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Diabetes Nov 2020Testosterone (T) affects β-cell function in men and women. T is a prohormone that undergoes intracrine conversion in target tissues to the potent androgen...
Testosterone (T) affects β-cell function in men and women. T is a prohormone that undergoes intracrine conversion in target tissues to the potent androgen dihydrotestosterone (DHT) via the enzyme 5α-reductase (5α-R) or to the active estrogen 17β-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5α-R type 1 isoform (SRD5A1) and aromatase are expressed in male and female β-cells. We show that cultured male and female human islets exposed to T produce DHT and downstream metabolites. In these islets, exposure to the 5α-R inhibitors finasteride and dutasteride inhibited T conversion into DHT. We did not detect T conversion into E2 from female islets. However, we detected T conversion into E2 in islets from two out of four male donors. In these donors, exposure to the aromatase inhibitor anastrozole inhibited E2 production. Notably, in cultured male and female islets, T enhanced glucose-stimulated insulin secretion (GSIS). In these islets, exposure to 5α-R inhibitors or the aromatase inhibitor both inhibited T enhancement of GSIS. In conclusion, male and female human islets convert T into DHT and E2 via the intracrine activities of SRD5A1 and aromatase. This process is necessary for T enhancement of GSIS.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Aromatase; Cells, Cultured; Female; Gene Expression Regulation, Enzymologic; Humans; Insulin; Insulin-Secreting Cells; Male; Testosterone
PubMed: 32855171
DOI: 10.2337/db20-0228 -
3 Biotech Sep 2021Pharmacological treatment for BPH includes 5- reductase inhibitors as Finasteride and Dutasteride as a monotherapy or in combination with antimuscarinic drugs,...
UNLABELLED
Pharmacological treatment for BPH includes 5- reductase inhibitors as Finasteride and Dutasteride as a monotherapy or in combination with antimuscarinic drugs, alpha-blockers, 5-phosphodiesterase inhibitor drugs. Androgen receptor inhibitors revealed several adverse events as decreased libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia. Hence, the emergence of complementary and alternative medications having safety profile-preferably, edible natural products-would be highly desirable. In-silico studies based on Maestro Molecular Modelling platform (version 10.5) by Schrӧdinger, LLC was used to identify the lead molecules. The in-vivo activity studied on rats gave the positive results. The findings based on experiments as antioxidant parameters showed the potential to quench the free radicals. The significant results were also seen in prostatic index and histopathological studies supported the above findings. Based on these data, sesamol and derivative have proven efficacy in protecting against testosterone induced BPH.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-021-02952-z.
PubMed: 34466348
DOI: 10.1007/s13205-021-02952-z -
BMC Cancer Sep 20205α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients....
BACKGROUND
5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database.
METHODS
The data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration.
RESULTS
Those who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71-0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82-1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6-1.1).
CONCLUSIONS
Patients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don't. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.
Topics: 5-alpha Reductase Inhibitors; Aged; Carcinoma; Carcinoma, Transitional Cell; Cholestenone 5 alpha-Reductase; Dutasteride; Finasteride; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prostatic Hyperplasia; Receptors, Androgen; Taiwan; Urothelium
PubMed: 32917158
DOI: 10.1186/s12885-020-07373-4 -
ChemistryOpen May 2024Phosphodiesterase type 5 (PDE5) is a multidomain protein that plays a crucial role in regulating cellular cyclic guanosine monophosphate (cGMP), a key signaling molecule...
Phosphodiesterase type 5 (PDE5) is a multidomain protein that plays a crucial role in regulating cellular cyclic guanosine monophosphate (cGMP), a key signaling molecule involved in various physiological processes. Dysregulation of PDE5 and cGMP signaling is associated with a range of vasodysfunctional disorders, necessitating the development of effective therapeutic interventions. This study adopts comprehensive approach, combining virtual screening and molecular dynamics (MD) simulations, to repurpose FDA-approved drugs as potential PDE5 inhibitors. The initial focus involves selecting compounds based on their binding affinity. Shortlisted compounds undergo a meticulous analysis for their drug profiling and biological significance, followed by the activity evaluation and interaction analysis. Notably, based on binding potential and drug profiling, two molecules, Dutasteride and Spironolactone, demonstrate strong potential as PDE5 inhibitors. Furthermore, all atom MD simulations were employed (500 ns) to explore dynamic behavior of Dutasteride and Spironolactone in complexes with PDE5. Principal components analysis (PCA) and free energy landscape (FEL) analyses are further leveraged to decipher that the binding of Dutasteride and Spironolactone stabilizes the structure of PDE5 with minimal conformational changes. In summary, Dutasteride and Spironolactone exhibit remarkable affinity for PDE5 and possess characteristics that suggest their potential as therapeutic agents for conditions associated with PDE5 dysfunction.
Topics: Drug Repositioning; Phosphodiesterase 5 Inhibitors; Humans; Molecular Dynamics Simulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Spironolactone; Dutasteride; Principal Component Analysis; Molecular Docking Simulation; Protein Binding
PubMed: 38060834
DOI: 10.1002/open.202300196 -
Oncology Letters Oct 2021The interaction between prostate cancer cells and osteoblasts is essential for the development of bone metastasis. Previously, novel androgen receptor axis-targeted...
The interaction between prostate cancer cells and osteoblasts is essential for the development of bone metastasis. Previously, novel androgen receptor axis-targeted agents (ARATs) were approved for metastatic castration-naïve and non-metastatic castration-resistant prostate cancer (CRPC); both of which are pivotal for investigating the association between the bone microenvironment and tumors. The present study established a novel 3D microenvironment model that simulated the bone microenvironment of CRPC, and evaluated the drug susceptibility of ARATs and the efficacy of the combination of abiraterone and dutasteride. Green fluorescent protein-transferred C4-2 cells (a CRPC cell line) and red fluorescent protein-transferred human osteoblasts differentiated from human mesenchymal stem cells were co-cultured in chitosan nanofiber matrix-coated culture plates to simulate the 3D scaffold of the bone microenvironment. The growth of C4-2 was quantified using live-cell imaging and the Cell3 iMager duos analysis system. The growth of C4-2 colonies were quantified for a maximum of 30 days. The expression of TGF-β increased and promoted EMT in C4-2 cells co-cultured with osteoblasts, indicating resistance to ARATs. The IC of each drug and the combination effect of abiraterone and dutasteride were evaluated using this model. Combination treatment with abiraterone and dutasteride synergistically inhibited the growth of C2-4 colonies compared with individual investigational agents. This could be attributed to the reduction of 3-keto-5α-abiraterone, an androgen receptor agonist. The bone microenvironment model of the present study is unique and useful for evaluating new drug susceptibility testing in prostate cancer cells. This model may help to reveal the unknown mechanisms underlying micro- to clinical bone metastasis in prostate cancer.
PubMed: 34457044
DOI: 10.3892/ol.2021.12950 -
Andrology Mar 20225α-reductase inhibitors are commonly prescribed medications with multiple side effects used in the treatment of male pattern hair loss and benign prostatic hyperplasia....
BACKGROUND
5α-reductase inhibitors are commonly prescribed medications with multiple side effects used in the treatment of male pattern hair loss and benign prostatic hyperplasia. These side effects including "post-finasteride syndrome" may result in lawsuits.
OBJECTIVES
To characterize lawsuits involving the adverse side effects of 5α-reductase inhibitor to better understand drivers of litigation and outcomes.
METHODS
Legal cases were queried from Nexis Uni using the search terms "5-alpha reductase inhibitor" as well as specific agents "finasteride," "dutasteride" in combination with "malpractice," "negligence," "damage," "loss," "side effect," and "complication." Secondary review was performed with publicly available data on "In Re: Propecia." Relevant cases were reviewed and pertinent characteristics were extracted and summarized using descriptive statistics.
RESULTS
Our search yielded 156 unique legal cases in the Nexis Uni database from April 2003 to May 2021. Only 18 of these cases met the inclusion criteria. Adverse events experienced by patients included medication side effects (n = 12, 66.7%), delayed cancer diagnosis (n = 3, 16.7%), and lack of symptom improvement (n = 3, 16.7%). The identity of the plaintiffs were most commonly patients themselves (n = 15, 83.3%). Defendants include pharmaceutical companies (n = 6, 33.3%), a combination of parties (n = 5, 27.8%), and physicians (n = 5, 27.8%) alone. The allegations included sexual side effects such as erectile dysfunction (n = 6, 33.3%) and decreased libido (n = 4, 22.2%). These prescriptions were made for benign prostatic hyperplasia (n = 9, 50%), male pattern hair loss (n = 7, 38.9%), and feminizing hormone therapy (n = 2, 11.1%). Several of these cases involved the same plaintiffs in related cases. No verdicts were against physicians. We noted a largely settled lawsuit involving more than 1000 plaintiffs with limited data on harms alleged and a $4.3 million settled amount. Of the total cases that resulted in a verdict, 9/18 were within the last 3 years.
DISCUSSION
The most common complications experienced by patients in our legal review were those involving sexual dysfunction with erectile dysfunction and decreased libido. The growing number of cases in the later years of our review suggests litigation may continue to increase in the coming future. Our review did not identify any individual cases that resulted in a monetary payout beyond a $4.3 million settlement outside of court.
CONCLUSION
5α-reductase inhibitor was alleged to have sexual, mental, and physical side effects, resulting in legal litigation. Despite this, no judgment against a physician or pharmaceutical company was identified. We do note and discuss a large number of lawsuits settled out of court. Given the increase in the number of lawsuits resulting in verdicts over the last 3 years, we suspect that the frequency of litigation around 5α-reductase inhibitors will continue for the foreseeable future.
Topics: 5-alpha Reductase Inhibitors; Dutasteride; Erectile Dysfunction; Finasteride; Humans; Male; Malpractice
PubMed: 34933409
DOI: 10.1111/andr.13145 -
Nature Communications Oct 2020Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme in steroid metabolism and catalyzes the reduction of testosterone to dihydrotestosterone. Mutations...
Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme in steroid metabolism and catalyzes the reduction of testosterone to dihydrotestosterone. Mutations in the SRD5A2 gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride, as SRD5A2 inhibitors, are widely used antiandrogen drugs for benign prostate hyperplasia. The molecular mechanisms underlying enzyme catalysis and inhibition for SRD5A2 and other eukaryotic integral membrane steroid reductases remain elusive due to a lack of structural information. Here, we report a crystal structure of human SRD5A2 at 2.8 Å, revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the transmembrane domain. Structural analysis together with computational and mutagenesis studies reveal the molecular mechanisms of the catalyzed reaction and of finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region that regulate NADPH/NADP exchange. Mapping disease-causing mutations of SRD5A2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and may facilitate drug development.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Amino Acid Motifs; Androgen Antagonists; Dutasteride; Finasteride; Humans; Membrane Proteins; Molecular Dynamics Simulation; NADP
PubMed: 33110062
DOI: 10.1038/s41467-020-19249-z -
Turkish Journal of Biology = Turk... 2021Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing...
Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here we took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARS-CoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr, Trp, and Tyr amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19.
PubMed: 34803446
DOI: 10.3906/biy-2012-52 -
Actas Dermo-sifiliograficas 2020Frontal fibrosing alopecia is an increasingly common form of scarring alopecia. The aim of this study was to describe the demographic and clinical characteristics of...
BACKGROUND AND OBJECTIVE
Frontal fibrosing alopecia is an increasingly common form of scarring alopecia. The aim of this study was to describe the demographic and clinical characteristics of patients with FFA seen at the trichology unit of a medium-sized regional hospital and to report on treatments used.
MATERIAL AND METHOD
We reviewed the medical records of all patients with FFA seen at the trichology unit of Hospital Universitario Infanta Sofía in Madrid, Spain between May 2016 and May 2018. We analyzed associations between disease severity, clinical patterns, need for oral medications, and other characteristics.
RESULTS
Seventy-five patients (73 women and 2 men) were studied. Diagnosis was clinical in most cases and 13 cases (17.3%) were confirmed histologically. Median (interquartile range) age at reported onset of symptoms was 61 (12) years. Involvement of the eyebrows was recorded in 70 patients (93.3%) and signs of oral and genital lichen planus in 7 (9.6%). Eleven patients (14.7%) had hypothyroidism and 15 (20.0%) had signs of rosacea. Only 5 of the patients who presented a linear pattern (21.7%) had severe hairline recession. Patients with unstable and/or symptomatic disease (n=24) were treated with oral medications (5-alpha reductase inhibitors, hydroxychloroquine, corticosteroids, and isotretinoin) or intralesional corticosteroids. Eighteen patients (75.0%) achieved disease stability. Ten of the 15 patients with signs of rosacea and 10 of those with facial papules required systemic treatment.
CONCLUSION
Most of the patients in this series of FFA were postmenopausal women. The prevalence of oral and genital lichen planus was higher than that observed in the general population. Patients with a linear pattern had less severe disease. Facial papules were more common in younger patients and both facial papules and rosacea were associated with a greater need for oral treatment.
Topics: Alopecia; Female; Forehead; Humans; Lichen Planus; Male; Retrospective Studies; Spain
PubMed: 32417453
DOI: 10.1016/j.ad.2020.03.003 -
Research Square Jul 2020Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene...
Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride as SRD5α2 inhibitors are widely used anti-androgen drugs for benign prostate hyperplasia, which have recently been indicated in the treatment of COVID-19. The molecular mechanisms underlying enzyme catalysis and inhibition remained elusive for SRD5α2 and other eukaryotic integral membrane steroid reductases due to a lack of structural information. Here, we report a crystal structure of human SRD5α2 at 2.8 Å revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the membrane. Structural analysis together with computational and mutagenesis studies reveals molecular mechanisms for the 5α-reduction of testosterone and the finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region regulating the NADPH/NADP exchange. Mapping disease-causing mutations of SRD5α2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and will facilitate drug development.
PubMed: 32702725
DOI: 10.21203/rs.3.rs-40159/v1