Approaches to assessing 3β-hydroxysteroid dehydrogenase-1.

The enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), encoded by the gene HSD3B1, plays an essential role in the peripheral conversion of 3β-OH, Δ-steroids to 3-keto, Δ-steroids. In human physiology, the adrenal produces dehydroepiandrosterone (DHEA) and DHEA-sulfate, which are major precursors for the biosynthesis of potent androgens and estrogens. DHEA is converted by 3βHSD1 and subsequently is converted by steroid-5α-reductase to potent androgens or by aromatase to estrogens.

Elevated periprostatic venous testosterone correlates with prostate cancer progression after radical prostatectomy.

BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.

Factors Affecting Awareness About E-Health Services in Saudi Arabia.

Aim Telemedicine or using e-health applications was maximized during the COVID-19 pandemic. This study aimed to explore awareness and satisfaction with several e-health services provided by the Ministry of Health (MOH), including Seha, Moed, 937 Services, and Wasfati.  Methods A population-based social media survey assessed awareness and satisfaction with these applications.

Current and future prospective of pharmaceutical manufacturing in Saudi Arabia.

This observational descriptive study that was carried out with the objective of exploring the contribution of the local pharmaceutical industry to the Saudi drug security. Using a drug formulary provided from the Saudi Food and Drug Authority, containing all registered pharmaceutical products available in Saudi Arabia, we extracted information about drug class, drug type, country and place of manufacturing, shelf-life and price. Results showed that the majority of drugs in the market are manufactured in Europe (43.

Cancer-associated fibroblast-secreted glucosamine alters the androgen biosynthesis program in prostate cancer via HSD3B1 upregulation.

After androgen deprivation, prostate cancer frequently becomes castration resistant (CRPC), with intratumoral androgen production from extragonadal precursors that activate the androgen receptor pathway. 3β-Hydroxysteroid dehydrogenase-1 (3βHSD1) is the rate-limiting enzyme for extragonadal androgen synthesis, which together lead to CRPC. Here, we show that cancer-associated fibroblasts (CAFs) increased epithelial 3βHSD1 expression, induced androgen synthesis, activated the androgen receptor, and induced CRPC.

BMX controls 3βHSD1 and sex steroid biosynthesis in cancer.

Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis.

An Exploration of the Public's Attitude toward Antibiotic Use and Prescription in Light of the Recent Ministry of Health Regulations: A Cross-Sectional Study in the Kingdom of Saudi Arabia.

Background: Restricting antibiotic (AB) use with prescriptions and ensuring proper knowledge and attitudes toward AB use is important to reduce antibiotic resistance (ABR). To prevent resistanse problem, several countries have applied prescribing restrictions. Thus, the aim of this work was to re-evaluate the public knowledge and attitudes related to AB use in light of the recent Ministry of Health (MOH) restrictions on AB prescriptions.

Granulocyte Colony-Stimulating Factor Utilization and Prescribing Patterns in Cancer Patients: A Single Institution Experience of a Saudi Cancer Center.

Background Febrile neutropenia (FN), owing to its negative association with immune function and infectious complications, acts as a treatment-limiting factor in myelotoxic cancer chemotherapy. This study aimed to analyze the incidence of FN, utilization of granulocyte colony-stimulating factor (G-CSF) in patients who experienced FN, and its association with age and comorbidities. Methodology This retrospective study was conducted in a major tertiary hospital in Riyadh, Kingdom of Saudi Arabia.

Characteristics of mechanically ventilated COVID-19 patients in the Al-Ahsa Region of Saudi Arabia: a retrospective study with survival analysis.

Background: About 5-10% of coronavirus disease 2019 (COVID-19) infected patients require critical care hospitalization and a variety of respiratory support, including invasive mechanical ventilation. Several nationwide studies from Saudi Arabia have identified common comorbidities but none were focused on mechanically ventilated patients in the Al-Ahsa region of Saudi Arabia.

Objectives: Identify characteristics and risk factors for mortality in mechanically ventilated COVID-19 patients.

The role of serotonergic and catecholaminergic systems for possible antidepressant activity of apigenin.

Background And Objective: Although, the anti-depressant like effects of apigenin (APG) are documented in the literature, the underlying mechanism for exerting such an effect is still not clear. In this research, an attempt was made to determine the possible role of APG for antidepressant activity through serotonergic and catecholaminergic systems using standardized animal models.

Materials And Methods: The antidepressant property of APG was determine by involving tail suspension (TST) and modified forced swimming tests (MFST).

Epidemiological determinants for the spread of COVID-19 in Riyadh Province of Saudi Arabia.

Background And Objective: Coronavirus Disease 2019 (COVID-19) has affected millions of individuals all over the world. In addition to the patients' compelling indications, various sociodemographic characteristics were identified to influence infection complications. The purpose of this study was to assess the impact of the aforementioned parameters on the dissemination of COVID-19 among residents of Saudi Arabia's Riyadh region.

Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation.

Prostate cancer resistance to next-generation hormonal treatment with enzalutamide is a major problem and eventuates into disease lethality. Biologically active glucocorticoids that stimulate glucocorticoid receptor (GR) have an 11β-OH moiety, and resistant tumors exhibit loss of 11β-HSD2, the oxidative (11β-OH → 11-keto) enzyme that normally inactivates glucocorticoids, allowing elevated tumor glucocorticoids to drive resistance by stimulating GR. Here, we show that up-regulation of hexose-6-phosphate dehydrogenase (H6PD) protein occurs in prostate cancer tissues of men treated with enzalutamide, human-derived cell lines, and patient-derived prostate tissues treated ex vivo with enzalutamide.

genotype identifies glucocorticoid responsiveness in severe asthma.

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma.

Rapid and structure-specific cellular uptake of selected steroids.

Steroid hormones and their respective nuclear receptors are essential mediators in numerous physiologic and pathophysiologic processes, ranging from regulation of metabolism, immune function, and reproductive processes to the development of hormone-dependent cancers such as those of the breast and prostate. Because steroids must enter cells before activating nuclear receptors, understanding the mechanisms by which cellular uptake occurs is critical, yet a clear understanding of these mechanisms has been elusive. It is generally assumed that diffusion-driven uptake is similar across various steroids whereas an elevated cellular concentration is thought to reflect active uptake, but these assumptions have not been directly tested.

A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients.

Δ-abiraterone (Δ4A) is an activemetabolite of abiraterone (ABI), which is approved in the treatment of metastatic castration resistant prostate cancer (mCRPC). The contribution of Δ4A to the clinical antitumor activity of ABI remains unknown. The aim of this study was to explore the relationship between plasma Δ4A concentration and survival in 36 mCRPC patients treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day).

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

Background: A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens.

AR Signaling in Prostate Cancer Regulates a Feed-Forward Mechanism of Androgen Synthesis by Way of HSD3B1 Upregulation.

3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant in HSD3B1, the gene that encodes 3βHSD1, encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation.

High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer.

Background: Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open-label, single-arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard-dose therapy.

Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities.

Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ,3β-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g.

Association of Tissue Abiraterone Levels and Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer.

Germline variation in solute carrier organic anion () genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by -encoded transporters and that gene variation may influence intracellular abiraterone levels and outcomes. Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy.

Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer.

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade.

Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum.

Development and validation of a novel LC-MS/MS method for simultaneous determination of abiraterone and its seven steroidal metabolites in human serum: Innovation in separation of diastereoisomers without use of a chiral column.

Abiraterone acetate (AA), the prodrug of abiraterone, is FDA-approved for the treatment of castration-resistant prostate cancer. Abiraterone is metabolized in patients to a more potent analogue, D4A. However, we have recently reported that this analogue is further metabolized to additional metabolites in patients treated with AA.

Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer.

Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival.