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British Journal of Pharmacology Oct 2023GABA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may...
BACKGROUND AND PURPOSE
GABA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate.
EXPERIMENTAL APPROACH
New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABA receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations.
KEY RESULTS
All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six- (compound 5) or five-membered heterocyclic ring (compound 6) on C-21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABA receptor, are the most likely cause of the distinctive functional profiles.
CONCLUSIONS AND IMPLICATIONS
Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next-generation GABA receptor drug design and development.
Topics: Receptors, GABA-A; Pregnenolone; gamma-Aminobutyric Acid
PubMed: 37194503
DOI: 10.1111/bph.16143 -
Experimental Physiology Sep 2023What is the topic of this review? The contribution of gut microbial signalling to skeletal muscle maintenance and development and identification of potential therapeutic... (Review)
Review
NEW FINDINGS
What is the topic of this review? The contribution of gut microbial signalling to skeletal muscle maintenance and development and identification of potential therapeutic targets in progressive muscle degenerative diseases such as Duchenne muscular dystrophy. What advances does it highlight? Gut microbe-derived metabolites are multifaceted signalling molecules key to muscle function, modifying pathways contributing to skeletal muscle wasting, making them a plausible target for adjunctive therapy in muscular dystrophy.
ABSTRACT
Skeletal muscle is the largest metabolic organ making up ∼50% of body mass. Because skeletal muscle has both metabolic and endocrine properties, it can manipulate the microbial populations within the gut. In return, microbes exert considerable influence on skeletal muscle via numerous signalling pathways. Gut bacteria produce metabolites (i.e., short chain fatty acids, secondary bile acids and neurotransmitter substrates) that act as fuel sources and modulators of inflammation, influencing host muscle development, growth and maintenance. The reciprocal interactions between microbes, metabolites and muscle establish a bidirectional gut-muscle axis. The muscular dystrophies constitute a broad range of disorders with varying disabilities. In the profoundly debilitating monogenic disorder Duchenne muscular dystrophy (DMD), skeletal muscle undergoes a reduction in muscle regenerative capacity leading to progressive muscle wasting, resulting in fibrotic remodelling and adipose infiltration. The loss of respiratory muscle in DMD culminates in respiratory insufficiency and eventually premature death. The pathways contributing to aberrant muscle remodelling are potentially modulated by gut microbial metabolites, thus making them plausible targets for pre- and probiotic supplementation. Prednisone, the gold standard therapy for DMD, drives gut dysbiosis, inducing a pro-inflammatory phenotype and leaky gut barrier contributing to several of the well-known side effects associated with chronic glucocorticoid treatment. Several studies have observed that gut microbial supplementation or transplantation exerts positive effects on muscle, including mitigating the side effects of prednisone. There is growing evidence in support of the potential for an adjunctive microbiota-directed regimen designed to optimise gut-muscle axis signalling, which could alleviate muscle wasting in DMD.
Topics: Animals; Mice; Muscular Dystrophy, Duchenne; Prednisone; Muscle, Skeletal; Glucocorticoids; Inflammation; Mice, Inbred mdx
PubMed: 37269541
DOI: 10.1113/EP091063 -
The Journal of Dermatological Treatment Dec 2023Psoriasis is a chronic skin disease, and topical sequential therapy with a combination of calcipotriol and calcipotriol betamethasone is currently approved topical...
BACKGROUND
Psoriasis is a chronic skin disease, and topical sequential therapy with a combination of calcipotriol and calcipotriol betamethasone is currently approved topical treatment. However, the exact mechanism by which this treatment regimen relieves psoriasis is unknown.
METHOD
We assembled a cohort of 65 psoriasis patients and divided post-treatment cohort into responder group and non-responder group according to the Psoriasis Area Severity Index (PASI) score after 12-week treatment. We measured the expression levels of proteins in collected 130 serum samples using our in-depth proteomics platform with a data-independent acquisition mass spectrometer and antibody microarray. We performed bioinformatics analyses of the biologic processes and signaling pathways that were changed in the responder group and constructed a proteomics landscape of psoriasis pathogenesis response to treatment. We then validated the biomarkers of disease severity in an independent cohort of 88 samples using an enzyme-linked immunosorbent assay.
RESULTS
We first identified 174 differentially expressed proteins (DEPs) for comparative analysis of proteins between responders and non-responders at baseline ( < 0.05). Then pathway analysis showed that the responders focused more on signaling molecules and interaction, complement and coagulation cascades, whereas the non-responders more on signal transduction and IL-17 signaling pathways. We further identified four candidate biomarkers (COLEC11, C1QA, BNC2, ITIH4) response to treatment. We also found 125 DEPs ( < 0.05) after treatment compared with before treatment in responder group. Pathway analysis showed an enrichment in pathways related to complement and coagulation cascades, phagosome, ECM-receptor interaction, cholesterol metabolism, vitamin digestion and absorption. CD14 was validated as potential biomarkers for the disease severity of psoriasis and treatment targets.
CONCLUSION
In this work, we analyzed the response to topical sequential therapy and finally identified four biomarkers. Additionally, we found that topical sequential therapy may alleviate psoriasis by regulating lipid metabolism and modulating the immune response by affecting the complement activation process.
Topics: Humans; Proteomics; Psoriasis; Betamethasone; Biomarkers; Computational Biology
PubMed: 37621164
DOI: 10.1080/09546634.2023.2248318 -
Redox Report : Communications in Free... Dec 2023Primary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are...
Primary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are gradually lost after isolation. Here, we illustrated that fatty acid metabolism is the major compromised metabolic process in isolated primary hepatocytes, along with drastically decreased GSH and ROS content, while lipid peroxidation is increased. Gain- and loss-of-function studies revealed that Slc7a11 expression is critical in maintaining fatty acid metabolism and facilitating hormone-induced fatty acid metabolic events, which is synergistic with dexamethasone treatment. Intriguingly, Slc7a11 expression and dexamethasone treatment cooperatively upregulated AKT and AMPK signaling and mitochondrial complex expression in primary hepatocytes. Furthermore, direct treatment with reduced GSH or inhibition of ferroptosis is sufficient to drive protective effects on fatty acid metabolism in primary hepatocytes. Our results demonstrate that Slc7a11 expression in isolated primary hepatocytes induces GSH production, which protects against ferroptosis, to increase fatty acid metabolic gene expression, AKT and AMPK signaling and mitochondrial function in synergy with dexamethasone treatment, thereby efficiently preserving primary hepatocyte metabolic signatures, thus providing a promising approach to better reserve primary hepatocyte metabolic activities after isolation to potentially improve the understanding of liver biological functions from studies using primary hepatocytes.
Topics: AMP-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Hepatocytes; Fatty Acids; Dexamethasone; Glutathione
PubMed: 37750478
DOI: 10.1080/13510002.2023.2260646 -
Systematic Reviews Jul 2023Self-administered depot medroxyprogesterone acetate subcutaneous injectable contraception (DMPA-SC) is registered in many countries. It shows great potential for... (Review)
Review
BACKGROUND
Self-administered depot medroxyprogesterone acetate subcutaneous injectable contraception (DMPA-SC) is registered in many countries. It shows great potential for improving contraceptive access, continuation, and autonomy. However, there are challenges in rolling out this new efficacious intervention, and major implementation problems have been encountered during scale-up.
OBJECTIVE
To describe the implementation strategies to scale up self-administered DMPA-SC and the barriers, facilitators, and outcomes of these programs.
METHOD
Recent guidelines, including the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews, were used to design and report this review. An article or report was eligible for inclusion if it reported interventions that could scale up self-administered DMPA-SC implementation or its facilitators, barriers, or outcomes. We searched six electronic databases and the grey literature for eligible articles and reports. Two reviewers independently screened the document titles, abstracts, and full texts to identify eligible documents. Data were extracted using structured forms. Using the Effective Practice and Organization of Care (EPOC) taxonomy of health systems framework for thematic analysis, data were presented in a narrative approach.
RESULTS
Of the 755 retrieved documents, 34 were included in this review. Most of the documents included were multi-country reports (n = 14), and all documents were published within the last 5 years (2018-2021). This review identified documents that reported interventions in all EPOC domains. The most-reported interventions were: task-sharing amongst health workforce cadres, engaged leadership, encouraging policies, training and education, DMPA-SC demand generation, integration into existing programs, improved funding mechanisms, collaboration with development partners, and supply chain strengthening. The main barriers were suboptimal funding, inadequate human resources, and poor logistics supply of DMPA-SC. There was minimal evidence of scale-up outcomes.
CONCLUSION
This scoping review reported a wide range of interventions employed by countries and programs to scale up DMPA-SC self-administration but minimal evidence of the scale-up outcomes. Evidence from this review can help design better programs that improves access to quality family planning services to achieve the Sustainable Development Goals (SDG) targets 3.7. However, efforts should focus on rigorous implementation research that assess scaled up self-administered DMPA-SC interventions and report their outcomes.
REGISTRATION
The protocol for this review was registered in the protocols.io repository ( https://www.protocols.io/view/a-protocol-for-a-scoping-review-of-implementation-x54v9yemmg3e/v1 ).
Topics: Female; Humans; Contraception; Contraceptive Agents, Female; Injections, Subcutaneous; Medroxyprogesterone Acetate; Self Administration
PubMed: 37403147
DOI: 10.1186/s13643-023-02216-2 -
Reproductive Sciences (Thousand Oaks,... Nov 2023Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA...
Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA cases are of unknown etiology. Our previous study found that the decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA) had low expression levels of serum and glucocorticoid-induced protein kinase (SGK) 1. Endometrial decidualization is a key link in the early stage of pregnancy and is crucial to the development and maintenance of pregnancy. Decidualization is the proliferation and differentiation of endometrial stromal cells into deciduals, which involves a complex physiological process such as ovarian steroid hormones (estrogen, progesterone, prolactin, etc.), growth factors, and intercellular signaling. The binding of estrogen and its receptor stimulates the synthesis of endometrial deciduating markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP-1), which mediates the occurrence of decidualization. Among them, SGK1/ENaC is a signaling pathway closely related to decidualization. The purpose of this study was to further investigate the expression of SGK1 and decidualization-related molecules in the decidual tissue of URSA patients and to explore the potential mechanism of SGK1's protective effect in URSA patients and in mouse models. Decidual tissue samples from 30 URSA patients and 30 women who actively terminated pregnancy were collected, and a URSA mouse model was established and treated with dydrogesterone. Expression levels of SGK1 and its signaling pathway-related proteins (p-Nedd4-2, 14-3-3 protein and ENaC-a), estrogen and progesterone receptors (ERβ, PR), and decidualization markers (PRLR, IGFBP-1) were assessed. Our study found that SGK1, p-Nedd4-2, 14-3-3 proteins, and ENaC-a expression levels were reduced in the decidual tissue, the SGK1/ENaC signaling pathway was inhibited, and the expression levels of the decidualization markers PRLR and IGFBP-1 were downregulated in the URSA group compared with the controls. Additionally, the concentrations of E, P, and PRL in the serum of mice were decreased in the URSA group compared with the controls. However, SGK1/ENaC pathway-related proteins, estrogen and progesterone and their receptors, and decidualization-related molecules were upregulated by dydrogesterone. These data suggest that estrogen and progesterone can induce decidualization by activating the SGK1/ENaC signaling pathway; disruption of this pathway can lead to the development of URSA. Dydrogesterone can increase the expression level of SGK1 protein in decidual tissue.
Topics: Humans; Pregnancy; Female; Mice; Animals; Progesterone; Decidua; Insulin-Like Growth Factor Binding Protein 1; Abortion, Spontaneous; Prolactin; Dydrogesterone; Signal Transduction; Estrogens; Abortion, Habitual; Stromal Cells
PubMed: 37280474
DOI: 10.1007/s43032-023-01273-1 -
Polish Archives of Internal Medicine Dec 2023Resistant hypertension is defined as not achieving sufficient control of blood pressure (BP), that is, maintaining BP values equal to or above 140/90 mm Hg when using 3...
Resistant hypertension is defined as not achieving sufficient control of blood pressure (BP), that is, maintaining BP values equal to or above 140/90 mm Hg when using 3 antihypertensive drugs, including diuretics, properly combined and at maximum doses. The uncontrolled treated hypertension should be confirmed in out‑of‑office BP measurements, preferably with 24‑hour ambulatory BP monitoring. Demographic and clinical characteristics indicate that patients with resistant hypertension are older than the general population of patients with arterial hypertension and more often suffer from comorbidities. When resistant hypertension is suspected, it is necessary to assess whether optimal pharmacotherapy has been prescribed, including appropriate combinations of antihypertensive drugs and diuretics at appropriate doses. It is also important to exclude parallel use of drugs that may have unfavorable interactions leading to an increase in BP. A common cause of pseudoresistant hypertension is a patient's failure to comply with therapeutic recommendations, including a lack of lifestyle changes and nonadherence to the prescribed medication regimen. An important step in management of resistant hypertension is targeted screening with diagnostic tests for secondary hypertension. Expanding of the drug therapy beyond a 3‑drug regimen should include a mineralocorticoid receptor antagonist, in particular spironolactone. In selected patients, device‑based hypertension treatment might be considered.
Topics: Humans; Antihypertensive Agents; Hypertension; Diuretics; Blood Pressure; Spironolactone
PubMed: 38088817
DOI: 10.20452/pamw.16624 -
The Journal of Clinical Endocrinology... Oct 2023There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be...
CONTEXT
There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications.
OBJECTIVE
We aimed to identify early, first-trimester prediction markers for GDM.
METHODS
The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55 randomly selected control and 55 women who developed GDM later.
RESULTS
Pregnant women who developed GDM later during the pregnancy were older and had higher body mass index. The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity, testosterone, cortisone, 21-deoxycortisol; soluble urokinase plasminogen activator receptor, dehydroepiandrosterone sulfate, dihydrotestosterone, cortisol, and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model, we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR).
CONCLUSION
Based on these measurements, we accurately predict the development of later-onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.
Topics: Female; Humans; Pregnancy; Cortisone; Desoxycorticosterone; Diabetes, Gestational; Fructosamine; Hydrocortisone; Pregnancy Trimester, First; Case-Control Studies
PubMed: 37247379
DOI: 10.1210/clinem/dgad301 -
Frontiers in Endocrinology 2023To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.
OBJECTIVE
To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.
METHODS
The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed.
RESULTS
Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports.
CONCLUSION
Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT02180217.
Topics: Humans; Pituitary ACTH Hypersecretion; Hydrocortisone; Quality of Life; Adrenocortical Hyperfunction
PubMed: 37680892
DOI: 10.3389/fendo.2023.1236465 -
Nutrients Jul 2023Emerging science shows that probiotic intake may impact stress and mental health. We investigated the effect of a 6-week intervention with (1 × 10 CFU/daily) on... (Randomized Controlled Trial)
Randomized Controlled Trial
Emerging science shows that probiotic intake may impact stress and mental health. We investigated the effect of a 6-week intervention with (1 × 10 CFU/daily) on stress-related psychological and physiological parameters in 45 healthy adults with mild-to-moderate stress using a randomized, placebo-controlled, two-arm, parallel, double-blind design. The main results showed that supplementation with the probiotic significantly reduced the perceived stress and improved the subjective sleep quality score compared to placebo. Comparing the two groups, momentary subjective assessments concomitant to the Maastricht Acute Stress Test revealed a lower amount of pain experience in the probiotic group and a higher amount of relief at the end of the procedure in the placebo group, reflected by higher scores in the positive affect state. The awakening of the salivary cortisol response was not affected by the intervention, yet the reduction observed in the salivary cortisol stress response post-intervention was higher in the placebo group than the probiotic group. Multivariate analysis further indicated that a reduction in perceived stress correlated with a reduction in anxiety, in depression, and in the cortisol awakening response after the 6-week intervention. This exploratory trial provides promising insights into to reduce perceived stress in a healthy population and supports the potential of nutritional solutions including probiotics to improve mental health.
Topics: Humans; Adult; Hydrocortisone; Bifidobacterium; Probiotics; Bifidobacterium longum; Stress, Psychological; Double-Blind Method
PubMed: 37513541
DOI: 10.3390/nu15143122