Gene Polymorphisms Affecting Erectile Dysfunction

Mostafa, Taymour; Taymour, Mai

doi:10.1016/j.sxmr.2020.02.001

Cited by 7 publications

(7 citation statements)

References 53 publications

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“…Moreover, based on PDE5 inhibitory mechanism, the effect and mechanism study on ED could be evaluated using cavernous smooth muscle cells (CSMCs) cellular assay in vitro. In this study, for the first time, 6 main 8-isopentenyl flavonoids, Icariin (1), 2-O"-rhamnosylicaridide II (2), Baohuoside I (3), Epimedin A, B, C (4)(5)(6) were separated from the PFES and identified by 1 H NMR, 13 C NMR and MS, and these compounds were detected PDE5A1 inhibitory activity with the novel HPLC assay. We also adapted a series of PDE5 inhibitors from different reports [11,13] to firstly establish CoMFA and CoMSIA models, aiming at finding the relationship between the biological activity and the key structural factors of 8-isopentenyl flavonoids from the models.…”

Section: Introductionmentioning

confidence: 79%

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Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Wu²,

et al. 2022

Preprint

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Background: As known, inhibition of phosphodiesterase 5 (PDE5) has the therapeutic effect on male erectile dysfunction (ED), and the processed folium of Epimedium sagittatum Maxim. (PFES) characterized by 8-isopentenyl flavonoids is a famous herb for treating ED. However, the main flavonoids inhibitory activities, structure-activity relationship (SAR) and signaling pathway have been not systematically studied so that its pharmacodynamic mechanism is unclear. Methods: We aimed to initially reveal the PFES efficacy mechanism for treating ED. For the first time, 6 main 8-isopentenyl flavonoids (1-6) from PFES were isolated and identified. Then based on HPLC detection, we proposed a novel method with superior applicability compared to traditional radioisotope assay to screen inhibitors among them. We further established three-dimensional quantitative structure-activity relationship (3D-QSAR) models through CoMFA and CoMSIA to analyze the SAR for those inhibitors. Results: The results were verified by cellular effects of the screened flavonoids. Among 6 compounds, Icariin (1), 2-O"-rhamnosylicaridide II (2) and Baohuoside I (3) were identified with significant activities (IC50 = 8.275, 3.233, 5.473 mM). Then 3D-QSAR studies showed that the replacement of C8 with bulky steric groups as isopentenyl, C3 with positive charge groups and C4' with a hydrogen bond acceptor substituent could increase inhibitory effects. In contrast, the substitution of C7 with bulky steric groups or hydrophilic groups tended to decrease the efficacies. And compounds1, 2, 3 could increase cGMP level and decrease cytoplasmic Ca2+ of rat corpus cavernosum smooth muscle cells (CCSMCs)by activating PKG. Conclusion: 8-isopentenyl flavonoids could be the main pharmacodynamic substances of PFES in the treatment for ED, and some had significant PDE5A1 inhibitory activities so as to activate cGMP/PKG/Ca2+ signaling pathway in CCSMCs, that was related to the substituents at the key sites such as C8, C3, C4' and C7 in the characteristic compounds.

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Section: Introductionmentioning

confidence: 79%

“…Erectile dysfunction (ED), defined as the inability of the penis to achieve or maintain sufficient erections, is one of the most common male sexual disorders [1].…”

Section: Introductionmentioning

confidence: 99%

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Wu²,

et al. 2022

Preprint

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“…Increasing evidence has shown that genetic risk factors contribute to the development of ED. 6 Thus, identifying genetic risk factors might improve the understanding of the pathogenic molecular basis for ED. The methylenetetrahydrofolate reductase ( MTHFR ) gene, which is localized on chromosome 1 (1p36.3) and is composed of 11 exons, encodes an enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.…”

Section: Introductionmentioning

confidence: 99%

“… 11 12 13 14 However, little is known about the genetic effect of the MTHFR C677T polymorphism on sexual function. Few studies have demonstrated the association between the MTHFR c.677C>T variant and ED risk, 6 and the role of the C677T polymorphism in relation to the risk of ED has not been examined in a study with a relatively large sample size. 6 The aim of this study was to investigate the association between the MTHFR C677T polymorphism and the risk of ED.…”

Section: Introductionmentioning

confidence: 99%

Association between MTHFR c.677C>T variant and erectile dysfunction among males attending fertility clinic

Bai,

Li,

Wan

et al. 2023

Asian Journal of Andrology

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Genetic risk factors have been shown to contribute to the development of sexual dysfunction. However, the role of methylenetetrahydrofolate reductase (MTHFR) gene variants in the risk of erectile dysfunction (ED) remains unclear. In this study, we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5. The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction (PCR). No significant difference in the genotypic frequency of the MTHFR C677T polymorphism (CC, CT, and TT) was observed between men from the ED and non-ED groups. In addition, on binary logistic regression analysis, both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism. Interestingly, a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED (P = 0.02). The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis, even after adjusting for potential confounders (odds ratio [OR] = 2.46, 95% confidence interval [CI]: 1.15–5.50, P = 0.02). These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED. Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routine clinical diagnosis.

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“…Erectile dysfunction (ED), defined as the inability of the penis to achieve or maintain sufficient erections, is one of the most common male sexual disorders [ 1 ]. Phosphodiesterase 5 (PDE5) is highly expressed in corpus cavernosum and has become a noteworthy target for drug screening in ED [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum maxim. as PDE5A inhibitors

Wu²,

et al. 2022

Chin Med

View full text Add to dashboard Cite

Background As known, inhibition of phosphodiesterase 5 (PDE5) has the therapeutic effect on male erectile dysfunction (ED), and the processed folium of Epimedium sagittatum Maxim. (PFES) characterized by 8-isopentenyl flavonoids is a famous herb for treating ED. However, the main flavonoids inhibitory activities, structure–activity relationship (SAR) and signaling pathway have been not systematically studied so that its pharmacodynamic mechanism is unclear. Methods We aimed to initially reveal the PFES efficacy mechanism for treating ED. For the first time, 6 main 8-isopentenyl flavonoids (1–6) from PFES were isolated and identified. Then based on HPLC detection, we proposed a novel method to screen inhibitors among them. We further analyze the three-dimensional quantitative structure–activity relationship (3D-QSAR) for those inhibitors. Results The results were verified by cellular effects of the screened flavonoids. Among 6 compounds, Icariin: (1), 2-Oʹʹrhamnosylicaridide II (2) and Baohuoside I (3) were identified with significant activities (IC50 = 8.275, 3.233, 5.473 μM). Then 3D-QSAR studies showed that the replacement of C8 with bulky steric groups as isopentenyl, C3 with positive charge groups and C4' with a hydrogen bond acceptor substituent could increase inhibitory effects. In contrast, the substitution of C7 with bulky steric groups or hydrophilic groups tended to decrease the efficacies. And compounds 1, 2, 3 could increase cGMP level and decrease cytoplasmic Ca2+ of rat corpus cavernosum smooth muscle cells (CCSMCs)by activating PKG. Conclusion 8-isopentenyl flavonoids could be the main pharmacodynamic substances of PFES in the treatment for ED, and some had significant PDE5A1 inhibitory activities so as to activate cGMP/PKG/Ca2+ signaling pathway in CCSMCs, that was related to the substituents at the key sites such as C8, C3, C4ʹ and C7 in the characteristic compounds.

show abstract

Gene Polymorphisms Affecting Erectile Dysfunction

Cited by 7 publications

References 53 publications

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Association between MTHFR c.677C>T variant and erectile dysfunction among males attending fertility clinic

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum maxim. as PDE5A inhibitors

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