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Research in Veterinary Science Aug 2023Inflammatory mammary cancer (IMC) is a disease that affects female dogs. It is characterized by poor treatment options and no efficient targets. However, anti-androgenic...
Inflammatory mammary cancer (IMC) is a disease that affects female dogs. It is characterized by poor treatment options and no efficient targets. However, anti-androgenic and anti-estrogenic therapies could be effective because IMC has a great endocrine influence, affecting tumor progression. IPC-366 is a triple negative IMC cell line that has been postulated as a useful model to study this disease. Therefore, the aim of this study was to inhibit steroid hormones production at different points of the steroid pathway in order to determine its effect in cell viability and migration in vitro and tumor growth in vivo. For this purpose, Dutasteride (anti-5αReductase), Anastrozole (anti-aromatase) and ASP9521 (anti-17βHSD) and their combinations have been used. Results revealed that this cell line is positive to estrogen receptor β (ERβ) and androgen receptor (AR) and endocrine therapies reduce cell viability. Our results enforced the hypothesis that estrogens promote cell viability and migration in vitro due to the function of E1SO4 as an estrogen reservoir for E2 production that promotes the IMC cells proliferation. Also, an increase in androgen secretion was associated with a reduction in cell viability. Finally, in vivo assays showed large tumor reduction. Hormone assays determined that high estrogen levels and the reduction of androgen levels promote tumor growth in Balb/SCID IMC mice. In conclusion, estrogen levels reduction may be associated with a good prognosis. Also, activation of AR by increasing androgen production could result in effective therapy for IMC because their anti-proliferative effect.
Topics: Mice; Dogs; Female; Animals; Androgens; Mice, SCID; Estrogens; Steroids; Cell Proliferation; Cell Line, Tumor
PubMed: 37290206
DOI: 10.1016/j.rvsc.2023.05.014 -
Pharmaceuticals (Basel, Switzerland) Feb 2023Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the...
Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM-PBSA calculations of the protein-ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies.
PubMed: 37259437
DOI: 10.3390/ph16020296 -
Pharmaceuticals (Basel, Switzerland) Jan 2023Parkinson's disease (PD) is characterized by neurodegeneration and neuroinflammation. PD prevalence and incidence are higher in men than in women and modulation of...
Parkinson's disease (PD) is characterized by neurodegeneration and neuroinflammation. PD prevalence and incidence are higher in men than in women and modulation of gonadal hormones could have an impact on the disease course. This was investigated in male and female gonadectomized (GDX) and SHAM operated (SHAM) mice. Dutasteride (DUT), a 5α-reductase inhibitor, was administered to these mice for 10 days to modulate their gonadal sex hormones. On the fifth day of DUT treatment, mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. We have previously shown in these mice the toxic effect of MPTP in SHAM and GDX males and in GDX females on dopamine markers and astrogliosis whereas SHAM females were protected by their female sex hormones. In SHAM males, DUT protected against MPTP toxicity. In the present study, microglial density and the number of doublets, representative of a microglial proliferation, were increased by the MPTP lesion only in male mice and prevented by DUT in SHAM males. A three-dimensional morphological microglial analysis showed that MPTP changed microglial morphology from quiescent to activated only in male mice and was not prevented by DUT. In conclusion, microgliosis can be modulated by sex hormone-dependent and independent factors in a mice model of PD.
PubMed: 37259303
DOI: 10.3390/ph16020152 -
Urology Aug 2023Testosterone and dihydrotestosterone are significant drivers of male external genital development, and therefore teratogens that alter these hormone profiles have been...
Testosterone and dihydrotestosterone are significant drivers of male external genital development, and therefore teratogens that alter these hormone profiles have been hypothesized to cause aberrations in development. Here, we present the first case report of genitalia anomalies after prenatal exposure to spironolactone and dutasteride through 8-weeks of gestation. The patient was born with abnormal male external genitalia which was surgically managed. Long-term outcomes such as gender identity, sexual function, hormonal maturation through puberty, and fertility remain unknown. These numerous considerations necessitate multi-disciplinary management with close follow-up to address sexual, psychological, and anatomic concerns.
Topics: Pregnancy; Humans; Male; Female; Cholestenone 5 alpha-Reductase; Gender Identity; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Testosterone; Dihydrotestosterone; Disorders of Sex Development
PubMed: 37178876
DOI: 10.1016/j.urology.2023.05.001 -
European Journal of Dermatology : EJD Feb 2023
Review
Topics: Humans; Dutasteride; Mesotherapy; Alopecia; Hair; Finasteride; 5-alpha Reductase Inhibitors
PubMed: 37178048
DOI: 10.1684/ejd.2023.4443 -
International Braz J Urol : Official... 2023To evaluate the penile morphology after the isolated and combined administration of dutasteride and tamsulosin in a rodent model.
PURPOSE
To evaluate the penile morphology after the isolated and combined administration of dutasteride and tamsulosin in a rodent model.
MATERIALS AND METHODS
Forty male rats were assigned into the following groups: Control group (C, receiving distilled water, n=10); Dutasteride group (D, receiving 0.5 mg/Kg/day of dutasteride, n=10); Tamsulosin group (T, receiving 0.4 mg/Kg/day of tamsulosin, n=10); and Dutasteride associated with Tamsulosin group (DT, receiving both drugs n = 10). All drugs were administered via oral gavage. After 40 days, the animals were submitted to euthanasia and their penises were collected for histomorphometric analyses. Data were compared using one-way ANOVA followed by Bonferroni's post-test, considering p<0.05 as significant.
RESULTS
The sinusoidal space and smooth muscle fiber surface densities (Sv), and the cross-sectional penile areas of rats in groups D, T and DT were reduced in comparison to controls with the most notable reductions in the combined therapy group. The connective tissue and elastic system fibers Sv were augmented in groups D, T and DT in comparison with the control group, again with the most pronounced changes observed in animals receiving the combined therapy.
CONCLUSION
Both treatments with dutasteride or tamsulosin promoted penile morphometric modifications in a rodent model. The combination therapy resulted in more notable modifications. The results of this study may help to explain the erectile dysfunction observed in some men using these drugs.
Topics: Humans; Male; Rats; Animals; Dutasteride; Tamsulosin; 5-alpha Reductase Inhibitors; Prostatic Hyperplasia; Rodentia; Cross-Sectional Studies; Drug Therapy, Combination
PubMed: 37115177
DOI: 10.1590/S1677-5538.IBJU.2022.0583 -
The Prostate Jul 2023Benign prostatic hyperplasia is common in older men, with many developing lower urinary tract symptoms (LUTS) that impair quality of life. Smoking has many...
BACKGROUND
Benign prostatic hyperplasia is common in older men, with many developing lower urinary tract symptoms (LUTS) that impair quality of life. Smoking has many well-established adverse effects, but its effects on benign prostatic hypertrophy (BPH) and associated LUTS are unclear. We sought to determine if smoking is a risk factor for the incidence of LUTS in asymptomatic men and for the progression of LUTS in symptomatic men.
METHODS
We performed a post-hoc analysis of Reduction by Dutasteride of Prostate Cancer Events in 3060 "asymptomatic" men with baseline International Prostate Symptom Score (IPSS) < 8 and in 2198 symptomatic men with baseline IPSS ≥ 8 not taking 5α-reductase inhibitors or α-blockers. We used multivariable Cox regression models to assess associations between smoking status at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first report of medical or surgical treatment for BPH, or sustained clinically significant LUTS (two reports of IPSS > 14). Among symptomatic men, LUTS progression was defined as IPSS increase of ≥4 points from baseline, surgical intervention for BPH, or starting a new BPH drug.
RESULTS
Of 3060 asymptomatic men, 15% (n = 467) were current, 40% (n = 1231) former, and 45% (n = 1362) never-smokers. Of 2198 symptomatic men, 14% (n = 320) were current, 39% (n = 850) former, and 47% (n = 1028) never-smokers. In asymptomatic men, compared with never-smokers, current and former smoking at baseline were not associated with LUTS incidence (adjusted hazard ratio [adj-HR] = 1.08; 95% confidence interval [95% CI]: 0.78-1.48 and adj-HR = 1.01; 95% CI: 0.80-1.30). In symptomatic men, compared with never-smokers, current and former smoking at baseline were not associated with the progression of LUTS (adj-HR = 1.11; 95% CI: 0.92-1.33 and adj-HR = 1.03; 95% CI: 0.90-1.18).
CONCLUSIONS
In REDUCE, smoking status was not associated with either incident LUTS in asymptomatic men or progression of LUTS in symptomatic men.
Topics: Male; Humans; Aged; Dutasteride; Prostatic Hyperplasia; Quality of Life; Prostatic Neoplasms; Lower Urinary Tract Symptoms; Smoking
PubMed: 37070723
DOI: 10.1002/pros.24541 -
Molecules (Basel, Switzerland) Mar 2023Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main...
Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of -9.7, -9.6, and -9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection.
Topics: Humans; COVID-19; SARS-CoV-2; Molecular Docking Simulation; Drug Repositioning; Sphingomyelin Phosphodiesterase; Protease Inhibitors; Molecular Dynamics Simulation; Antiviral Agents
PubMed: 37049752
DOI: 10.3390/molecules28072989 -
JAAD Case Reports May 2023
PubMed: 37034026
DOI: 10.1016/j.jdcr.2023.02.021 -
BJUI Compass May 2023The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with...
OBJECTIVES
The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to pathogenic variants (PVs), the IMPACT study.
METHODS
Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by PVs status.
RESULTS
A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 PVs carriers, 313 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, or PVs carriers.
CONCLUSIONS
Male 1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without PVs. Mechanisms related to the particularly aggressive phenotype of PCa in PVs carriers may therefore not be linked with circulating hormonal levels.
PubMed: 37025481
DOI: 10.1002/bco2.156