, cardiovascular, and neurological complications occurs following bariatric procedures. Bariatric surgery significantly reduces mortality and results in remarkable weight loss and reversal in several obesity-related comorbidities. There is indisputable evidence that the resolution of inflammation that occurs after bariatric surgery mitigates some of these comorbidities. With the increasing use of bariatric surgery for the treatment of severe obesity, it is pivotal to elucidate the underlying mechanisms responsible for the notable improvements seen after the procedure. This review summarizes underlying mechanisms responsible for the remission of obesity-related abnormalities and discusses the common adverse effects of bariatric surgery. Well-stratified, large-scale studies are still needed for a proper evaluation of these underlying mechanisms.

Organisms that inhabit the temperate zone exhibit various seasonal adaptive behaviors, including reproduction, hibernation, molting, and migration. Day length, known as photoperiod, is the most noise-free and widely used environmental cue that enables animals to anticipate the oncoming seasons and adapt their physiologies accordingly. Although less clear, some human traits also exhibit seasonality, such as birthrate, mood, cognitive brain responses, and various diseases. However, the molecular basis for human seasonality is poorly understood. Herein, we first review the underlying mechanisms of seasonal adaptive strategies of animals, including seasonal reproduction and stress responses during the breeding season. We then briefly summarize our recent discovery of signaling pathways involved in the winter depression–like phenotype in medaka fish. We believe that exploring the regulation of seasonal traits in animal models will provide insight into human seasonality and aid in the understanding of human diseases such as seasonal affective disorder (SAD).

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.

Ovarian tissue cryopreservation and banking provides a fertility preservation option for patients who cannot undergo oocyte retrieval; it is quickly becoming a critical component of assisted reproductive technology programs across the world. While the transplantation of cryopreserved ovarian tissue has resulted in over 130 live births, the field has ample room for technological improvements. Specifically, the functional timeline of grafted tissue and each patient’s probability of achieving pregnancy is largely unpredictable due to patient-to-patient variability in ovarian reserve, lack of a reliable method for quantifying follicle numbers within tissue fragments, potential risk of reintroduction of cancer cells harbored in ovarian tissues, and an inability to control follicle activation rates. This review focuses on one of the most common physiological techniques used to study human ovarian tissue transplantation, xenotransplantation of human ovarian tissue to mice and endeavors to inform future studies by discussing the elements of the xenotransplantation model, challenges unique to the use of human ovarian tissue, and novel tissue engineering techniques currently under investigation.

Coronavirus disease–2019 (COVID-19), a disease caused by Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has become an unprecedented global health emergency, with fatal outcomes among adults of all ages in the United States, and the highest incidence and mortality in adult men. As the pandemic evolves there is limited understanding of a potential association between symptomatic viral infection and age. To date, there is no knowledge of the role children (prepubescent, ages 9-13 years) play as “silent” vectors of the virus, with themselves being asymptomatic. Throughout different time frames and geographic locations, the current evidence on COVID-19 suggests that children are becoming infected at a significantly lower rate than other age groups—as low as 1%. Androgens upregulate the protease TMPRSS2 (type II transmembrane serine protease-2), which facilitates efficient virus-host cell fusion with the epithelium of the lungs, thus increasing susceptibility to SARS-CoV-2 infection and development of severe COVID-19. Owing to low levels of steroid hormones, prepubertal children may have low expression of TMPRSS2, thereby limiting the viral entry into host cells. As the world anticipates a vaccine against SARS-CoV-2, the role of prepubescent children as vectors transmitting the virus must be interrogated to prepare for a potential resurgence of COVID-19. This review discusses the current evidence on the low incidence of COVID-19 in children and the effect of sex-steroid hormones on SARS-CoV-2 viral infection and clinical outcomes of pediatric patients. On reopening society at large, schools will need to implement heightened health protocols with the knowledge that children as the “silent” viral transmitters can significantly affect the adult populations.

Inflammasomes are multiprotein complexes that respond to pathogen or host associated damage markers, leading to caspase-1 maturation and processing of pro-inflammatory cytokines. Initially, inflammasomes were implicated primarily in inflammatory and infectious conditions. However, increasing evidence demonstrates broader roles beyond inflammation, including regulation of adipose tissue metabolism after burns. Here, we conducted a search for articles on PubMed, Web of Science, Embase, Scopus, and UpToDate with applied search strategies including a combination of “burns,” “trauma,” “(NLRP3) inflammasome,” “metabolic conditions,” “white adipose tissue,” “macrophages,” “browning,” and “lipolysis” and included papers from 2000 to 2020. We discuss unexpected roles for NLRP3, the most characterized inflammasome to date, as a key metabolic driver in a variety of conditions. In particular, we highlight the function of NLRP3 inflammasome in burn trauma, which is characterized by both hyperinflammation and hypermetabolism. We identify a critical part for NLRP3 activation in macrophage dynamics and delineate a novel role in postburn white adipose tissue remodeling, a pathological response associated with hypermetabolism and poor clinical outcomes. Mechanistically, how inflammation and inflammasome activation is linked to postburn hypermetabolism is a novel concept to contemplate, and herein we provide evidence of an immunometabolic crosstalk between adipocytes and infiltrating macrophages.

Early-life exposures to environmental insults can misprogram development and increase metabolic disease risk in a sex-dependent manner by mechanisms that remain poorly characterized. Modifiable factors of increasing public health relevance, such as diet, psychological stress, and endocrine-disrupting chemicals, can affect glucocorticoid receptor signaling during gestation and lead to sex-specific postnatal metabolic derangements. Evidence from humans and animal studies indicate that glucocorticoids crosstalk with sex steroids by several mechanisms in multiple tissues and can affect sex-steroid–dependent developmental processes. Nonetheless, glucocorticoid sex-steroid crosstalk has not been considered in the glucocorticoid-induced misprogramming of metabolism. Herein we review what is known about the mechanisms by which glucocorticoids crosstalk with estrogen, androgen, and progestogen action. We propose that glucocorticoid sex-steroid crosstalk is an understudied mechanism of action that requires consideration when examining the developmental misprogramming of metabolism, especially when assessing sex-specific outcomes.

Provocative mouse studies and observational human data have generated considerable enthusiasm for modulating follicle-stimulating hormone (FSH) action in humans to prevent bone loss and, in addition, to treat obesity. This perspective summarizes the strengths and potential weaknesses of the mouse studies examining the skeletal phenotype of FSHβ or FSH receptor null mice, as well as more recent studies using FSH neutralizing antibodies. Although human observational studies do demonstrate correlation of serum FSH levels with postmenopausal bone loss, these studies cannot distinguish whether serum FSH is simply a better biomarker than estradiol or causally related to the bone loss. Establishing causality requires direct interventional studies either suppressing or infusing FSH in humans and to date, such studies have uniformly failed to demonstrate an effect of FSH on bone turnover independent of changes in sex steroid levels. In addition, suppression of FSH is unable to prevent increases in body fat following the induction of sex steroid deficiency, at least in men. Thus, although the preclinical mouse and human observational data are intriguing, there is currently no direct evidence from interventional studies that FSH regulates bone or fat metabolism in vivo in humans.

Ovarian hormones, including 17β-estradiol, are implicated in numerous physiological processes, including sleep. Beginning at puberty, girls report more sleep complaints than boys, which is maintained throughout the reproductive life stage. Sleep problems are exacerbated during the menopausal transition, evidenced by greater risk for sleep disorders. There is emerging evidence that menopause-associated hormone loss contributes to this elevated risk, but age is also an important factor. The extent to which menopause-associated sleep disturbance persists into postmenopause above and beyond the effects of age remains unknown. Untreated sleep disturbances have important implications for cognitive health, as they are emerging as risk factors for dementia. Given that sleep loss impairs memory, an important knowledge gap concerns the role played by menopause-associated hormone loss in exacerbating sleep disturbance and, ultimately, cognitive function in aging women. In this review, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining the sleep–wake cycle in younger and middle-aged females, with evidence implicating 17β-estradiol in supporting the memory-promoting effects of sleep. Sleep physiology is briefly reviewed before turning to behavioral and neural evidence from young females linking 17β-estradiol to sleep–wake cycle maintenance. Implications of menopause-associated 17β-estradiol loss is also reviewed before discussing how ovarian hormones may support the memory-promoting effects of sleep, and why menopause may exacerbate pathological aging via effects on sleep. While still in its infancy, this research area offers a new sex-based perspective on aging research, with a focus on a modifiable risk factor for pathological aging.