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Biology of Reproduction Jul 2018Herein we summarize important discoveries made over many years about Leydig cell function and regulation. Fetal Leydig cells produce the high levels of androgen... (Review)
Review
Herein we summarize important discoveries made over many years about Leydig cell function and regulation. Fetal Leydig cells produce the high levels of androgen (testosterone or androstenedione, depending upon the species) required for differentiation of male genitalia and brain masculinization. Androgen production declines with loss of these cells, reaching a nadir at postpartum. Testosterone then gradually increases to high levels with adult Leydig cell development from stem cells. In the adult, luteinizing hormone (LH) binding to Leydig cell LH receptors stimulates cAMP production, increasing the rate of cholesterol translocation into the mitochondria. Cholesterol is metabolized to pregnenolone by the CYP11A1 enzyme at the inner mitochondrial membrane, and pregnenolone to testosterone by mitochondria and smooth endoplasmic reticulum enzymes. Cholesterol translocation to the inner mitochondrial membrane is mediated by a protein complex formed at mitochondrial contact sites that consists of the cholesterol binding translocator protein, voltage dependent anion channel, and other mitochondrial and cytosolic proteins. Steroidogenic acute regulatory protein acts at this complex to enhance cholesterol movement across the membranes and thus increase testosterone formation. The 14-3-3γ and ε adaptor proteins serve as negative regulators of steroidogenesis, controlling the maximal amount of steroid formed. Decline in testosterone production occurs in many aging and young men, resulting in metabolic and quality-of-life changes. Testosterone replacement therapy is widely used to elevate serum testosterone levels in hypogonadal men. With knowledge gained of the mechanisms involved in testosterone formation, it is also conceivable to use pharmacological means to increase serum testosterone by Leydig cell stimulation.
Topics: Animals; Cholesterol; Humans; Leydig Cells; Male; Testis; Testosterone
PubMed: 29566165
DOI: 10.1093/biolre/ioy059 -
Acta Pharmaceutica Sinica. B Jan 2024Neurons are believed to be non-proliferating cells. However, neuronal stem cells are still present in certain areas of the adult brain, although their proliferation... (Review)
Review
Neurons are believed to be non-proliferating cells. However, neuronal stem cells are still present in certain areas of the adult brain, although their proliferation diminishes with age. Just as with other cells, their proliferation and differentiation are modulated by various mechanisms. These mechanisms are foundational to the strategies developed to induce neuronal proliferation and differentiation, with potential therapeutic applications for neurodegenerative diseases. The most common among these diseases are Parkinson's disease and Alzheimer's disease, associated with the formation of -amyloid (A) aggregates which cause a reduction in the number of neurons. Compounds such as LiCl, 4-aminothiazoles, Pregnenolone, ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFB, Wnt, BDNF, and NPAS3. Moreover, combinations of these compounds can potentially transform somatic cells into neurons. This transformation process involves the activation of neuron-specific transcription factors such as NEUROD1, NGN2, ASCL1, and SOX2, which subsequently leads to the transcription of downstream genes, culminating in the transformation of somatic cells into neurons. Neurodegenerative diseases are not the only conditions where inducing neuronal proliferation could be beneficial. Consequently, the impact of pro-proliferative compounds on neurons has also been researched in mouse models of Alzheimer's disease.
PubMed: 38239239
DOI: 10.1016/j.apsb.2023.10.007 -
Journal of Lipid Research Apr 2020Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and...
Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and lack the evaluation of accuracy. Here, we developed an LC/MS/MS method for the simultaneous quantification of 12 steroid hormones: testosterone, pregnenolone, progesterone, androstenedione, corticosterone, 11-deoxycortisol, cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, estriol, and estradiol. Steroids and spiked internal standards in 100 μl serum were extracted by protein precipitation and liquid-liquid extraction. The organic phase was dried by evaporation, and isonicotinoyl chloride was added for steroid derivatization, followed by evaporation under nitrogen and redissolution in 50% methanol. Chromatographic separation was performed on a reverse-phase PFP column, and analytes were detected on a triple quadrupole mass spectrometer with ESI. The lower limits of quantification ranged from 0.005 ng/ml for estradiol to 1 ng/ml for cortisol. Apparent recoveries of steroids at high, medium, and low concentrations in quality control samples were between 86.4% and 115.0%. There were limited biases (-10.7% to 10.5%) between the measured values and the authentic values, indicating that the method has excellent reliability. An analysis of the steroid metabolome in pregnant women highlighted the applicability of the method in clinical serum samples. We conclude that the LC/MS/MS method reported here enables steroid metabolome analysis with high accuracy and reduced serum consumption, indicating that it may be a useful tool in both clinical and scientific laboratory research.
Topics: Analytic Sample Preparation Methods; Blood Chemical Analysis; Chromatography, Liquid; Female; Humans; Limit of Detection; Metabolomics; Pregnancy; Solvents; Steroids; Tandem Mass Spectrometry
PubMed: 31964762
DOI: 10.1194/jlr.D119000591 -
Neuroscience and Biobehavioral Reviews Jun 2023Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These steroids... (Review)
Review
Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These steroids modulate major signaling systems in the brain and intracellular processes including inflammation, cellular stress and autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which are physiochemically identical to their natural counterparts except for rotation of polarized light. These studies led to insights in how NAS interact with receptors, ion channels and intracellular sites of action. Certain effects of NAS show high enantioselectivity, consistent with actions in chiral environments and likely direct interactions with signaling proteins. Other effects show no enantioselectivity and even reverse enantioselectivity. The spectrum of effects of NAS enantiomers raises the possibility that these agents, once considered only as tools for preclinical studies, have therapeutic potential that complements and in some cases may exceed their natural counterparts. Here we review studies of NAS enantiomers from the perspective of their potential development as novel neurotherapeutics.
Topics: Humans; Neurosteroids; Brain; Receptors, GABA-A
PubMed: 37085023
DOI: 10.1016/j.neubiorev.2023.105191 -
International Journal of Molecular... Dec 2020Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into... (Review)
Review
Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids-allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)-are known to modulate GABA receptor-mediated transmission, thus playing a role in controlling neuronal network excitability. Given the role of GABA signaling in epileptic disorders, neurosteroids have profound effects on seizure generation and play a role in the development of chronic epileptic conditions (i.e., epileptogenesis). We review here studies showing the effects induced by neurosteroids on epileptiform synchronization in in vitro brain slices, on epileptic activity in in vivo models, i.e., in animals that were made epileptic with chemoconvulsant treatment, and in epileptic patients. These studies reveal that neurosteroids can modulate ictogenesis and the occurrence of pathological network activity such as interictal spikes and high-frequency oscillations (80-500 Hz). Moreover, they can delay the onset of spontaneous seizures in animal models of mesial temporal lobe epilepsy. Overall, this evidence suggests that neurosteroids represent a new target for the treatment of focal epileptic disorders.
Topics: Animals; Anticonvulsants; Brain Waves; Epilepsy, Temporal Lobe; Humans; Neurosteroids; Synaptic Transmission
PubMed: 33321734
DOI: 10.3390/ijms21249391 -
Frontiers in Cell and Developmental... 2021Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an... (Review)
Review
Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores. This regulated ion permeation results in different electrical and chemical signals that are necessary to maintain physiological excitatory and inhibitory processes in the brain. Therefore, it is no surprise that disturbances in the functions of cerebral ion channels can result in a plethora of neurological disorders, which present a tremendous health care burden for our current society. The identification of ion channel-related brain disorders also fuel the research into the roles of ion channel proteins in various brain states. In the last decade, mounting evidence has been collected that indicates a pivotal role for transient receptor potential (TRP) ion channels in the development and various physiological functions of the central nervous system. For instance, TRP channels modulate neurite growth, synaptic plasticity and integration, and are required for neuronal survival. Moreover, TRP channels are involved in numerous neurological disorders. TRPM3 belongs to the melastatin subfamily of TRP channels and represents a non-selective cation channel that can be activated by several different stimuli, including the neurosteroid pregnenolone sulfate, osmotic pressures and heat. The channel is best known as a peripheral nociceptive ion channel that participates in heat sensation. However, recent research identifies TRPM3 as an emerging new player in the brain. In this review, we summarize the available data regarding the roles of TRPM3 in the brain, and correlate these data with the neuropathological processes in which this ion channel may be involved.
PubMed: 33732703
DOI: 10.3389/fcell.2021.635659 -
ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.EMBO Reports Aug 2023Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via...
Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.
Topics: tau Proteins; Mitochondria; Endoplasmic Reticulum; Protein Tyrosine Phosphatases; Cholesterol
PubMed: 37401859
DOI: 10.15252/embr.202357499 -
Frontiers in Immunology 2019Maternal glucocorticoids critically rise during pregnancy reaching up to a 20-fold increase of mid-pregnancy concentrations. Concurrently, another steroid hormone,... (Review)
Review
Maternal glucocorticoids critically rise during pregnancy reaching up to a 20-fold increase of mid-pregnancy concentrations. Concurrently, another steroid hormone, progesterone, increases. Progesterone, which shows structural similarities to glucocorticoids, can bind the intracellular glucocorticoid receptor, although with lower affinity. Progesterone is essential for the establishment and continuation of pregnancy and it is generally acknowledged to promote maternal immune tolerance to fetal alloantigens through a wealth of immunomodulatory mechanisms. Despite the potent immunomodulatory capacity of glucocorticoids, little is known about their role during pregnancy. Here we aim to compare general aspects of glucocorticoids and progesterone during pregnancy, including shared common steroidogenic pathways, plasma transporters, regulatory pathways, expression of receptors, and mechanisms of action in immune cells. It was recently acknowledged that progesterone receptors are not ubiquitously expressed on immune cells and that pivotal features of progesterone induced- maternal immune adaptations to pregnancy are mediated via the glucocorticoid receptor, including e.g., T regulatory cells expansion. We hypothesize that a tight equilibrium between progesterone and glucocorticoids is critically required and recapitulate evidence supporting that their disequilibrium underlie pregnancy complications. Such a disequilibrium can occur, e.g., after maternal stress perception, which triggers the release of glucocorticoids and impair progesterone secretion, resulting in intrauterine inflammation. These endocrine misbalance might be interconnected, as increase in glucocorticoid synthesis, e.g., upon stress, may occur in detriment of progesterone steroidogenesis, by depleting the common precursor pregnenolone. Abundant literature supports that progesterone deficiency underlies pregnancy complications in which immune tolerance is challenged. In these settings, it is largely yet undefined if and how glucocorticoids are affected. However, although progesterone immunomodulation during pregnancy appear to be chiefly mediated glucocorticoid receptors, excess glucocorticoids cannot compensate by progesterone deficiency, indicating that additional und still undercover mechanisms are at play.
Topics: Animals; Female; Fetal Development; Glucocorticoids; Humans; Pregnancy; Progesterone; Receptors, Glucocorticoid; Receptors, Progesterone
PubMed: 32038609
DOI: 10.3389/fimmu.2019.03017 -
Plants (Basel, Switzerland) Sep 2020Steroids are a group of organic compounds that include sex hormones, adrenal cortical hormones, sterols, and phytosterols. In mammals, steroid biosynthesis starts from... (Review)
Review
Steroids are a group of organic compounds that include sex hormones, adrenal cortical hormones, sterols, and phytosterols. In mammals, steroid biosynthesis starts from cholesterol via multiple steps to the final steroid and occurs in the gonads, adrenal glands, and placenta. This highly regulated pathway involves several cytochrome P450, as well as different dehydrogenases and reductases. Steroids in mammals have also been associated with drug production. Steroid pharmaceuticals such as testosterone and progesterone represent the second largest category of marketed medical products. There heterologous production through microbial transformation of phytosterols has gained interest in the last couple of decades. Phytosterols being the plants sterols serve as inexpensive substrates for the production of steroid derivatives. Various genes and biochemical pathways involved in phytosterol degradation have been identified in many Rhodococcus and Mycobacterium species. Apart from an early investigation in mammals, presence of steroids such as androsteroids and progesterone has also been demonstrated in plants. Their main role is linked with growth, development, and reproduction. Even though plants share some chemical features with mammals, the biosynthesis is different, with the first C22 hydroxylation as an example. This is performed by CYP11A1 in mammals and CYP90B1 in plants. Moreover, the entire plant steroid biosynthesis is not fully elucidated. Knowing this pathway could provide new processes for the industrial biotechnological production of steroid hormones in plants.
PubMed: 32899410
DOI: 10.3390/plants9091144 -
Cell Metabolism Feb 2022Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we...
Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypothalamus; Metabolic Diseases; Mice; Mice, Inbred C57BL; Pregnenolone; Pro-Opiomelanocortin
PubMed: 35108514
DOI: 10.1016/j.cmet.2021.12.023