Use of phosphodiesterase-5 inhibitors and the incidence of melanoma

Wayne, George; Demus, Timothy; Jivanji, Dhaval; Atri, Elias; Herzog, Bryan; Wong, Vivian; Garcia, Maurilio; Cedeno, Juan D.; Nagoda, Elizabeth; Polackwich, A. Scott

doi:10.1016/j.canep.2022.102251

Cited by 4 publications

(4 citation statements)

References 21 publications

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“…After trypsin digestion, the cell concentration was adjusted to 5×10 4 cells/mL in serum-free DMEM medium. And 200 μL of cell suspension was added to the upper chamber of the transwell, and 10% FBS DMEM culture medium was added to the lower chamber.…”

Section: Methodsmentioning

confidence: 99%

“…2,3 Moreover, DMED patients are found to be resistant to PDE5 inhibitors. 4 However, these drugs were limited use because the adverse effects.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Moreover, DMED patients are found to be resistant to PDE5 inhibitors. 4 However, these drugs were limited use because the adverse effects. Therefore, finding safer and more effective ED treatments is especially urgent.…”

Section: Introductionmentioning

confidence: 99%

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MALAT1 mediates miR-206/CDC42/PAK1/Paxillin signaling axis to alleviate erectile dysfunction in rats

Luo,

Wang,

Tong

et al. 2024

Preprint

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Erectile dysfunction (ED) is a male sexual dysfunction with a gradually increasing prevalence, and current treatments are ineffective. This study aims to find a safer and more effective treatment for erectile dysfunction. Bone marrow-derived mesenchymal stem cells (BM-MSCs) treated with VEGFA. The expression of endothelial markers vWF, VE-cadherin and eNOS were determined by overexpressing MALAT1 and CDC42, respectively. The results showed that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs and the expression of endothelial marker-related proteins. Moreover, MALAT1 induced differentiation of BM-MCs to ECs through the CDC42/PAK1/Paxillin pathway was explored by transfecting si-MALAT1 and overexpressing CDC42 as well as PAK1 in the BM-MSCs. Next, miR-206 was overexpressed within BM-MCs to determine CDC42 expression. The binding sites of MALAT1, miR-206 and CDC42 were reported using luciferase. it was found that the MALAT1 competes with CDC42 3'-UTR for binding miR-206, which in turn is involved in differentiating BM-MSCs to ECs. Finally, DMED rat modeling success was demonstrated by APO experiments. MALAT1 overexpression-modified BM-MSCs had significant therapeutic effects in DMED rats.

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Section: Methodsmentioning

confidence: 99%

“…2,3 Moreover, DMED patients are found to be resistant to PDE5 inhibitors. 4 However, these drugs were limited use because the adverse effects.…”

Section: Introductionmentioning

confidence: 99%

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MALAT1 mediates miR-206/CDC42/PAK1/Paxillin signaling axis to alleviate erectile dysfunction in rats

Luo,

Wang,

Tong

et al. 2024

Preprint

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“…Sildenafil, tadalafil, and phosphodiesterase type 5 (PDE5) inhibitors are commonly used to prevent and control DMED in Western medicine, but they only improve local symptoms [ 3 , 4 ]. DMED patients are resistant to PDE5 inhibitors [ 5 ]. In addition, these medicines have limited use due to their side effects.…”

Section: Introductionmentioning

confidence: 99%

LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis

Luo,

Wang,

Tong

et al. 2024

Reprod Biol Endocrinol

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Background Erectile dysfunction (ED) is a common male sexual dysfunction, with an increasing incidence, and the current treatment is often ineffective. Methods Vascular endothelial growth factor (VEGFA) was used to treat bone marrow-derived mesenchymal stem cells (BM-MSCs), and their cell migration rates were determined by Transwell assays. The expression of the von Willebrand Factor (vWF)VE-cadherin, and endothelial nitric oxide synthase(eNOS) endothelial markers was determined by qRT‒PCR and Western blot analyses. The MALAT1-induced differentiation of BM-MCs to ECs via the CDC42/PAK1/paxillin pathway was explored by transfecting VEGFA-induced BM-MSC with si-MALAT1 and overexpressing CDC42 and PAK1. The binding capacity between CDC42, PAK1, and paxillin in VEGFA-treated and non-VEGFA-treated BM-MSCs was examined by protein immunoprecipitation. MiR-206 was overexpressed in VEGFA-induced BM-MSC, and the binding sites of MALAT1, miR-206, and CDC42 were identified using a luciferase assay. Sixty male Sprague‒Dawley rats were divided into six groups (n = 10/group). DMED modelling was demonstrated by APO experiments and was assessed by measuring blood glucose levels. Erectile function was assessed by measuring the intracavernosa pressure (ICP) and mean arterial pressure (MAP). Penile erectile tissue was analysed by qRT‒PCR, Western blot analysis, and immunohistochemical staining. Results MALAT1 under VEGFA treatment conditions regulates the differentiation of BM-MSCs into ECs by modulating the CDC42/PAK1/paxillin axis. In vitro experiments demonstrated that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs. CDC42 binds to PAK1, and PAK1 binds to paxillin. In addition, CDC42 in the VEGFA group had a greater ability to bind to PAK1, whereas PAK1 in the VEGFA group had a greater ability to bind to paxillin. Overexpression of miR-206 in VEGFA-induced BM-MSCs demonstrated that MALAT1 competes with the CDC42 3’-UTR for binding to miR-206, which in turn is involved in the differentiation of BM-MSCs to ECs. Compared to the DMED model group, the ICP/MAP ratio was significantly greater in the three BM-MSCs treatment groups. Conclusions MALAT1 facilitates BM-MSC differentiation into ECs by regulating the miR-206/CDC42/PAK1/paxillin axis to improve ED. The present findings revealed the vital role of MALAT1 in the repair of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSC-mediated repair of DMED.

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Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health

Kloner,

Burnett,

Miner

et al. 2023

The Journal of Sexual Medicine

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Background In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug–drug interactions, but also a potential cardioprotective effect of these drugs. Aim In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. Method A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. Outcomes Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. Results An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug–drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non–PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non–PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. Clinical Implications Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. Strengths and Limitations Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. Conclusion The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

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Use of phosphodiesterase-5 inhibitors and the incidence of melanoma

Cited by 4 publications

References 21 publications

MALAT1 mediates miR-206/CDC42/PAK1/Paxillin signaling axis to alleviate erectile dysfunction in rats

MALAT1 mediates miR-206/CDC42/PAK1/Paxillin signaling axis to alleviate erectile dysfunction in rats

LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis

Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health

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