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International Journal of Molecular... Dec 2022Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic... (Review)
Review
Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic agents for pathologies such as anxiety and depression. Enzymes involved in the metabolism of 3α-THP are expressed in classical and nonclassical steroidogenic tissues. Additionally, due to its chemical structure, 3α-THP presents high affinity and agonist activity for nuclear and membrane receptors of neuroactive steroids and neurotransmitters, such as the Pregnane X Receptor (PXR), membrane progesterone receptors (mPR) and the ionotropic GABA receptor, among others. 3α-THP has immunomodulator and antiapoptotic properties. It also induces cell proliferation and migration, all of which are critical processes involved in cancer progression. Recently the study of 3α-THP has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer, such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we explore current knowledge on the metabolism and mechanisms of action of 3α-THP in normal and tumor cells.
Topics: Humans; Gonadal Steroid Hormones; Pregnanolone; Progesterone; Receptors, Progesterone; Neoplasms
PubMed: 36614002
DOI: 10.3390/ijms24010560 -
Hormone Molecular Biology and Clinical... Jun 2023Major Depressive Disorder (MDD) is a mood disorder classified as a persistent depressive mood and loss of interest lasting for more than two weeks and accompanied by a... (Review)
Review
Major Depressive Disorder (MDD) is a mood disorder classified as a persistent depressive mood and loss of interest lasting for more than two weeks and accompanied by a list of symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria. MDD affects approximately 264 million people worldwide and is the most prevailing form of neuropsychiatric disorder. Owing to the probable hypothesized pathophysiology of MDD being an outcome of abnormalities in the amino acid neurotransmitter system, including glutamate (the primary excitatory neurotransmitter) and -aminobutyric acid (GABA), SAGE-217 (Zuranolone) is being evaluated as a possible therapeutic treatment for MDD. Zuranolone is a synthetic, neuroactive steroid (NAS) and positive allosteric modulator (PMA) of GABAA receptors, regulating both synaptic and extra-synaptic release of GABA. It is administered as a once-daily oral dose for 2 weeks due to its low-moderate clearance. A change in total HAM-D score from baseline was the primary end-point of all the trials. A phase II trial conducted to evaluate the efficacy and safety of Zuranolone (30 mg, once-daily dose), described a significant reduction in total HAM-D score at day 14 and reported the drug to be well tolerated with headache, dizziness, nausea, and somnolence as the most common adverse events (AE). Additional phase III trials were also conducted to evaluate similar outcomes, the interim topline results of which have been released. Consequently, this article attempts to briefly analyze the pharmacology of Zuranolone, review the available clinical data and outcomes regarding its use, and evaluate its place as a prospective novel therapy in the effective management of MDD.
Topics: Humans; Depressive Disorder, Major; Prospective Studies; Pregnanes; gamma-Aminobutyric Acid; Double-Blind Method
PubMed: 36848317
DOI: 10.1515/hmbci-2022-0042 -
Steroids Jul 2016Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic... (Review)
Review
Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic transcription, steroids also exert nongenomic actions. The current article focuses on the nongenomic actions of neurosteroids, including pregnenolone (P5), 7α-hydroxypregnenolone, pregnenolone sulfate and allopregnanolone. Pregnenolone and its derivatives promote neuronal activity by enhancing learning and memory, relieving depression, enhancing locomotor activity, and promoting neuronal cell survival. They exert these effects by activating various target proteins located in the cytoplasm or cell membrane. Pregnenolone and its metabolites bind to receptors such as microtubule-associated proteins and neurotransmitter receptors to elicit a series of reactions including stabilization of microtubules, increase of ion flux into cells, and dopamine release. The wide actions of neurosteroids indicate that pregnenolone derivatives have great potential in future treatment of neurological diseases.
Topics: 17-alpha-Hydroxypregnenolone; Animals; Depression; Humans; Microtubules; Neurodegenerative Diseases; Neurotransmitter Agents; Pregnanolone; Pregnenolone
PubMed: 26844377
DOI: 10.1016/j.steroids.2016.01.017 -
Journal of the American College of... Dec 2017
Topics: Atrial Fibrillation; Atrial Remodeling; Eplerenone; Heart Atria; Humans; Spironolactone
PubMed: 29216986
DOI: 10.1016/j.jacc.2017.10.043 -
Frontiers in Endocrinology 2022The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity.
DESIGN
This is a multicenter randomized study (NCT number: NCT04860180).
METHODS
Sixty-two AI outpatients (40-75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated.
RESULTS
BP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively ( = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively ( = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8-108.3, < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%).
CONCLUSIONS
AI patients with PACS benefit from surgery in terms of BP and glycometabolic control.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Blood Pressure; Cortisone; Female; Humans; Hydrocortisone
PubMed: 35721734
DOI: 10.3389/fendo.2022.898084 -
Steroids Jan 2022Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma,...
Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma, allergic rhinitis, and dermatoses. However, existing synthetic routes to this active pharmaceutical ingredient (API) contain steps resulting in low and/or inconsistent yields, and use obsolete reagents. Such inconsistencies coupled with a lack of reliable experimental data makes laboratory-scale and large-scale synthesis of this API difficult and time-consuming. In this paper, we report a practical and scalable approach to synthesize 1 from the readily available steroidal intermediate, 16β-methyl epoxide (3, DB-11). A gram-scale to kilogram-scale synthesis of 1 was achieved with 82% yield, using a cost-effective and scalable methodology. Selective propionylation of the hydroxyl groups at C and C demonstrate the fact that this approach can be conveniently implemented in fine chemical industries.
Topics: Beclomethasone; Molecular Conformation; Stereoisomerism
PubMed: 34871605
DOI: 10.1016/j.steroids.2021.108948 -
Steroids Nov 2015In plants androstanes, estranes, pregnanes and corticoids have been described. Sometimes 17β-estradiol, androsterone, testosterone or progesterone were summarized as... (Review)
Review
In plants androstanes, estranes, pregnanes and corticoids have been described. Sometimes 17β-estradiol, androsterone, testosterone or progesterone were summarized as sex hormones. These steroids influence plant development: cell divisions, root and shoot growth, embryo growth, flowering, pollen tube growth and callus proliferation. First reports on the effect of applicated substances and of their endogenous occurrence date from the early twenties of the last century. This caused later on doubts on the identity of the compounds. Best investigated is the effect of progesterone. Main steps of the progesterone biosynthetic pathway have been analyzed in Digitalis. Cholesterol-side-chain-cleavage, pregnenolone and progesterone formation as well as the stereospecific reduction of progesterone are described and the corresponding enzymes are presented. Biosynthesis of androstanes, estranes and corticoids is discussed. Possible progesterone receptors and physiological reactions on progesterone application are reviewed.
Topics: Plant Development; Plant Growth Regulators; Plant Physiological Phenomena; Plants; Pregnanes; Progesterone
PubMed: 26282543
DOI: 10.1016/j.steroids.2015.08.007 -
Journal of Neuroendocrinology Feb 2022Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the... (Review)
Review
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
Topics: Neurosteroids; Pregnanolone; Progesterone
PubMed: 34189791
DOI: 10.1111/jne.12996 -
Psychopharmacology Sep 2014The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects... (Review)
Review
RATIONALE
The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years.
OBJECTIVES
New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update.
RESULTS
Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca(2+)- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~ 2 pM) direct enhancement of intracellular Ca(2+) levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed.
CONCLUSIONS
PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification.
Topics: Animals; Humans; Neuronal Plasticity; Neurotransmitter Agents; Nootropic Agents; Pregnanolone; Synapses
PubMed: 24997854
DOI: 10.1007/s00213-014-3643-x -
Phytochemistry Jun 2023Phytochemical investigation on the stems of Strophanthus divaricatus led to the isolation of four undescribed cardiac glycosides and one undescribed C pregnane, together...
Phytochemical investigation on the stems of Strophanthus divaricatus led to the isolation of four undescribed cardiac glycosides and one undescribed C pregnane, together with eleven known steroids. Their structures were elucidated by a comprehensive analysis of HRESIMS, 1D and 2D NMR spectra. The absolute configuration of 16 was determined by comparison of the experimental and computed ECD spectra. Compounds 1-13 and 15 displayed potent to significant cytotoxicity against human cancer cell lines K562, SGC-7901, A549 and HeLa with IC values of 0.02-16.08, 0.04-23.13, 0.06-22.31 and 0.06-15.13 μM, respectively.
Topics: Humans; Strophanthus; Glycosides; Pregnanes; Antineoplastic Agents; Cell Line, Tumor; Molecular Structure
PubMed: 37019169
DOI: 10.1016/j.phytochem.2023.113668