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International Journal of Molecular... May 2021Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the... (Review)
Review
Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.
Topics: Adaptation, Physiological; Animals; Antidepressive Agents; Chronic Disease; Corticosterone; Depressive Disorder, Major; Feedback, Physiological; Female; GABA-A Receptor Agonists; Humans; Hypothalamo-Hypophyseal System; Male; Models, Biological; Pituitary-Adrenal System; Pregnanolone; Receptors, GABA-A; Sex Characteristics; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological; gamma-Aminobutyric Acid
PubMed: 34071053
DOI: 10.3390/ijms22115495 -
Sovremennye Tekhnologii V Meditsine 2021This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the... (Review)
Review
This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the pharmacological action of progestins have been studied. Data on the clinical use of gestagens by nosological groups are presented. Particular attention is paid to progesterone, megestrol acetate, medroxyprogesterone acetate due to broadening of their spectrum of action. The possibilities of using gestagens as neuroprotectors, immunomodulators, and chemosensitizers are considered.
Topics: Medroxyprogesterone; Medroxyprogesterone Acetate; Megestrol; Progesterone; Progestins
PubMed: 34513071
DOI: 10.17691/stm2021.13.1.11 -
The Journal of Neuroscience : the... Mar 2021NMDARs are ligand-gated ion channels that cause an influx of Na and Ca into postsynaptic neurons. The resulting intracellular Ca transient triggers synaptic plasticity....
NMDARs are ligand-gated ion channels that cause an influx of Na and Ca into postsynaptic neurons. The resulting intracellular Ca transient triggers synaptic plasticity. When prolonged, it may induce excitotoxicity, but it may also activate negative feedback to control the activity of NMDARs. Here, we report that a transient rise in intracellular Ca (Ca challenge) increases the sensitivity of NMDARs but not AMPARs/kainate receptors to the endogenous inhibitory neurosteroid 20-oxo-5β-pregnan-3α-yl 3-sulfate and to its synthetic analogs, such as 20-oxo-5β-pregnan-3α-yl 3-hemipimelate (PAhPim). In cultured hippocampal neurons, 30 μm PAhPim had virtually no effect on NMDAR responses; however, following the Ca challenge, it inhibited the responses by 62%; similarly, the Ca challenge induced a 3.7-fold decrease in the steroid IC on recombinant GluN1/GluN2B receptors. The increase in the NMDAR sensitivity to PAhPim was dependent on three cysteines (C849, C854, and C871) located in the carboxy-terminal domain of the GluN2B subunit, previously identified to be palmitoylated (Hayashi et al., 2009). Our experiments suggested that the Ca challenge induced receptor depalmitoylation, and single-channel analysis revealed that this was accompanied by a 55% reduction in the probability of channel opening. Results of modeling indicate that receptor palmitoylation promotes anchoring of the GluN2B subunit carboxy-terminal domain to the plasma membrane and facilitates channel opening. Depalmitoylation-induced changes in the NMDAR pharmacology explain the neuroprotective effect of PAhPim on NMDA-induced excitotoxicity. We propose that palmitoylation-dependent changes in the NMDAR sensitivity to steroids serve as an acute endogenous mechanism that controls NMDAR activity. There is considerable interest in negative allosteric modulators of NMDARs that could compensate for receptor overactivation by glutamate or gain-of-function mutations in neurodevelopmental disorders. By a combination of electrophysiological, pharmacological, and computational techniques we describe a novel feedback mechanism regulating NMDAR activity. We find that a transient rise in intracellular Ca increases NMDAR sensitivity to inhibitory neurosteroids in a process dependent on GluN2B subunit depalmitoylation. These results improve our understanding of the molecular mechanisms of steroid action at the NMDAR and indeed of the basic properties of this important glutamate-gated ion channel and may aid in the development of therapeutics for treating neurologic and psychiatric diseases related to overactivation of NMDARs without affecting normal physiological functions.
Topics: Animals; HEK293 Cells; Hippocampus; Humans; Lipoylation; Male; Neuroprotection; Pregnanes; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate
PubMed: 33526476
DOI: 10.1523/JNEUROSCI.2654-20.2021 -
Frontiers in Public Health 2022It is difficult to study the intestinal damage induced by space radiation to astronauts directly, and few prediction models exist. However, we can simulate it in...
It is difficult to study the intestinal damage induced by space radiation to astronauts directly, and few prediction models exist. However, we can simulate it in patients with pelvic tumor radiotherapy (RT). Radiation-induced intestinal injury (RIII) is common in cancer patients who receieved pelvic and abdominal RT. We dynamically analyzed gut microbiota and metabolites alterations in 17 cervical and endometrial cancer patients after pelvic RT. In patients who later developed grade 2 RIII, dysbiosis of gut microbiota and metabolites were observed. Univariate analysis showed that and ptilosteroid A were related to the occurrence of grade 2 RIII. Notably, a strong positive correlation between gut bacteria relative abundance and gut metabolite ptilosteroid A expression was found. Furthermore, combinations of and ptilosteroid A could provide good diagnostic markers for grade 2 RIII. In conclusion, gut bacteria and its related metabolite ptilosteroid A may collaboratively predict RIII, and could be diagnostic biomarkers for RIII and space radiation injury.
Topics: Bacteria; Dysbiosis; Gastrointestinal Microbiome; Humans; Pregnanes; Radiation Injuries
PubMed: 35419331
DOI: 10.3389/fpubh.2022.862598 -
Molecules (Basel, Switzerland) Mar 2023The ethnobotanical plant has been used for hundreds of years for Dai people in Yunnan Province, China. Previously, chemical investigations on this plant have revealed...
The ethnobotanical plant has been used for hundreds of years for Dai people in Yunnan Province, China. Previously, chemical investigations on this plant have revealed that pregnane glycosides were the main biological constituents. Nine new pregnane glycosides, marsdeosides A-I (-), were isolated from cultivated dried stems of the medicinal plant in this study. The structures were analyzed by extensive spectroscopic analysis, including 1D, 2D NMR, HRESIMS, and IR spectroscopic analysis. The absolute configurations of the sugar moieties were identified by comparing the values and specific optical rotations with those of the commercially available standard samples and the data reported in the literature. Marsdeosides A () featured an unusual 8,14--pregnane skeleton. Compounds , , and showed activity against nitric oxide production in lipopolysaccharide-activated macrophage RAW264.7, with IC values of 37.5, 38.8, and 42.8 μM (L-NMMA was used as a positive control, IC 39.3 μM), respectively. This study puts the knowledge of the chemical profile of the botanical plant one step forward and, thereby, promotes the sustainable utilization of the resources of traditional folk medicinal plants.
Topics: Humans; Plants, Medicinal; Marsdenia; China; Pregnanes; Glycosides
PubMed: 36985677
DOI: 10.3390/molecules28062705 -
Journal of Enzyme Inhibition and... Dec 2019Synthetic progesterone and 5α/β-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two...
In vitro modulation of multidrug resistance by pregnane steroids and in vivo inhibition of tumour development by 7α-OBz-11α(R)-OTHP-5β-pregnanedione in K562/R7 and H295R cell xenografts.
Synthetic progesterone and 5α/β-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma cells, both resistant to doxorubicin. The maximal effect in both cell lines was observed for 7α-O-benzoyloxy,11α(R)-O-tetrahydropyranyloxy-5β-pregnane-3,20-dione 4. This modulator co-injected with doxorubicin significantly decreased the tumour size and increased the survival time of immunodeficient mice xenografted with NCI-H295R or K562/R7 cells.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, SCID; Molecular Conformation; Neoplasms, Experimental; Pregnanes; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 30777494
DOI: 10.1080/14756366.2019.1575825 -
Scientific Reports May 2023Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of...
Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of chronic stress on tissue levels of corticosterone (CORT), progesterone (PROG), 11-deoxycorticosterone (11DOC) and 11-dehydrocorticosterone (11DHC) and on gut microbiota, which may reshape the stress response. Male BALB/c mice, liquid chromatography-tandem mass spectrometry and 16S RNA gene sequencing were used to screen steroid levels and fecal microbiome, respectively. Stress induced greater increase of CORT in the brain, liver, and kidney than in the colon and lymphoid organs, whereas 11DHC was the highest in the colon, liver and kidney and much lower in the brain and lymphoid organs. The CORT/11DHC ratio in plasma was similar to the brain but much lower in other organs. Stress also altered tissue levels of PROG and 11DOC and the PROG/11DOC ratio was much higher in lymphoid organs that in plasma and other organs. Stress impacted the β- but not the α-diversity of the gut microbiota and LEfSe analysis revealed several biomarkers associated with stress treatment. Our data indicate that social defeat stress modulates gut microbiota diversity and induces tissue-dependent changes in local levels of corticosteroids, which often do not reflect their systemic levels.
Topics: Mice; Animals; Male; Corticosterone; Progesterone; Desoxycorticosterone; Steroids; Brain; Chromatography, Liquid
PubMed: 37142643
DOI: 10.1038/s41598-023-34395-2 -
Biomolecules Apr 2023: Allopregnanolone is one of the most studied neuroactive steroids; yet, despite its relevance to neuropsychiatric research, it is not known how it, as well as its ratio...
: Allopregnanolone is one of the most studied neuroactive steroids; yet, despite its relevance to neuropsychiatric research, it is not known how it, as well as its ratio to progesterone, varies across all six subphases of the menstrual cycle. Two enzymes-5α-dihydroprogesterone and 5α-reductase-convert progesterone to allopregnanolone, and, based on immunohistochemical studies in rodents, the activity of 5α-reductase is considered the rate-limiting step in the formation of allopregnanolone. It is not clear, however, whether the same phenomenon is observed across to the menstrual cycle, and, if so, at what point this takes place. : Thirty-seven women completed the study during which they attended eight clinic visits across one menstrual cycle. We analyzed their allopregnanolone and progesterone serum concentrations using ultraperformance liquid chromatography-tandem mass spectrometry, and we implemented a validated method to realign the data from the original eight clinic study visits, following which we imputed the missing data. Hence, we characterized allopregnanolone concentrations, and the ratio of allopregnanolone:progesterone at six menstrual cycle subphases: (1) early follicular, (2) mid-follicular, (3) periovulatory, (4) early luteal, (5) mid-luteal, and (6) late luteal. : There were significant differences in allopregnanolone levels between (1) early follicular and early luteal, (2) early follicular and mid-luteal, (3) mid-follicular and mid-luteal, (4) periovulatory and mid-luteal, and (5) mid-luteal and late luteal. We detected a sharp drop in allopregnanolone:progesterone ratio in the early luteal subphase. Within the luteal subphase, the ratio was the lowest in the mid-luteal subphase. : Allopregnanolone concentrations are the most distinct, relative to the other subphases, in the mid-luteal subphase. The shape of the allopregnanolone trajectory across the cycle is similar to that of progesterone; however, the proportion of the two neuroactive steroid hormones is drastically different due to enzymatic saturation, which takes place at the start of the early luteal subphase, but continuing through, and peaking, in the mid-luteal subphase. Hence, the estimated activity of 5α-reductase decreases, but does not cease, at any point across the menstrual cycle.
Topics: Female; Animals; Progesterone; Pregnanolone; Menstrual Cycle
PubMed: 37189398
DOI: 10.3390/biom13040652 -
International Journal of Molecular... Jan 2021The peripheral zone (PZ) and transition zone (TZ) represent about 70% of the human prostate gland with each zone having differential ability to develop prostate cancer....
The peripheral zone (PZ) and transition zone (TZ) represent about 70% of the human prostate gland with each zone having differential ability to develop prostate cancer. Androgens and their receptor are the primary driving cause of prostate cancer growth and eventually castration-resistant prostate cancer (CRPC). De novo steroidogenesis has been identified as a key mechanism that develops during CRPC. Currently, there is very limited information available on human prostate tissue steroidogenesis. The purpose of the present study was to investigate steroid metabolism in human prostate cancer tissues with comparison between PZ and TZ. Human prostate cancer tumors were procured from the patients who underwent radical prostatectomy without any neoadjuvant therapy. Human prostate homogenates were used to quantify steroid levels intrinsically present in the tissues as well as formed after incubation with 2 µg/mL of 17-hydroxypregnenolone (17-OH-pregnenolone) or progesterone. A Waters Acquity ultraperformance liquid chromatography coupled to a Quattro Premier XE tandem quadrupole mass spectrometer using a C column was used to measure thirteen steroids from the classical and backdoor steroidogenesis pathways. The intrinsic prostate tissue steroid levels were similar between PZ and TZ with dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), pregnenolone and 17-OH-pregnenolone levels higher than the other steroids measured. Interestingly, 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one, and 5-pregnan-17-ol-3,20-dione formation was significantly higher in both the zones of prostate tissues, whereas, androstenedione, testosterone, DHT, and progesterone levels were significantly lower after 60 min incubation compared to the 0 min control incubations. The incubations with progesterone had a similar outcome with 5-pregnan-3,20-dione and 5-pregnan-3-ol-20-one levels were elevated and the levels of DHT were lower in both PZ and TZ tissues. The net changes in steroid formation after the incubation were more observable with 17-OH-pregnenolone than with progesterone. In our knowledge, this is the first report of comprehensive analyses of intrinsic prostate tissue steroids and precursor-driven steroid metabolism using a sensitive liquid chromatography-mass spectrometry assay. In summary, the PZ and TZ of human prostate exhibited similar steroidogenic ability with distinction in the manner each zone utilizes the steroid precursors to divert the activity towards backdoor pathway through a complex matrix of steroidogenic mechanisms.
Topics: Androstenedione; Androsterone; Chromatography, High Pressure Liquid; Humans; Male; Mass Spectrometry; Progesterone; Prostate; Prostatic Neoplasms; Steroids; Testosterone
PubMed: 33418978
DOI: 10.3390/ijms22020487 -
Asian Pacific Journal of Cancer... Jun 2021Nature has provided us with many pharmaceutical resources so far. Breast cancer shows an increasing trend in the world for the last decade and becomes one of five...
OBJECTIVE
Nature has provided us with many pharmaceutical resources so far. Breast cancer shows an increasing trend in the world for the last decade and becomes one of five leading causes of death. Among the plants, Melia azedarach L. has been used widely in traditional medicine for many ailments including breast cancer. Following our previous findings that the ethyl acetate fraction was the most active cytotoxic fraction against T47D cells, we aimed to isolate the cytotoxic compounds and further elucidate their apoptotic mechanisms.
METHODS
The compounds were isolated through a series of chromatography with cytotoxicity evaluations. Identification of the isolated compounds was achieved by intensive spectroscopic analysis such as NMR, MS, and IR spectra. Cytotoxicity was evaluated by MTT method using doxorubicin as a reference compound. The expression of apoptosis-related factors was quantified by flow cytometry and immunocytochemistry.
RESULTS
Two isomers of pregnane steroids with molecular weight 330.2087 (C21H30O3) were isolated from the EtOAc extract. Spectroscopic analysis revealed the structures as 17-ethylene-3,4-dihydroxy-14-methyl-18-norandrostene-16-one (1) and 17-ethylene-3,4-dihydroxy-5-pregnene-16-one (2), respectively. These compounds showed moderate cytotoxicity (IC50 172.9 and 62.2 µg/mL, respectively) comparable to doxorubicin (IC50 3.08 µg/mL). The execution of apoptosis may be related to the increase of the ratio of BAX/bcl-2 of the cells. Conclusion: The EtOAc fraction of Melia azedarach L. leaves and the isolated 5-pregnene-16-one steroids are promising reagents for breast cancer treatment by introducing apoptosis to tumor cells. However, further researches are required to highlight its safety and usage in vivo.
.Topics: Apoptosis; Breast Neoplasms; Doxorubicin; Female; Humans; Melia azedarach; Molecular Structure; Molecular Weight; Plant Leaves; Pregnanes; Steroids; Tumor Cells, Cultured
PubMed: 34181358
DOI: 10.31557/APJCP.2021.22.6.1967