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Clinical Chemistry Jun 2023
Topics: Humans; Hydrocortisone; Prednisolone; Kidney Transplantation
PubMed: 37258489
DOI: 10.1093/clinchem/hvad040 -
Cellular and Molecular Neurobiology Jan 2022Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better... (Review)
Review
Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Mice; Motor Neurons; Neuroprotective Agents; Pregnanolone; Progesterone; Spinal Cord
PubMed: 34138412
DOI: 10.1007/s10571-021-01118-y -
Journal of Natural Products Mar 2023subsp. , more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for...
subsp. , more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel -pregnane aglycones cynavimigenin A () and cynaviminoside A (), together with new pregnane glycosides cynaviminoside B () and cynavimigenin B (). Cynavimigenin B () contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the -pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and bioassays, suggesting that - are not associated with the reported toxicity of this plant species.
Topics: Humans; Cynanchum; Caustics; Acetylcholinesterase; Australia; Glycosides; Pregnanes; Plant Roots
PubMed: 36795946
DOI: 10.1021/acs.jnatprod.2c01037 -
Molecules (Basel, Switzerland) Sep 2022Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, species are indicated to treat asthma...
Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, species are indicated to treat asthma and skin infections, their anti-inflammatory potential and wound healing properties are also reported in the literature. Concerning their chemical composition, this group of plants is a conspicuous producer of pregnane glycosides. is an endemic species from the Brazilian semiarid region not studied by any phytochemical methods. In view of the medicinal potential of species, this study aimed to isolate new pregnane glycosides from . To achieve this main goal, modern chromatography techniques were employed. Five new pregnane glycosides, dardanols A-E, were isolated from the roots of by HPLC. Their structures were determined using extensive 1D and 2D-NMR and mass spectrometry (MS and HRESIMS) data. The cytotoxicity and the anti-inflammatory potential of these compounds were evaluated. The first was evaluated by measuring proinflammatory cytokines and nitric oxide production by stimulated macrophages. Dardanols were able to inhibit the production of nitric oxide and reduce IL-1β and TNF-α. The current work demonstrates the chemodiversity of Brazilian semiarid species and contributes to amplifying knowledge about the biological potential of the genus.
Topics: Anti-Inflammatory Agents; Apocynaceae; Glycosides; Nitric Oxide; Plant Extracts; Plants; Pregnanes; Tumor Necrosis Factor-alpha
PubMed: 36144723
DOI: 10.3390/molecules27185992 -
Respirology (Carlton, Vic.) Nov 2018
Topics: Connective Tissue Diseases; Humans; Lung Diseases, Interstitial; Methylprednisolone; Prednisone; Tacrolimus
PubMed: 30129264
DOI: 10.1111/resp.13386 -
ACS Chemical Neuroscience May 2023Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid...
Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid metabolism on neuroactive steroid signaling is not well understood. To begin to address this question, we set out to identify major metabolites of a neuroprotective synthetic steroid 20-oxo-5β-pregnan-3α-yl l-glutamyl 1-ester (pregnanolone glutamate, PAG) and characterize their effects on GABA and NMDA receptors (GABARs, NMDARs) and their influence on zebrafish behavior. Gas chromatography-mass spectrometry was used to assess concentrations of PAG and its metabolites in the hippocampal tissue of juvenile rats following intraperitoneal PAG injection. PAG is metabolized in the peripheral organs and nervous tissue to 20-oxo-17α-hydroxy-5β-pregnan-3α-yl l-glutamyl 1-ester (17-hydroxypregnanolone glutamate, 17-OH-PAG), 3α-hydroxy-5β-pregnan-20-one (pregnanolone, PA), and 3α,17α-dihydroxy-5β-pregnan-20-one (17-hydroxypregnanolone, 17-OH-PA). Patch-clamp electrophysiology experiments in cultured hippocampal neurons demonstrate that PA and 17-OH-PA are potent positive modulators of GABARs, while PAG and 17-OH-PA have a moderate inhibitory effect at NMDARs. PAG, 17-OH-PA, and PA diminished the locomotor activity of zebrafish larvae in a dose-dependent manner. Our results show that PAG and its metabolites are potent modulators of neurotransmitter receptors with behavioral consequences and indicate that neurosteroid-based ligands may have therapeutic potential.
Topics: Rats; Animals; Pregnanolone; Receptors, N-Methyl-D-Aspartate; Zebrafish; Glutamic Acid; Esters; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 37126803
DOI: 10.1021/acschemneuro.3c00131 -
Clinical Pharmacokinetics Jan 2020SAGE-217, a novel γ-aminobutyric acid A (GABA) receptor positive allosteric modulator, was evaluated in phase I, double-blind, placebo-controlled, single ascending dose... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
SAGE-217, a novel γ-aminobutyric acid A (GABA) receptor positive allosteric modulator, was evaluated in phase I, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) studies to assess the safety and pharmacokinetics (PK) of SAGE-217 following administration as an oral solution.
METHODS
In the SAD study, subjects were randomized 6:2 to a single dose of SAGE-217 or placebo. Doses ranged from 0.25 to 66 mg across nine cohorts. In the MAD study, subjects were randomized 9:3 and received SAGE-217 (15, 30, or 35 mg) or placebo once daily for 7 days. In both studies, PK, maximum tolerated dose (MTD; against predetermined criteria), safety, and tolerability were assessed.
RESULTS
A total of 108 healthy volunteers enrolled in the studies-72 subjects in the SAD study and 36 subjects in the MAD study. SAGE-217 was orally bioavailable, with a terminal-phase half-life of 16-23 h and a t of approximately 1 h. The MTDs for the oral solution of SAGE-217 in the SAD and MAD studies were determined to be 55 and 30 mg daily, respectively. In both studies, SAGE-217 was generally well tolerated, and no serious adverse events (SAEs) were reported. Most AEs were mild, dose-dependent, transient, occurred around the t, and related to drug pharmacology.
CONCLUSIONS
SAGE-217 was generally well tolerated, and its PK profile was well characterized. Based on this profile, SAGE-217 has been advanced into multiple phase II clinical programs and pivotal studies of major depressive disorder and postpartum depression.
Topics: Administration, Oral; Adult; Allosteric Regulation; Depression, Postpartum; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; GABA-A Receptor Agonists; Healthy Volunteers; Humans; Male; Middle Aged; Pharmacology, Clinical; Placebos; Pregnanes; Pyrazoles; Safety
PubMed: 31338688
DOI: 10.1007/s40262-019-00801-0 -
Journal of Natural Products Jun 2019Three new C pregnane steroids, chonemorphols A-C (1, 3, and 4), 11 new C steroidal glycosides, chonemorphosides A-K (2 and 5-14), and 11 known compounds (15-25) were...
Three new C pregnane steroids, chonemorphols A-C (1, 3, and 4), 11 new C steroidal glycosides, chonemorphosides A-K (2 and 5-14), and 11 known compounds (15-25) were obtained from the vines and leaves of Chonemorpha megacalyx Pierre. Their structures were established using extensive spectroscopic data. The X-ray crystallographic data of 1 and 3 permitted definition of their absolute configurations. Notably, 1 and 2 possessed an uncommon 6/5/6/5/5-fused steroidal ring system. Compound 7 displayed significant cytotoxicity against several cancer cell lines with IC values of 2.0-3.6 μM.
Topics: Apocynaceae; Cell Line, Tumor; Glycosides; Humans; Molecular Structure; Plant Leaves; Pregnanes
PubMed: 31148449
DOI: 10.1021/acs.jnatprod.9b00013 -
Drug Design, Development and Therapy 2016The introduction of modified-release (MR) prednisone adds a drug with encouraging potential to the armamentarium of the rheumatologist. In particular, for patients... (Review)
Review
The introduction of modified-release (MR) prednisone adds a drug with encouraging potential to the armamentarium of the rheumatologist. In particular, for patients experiencing a reduced quality of life due to prolonged morning stiffness, it is a promising therapeutic approach. Two clinical trials and one open-label observational study investigated the effectiveness of MR prednisone in reducing rheumatoid arthritis-related morning stiffness for both new and current users of corticosteroids. The efficacy and safety of MR prednisone use in rheumatoid arthritis patients are reviewed in this article. This includes pivotal trials as well as pathophysiological considerations and clinical implications.
Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Humans; Prednisone
PubMed: 27022244
DOI: 10.2147/DDDT.S87792 -
International Journal of Molecular... Dec 2023C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation...
C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C steroids was more efficient than C11-oxy C steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear-C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent-C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as "inactive" C11-oxy steroids, suggesting novel regulatory tiers.
Topics: Humans; Progesterone; Receptors, Progesterone; Androgens; Progestins; HEK293 Cells; Steroids; Receptors, Steroid; 11-beta-Hydroxysteroid Dehydrogenases
PubMed: 38203272
DOI: 10.3390/ijms25010101