Practical Approaches to Treat ED in PDE5i Nonresponders

Cai, Zhonglin; Song, Xiaoqing; Zhang, Jianzhong; Yang, Bin; Liu, Hongjun

doi:10.14336/ad.2019.1028

Cited by 13 publications

(14 citation statements)

References 136 publications

(171 reference statements)

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“…Due to the complex (Mitidieri et al, 2020). However, for ED, which is associated with aging, diabetes, and nerve damage, the treatment is not effective (Burnett, 2009;Cai et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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Co‐overexpression of VEGF and Smad7 improved the therapeutic effects of adipose‐derived stem cells on neurogenic erectile dysfunction in the rat model

Xiao

et al. 2022

Andrologia

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Cavernous nerve injury is the main cause of erectile dysfunction (ED) after radical prostatectomy (RP). In our previous study, injection of adipose-derived stem cells (ADSCs) into the cavernosum can repair damaged cavernosum nerves and ED can be restored to a certain extent. In order to improve these therapeutic effects, we evaluated the efficacy of ADSCs co-modified with VEGF and Smad7 in a rat model. SD rats were randomly divided into six groups: a sham surgery group, and the five bilateral cavernous nerve injury (BCNI) groups were injected with ADSC or ADSCs genetically modified by VEGF (ADSC-V), Smad7 (ADSC-S), or VEGF&Smad7 (ADSC-V&S) or phosphatebuffered saline (PBS). The results indicated that the erectile function of the ADSC-V, ADSC-S, and ADSC-V&S groups was significantly recovered, and the erectile function of the ADSC-V&S group was more distinctly recovered as compared to the other groups. The same results are shown in the expression of neuronal nitric oxide synthase and the smooth muscle/collagen ratio of penile tissue comparing the ADSC-V&S group to the ADSC-V and ADSC-S group. These experimental data suggest that ADSCs cooverexpressed with VEGF and Smad7 can significantly improve erectile function after BCNI. This study provides new therapeutic thoughts for ED following RP.

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“…Due to the complex (Mitidieri et al, 2020). However, for ED, which is associated with aging, diabetes, and nerve damage, the treatment is not effective (Burnett, 2009;Cai et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…For example, phosphodiesterase 5 (PDE5) inhibitors are commonly used in the clinical treatment of ED (Mitidieri et al, 2020). However, for ED, which is associated with aging, diabetes, and nerve damage, the treatment is not effective (Burnett, 2009; Cai et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Co‐overexpression of VEGF and Smad7 improved the therapeutic effects of adipose‐derived stem cells on neurogenic erectile dysfunction in the rat model

Xiao

et al. 2022

Andrologia

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“…The relaxing response induced by tadalafil was also reduced in CC from obese mice, which can be explained by the lower bioavailability of NO seen in obese mice 37 . The efficacy of PDE5 inhibitors is strongly reduced when endogenous NO is reduced and/or sGC is oxidized 43 …”

Section: Discussionmentioning

confidence: 99%

“…37 The efficacy of PDE5 inhibitors is strongly reduced when endogenous NO is reduced and/or sGC is oxidized. 43 The main cellular targets of cGMP involve the interaction with at least four proteins, such as cGMP-dependent protein kinases (PKG), the cGMP-regulated PDEs, the cyclic nucleotide-gated channel, and the efflux transporters, MRP4 and MRP5. 44 In the smooth muscle cells, the activation of PKG in response to NO involves the phosphorylation of different proteins, such as calcium-activated potassium channels (BK Ca ), 45 InsP3R-associated cGMP kinase substrate (IRAG), 46 myosin phosphatase target subunit 1 (MYTP1), 47 PDE5, 48 phospholamban, 49 and VASP.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of multidrug resistance proteins by MK571 restored the erectile function in obese mice through cGMP accumulation

et al. 2022

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Background: Intracellular levels of cyclic nucleotides can also be controlled by the action of multidrug resistance protein types 4 (MRP4) and 5 (MRP5). To date, no studies evaluated the role of their inhibition in an animal model of erectile dysfunction (ED).Objectives: To evaluate the effect of a 2-week treatment with MK571, an inhibitor of the efflux of cyclic nucleotides in the ED of obese mice.Materials and methods: Mice were divided in three groups: (i) lean, (ii) obese, and (iii) obese + MK571. The corpus cavernosum (CC) were isolated, and concentrationresponse curves to acetylcholine (ACh), sodium nitroprusside (SNP), and tadalafil in addition to electrical field stimulation (EFS) were carried out in phenylephrine precontracted tissues. Expression of ABCC4 and ABCC5, intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), the protein levels for pVASP Ser157 and pVASP Ser239 , and the intracavernous pressure (ICP) were also determined. The intracellular and extracellular (supernatant) ratios in CC from obese and lean stimulated with a cGMP-increasing substance (BAY 58-2667) in the absence and presence of MK571 (20 μM, 30 min) were also assessed. Results:The treatment with MK571 completely reversed the lower relaxing responses induced by EFS, ACh, SNP, and tadalafil observed in obese mice CC in comparison with untreated obese mice. Cyclic GMP and p-VASP Ser239 expression were significantly reduced in CC from obese groups. MK571 promoted a sixfold increase in cGMP without interfering in the protein expression of p-VASP Ser239 . Neither the cAMP levels nor p-VASP Ser157 were altered in MK571-treated animals. The ICP was ∼50% lower in obese than in the lean mice; however, the treatment with MK571 fully reversed this response. Expressions of ABCC4 and ABCC5 were not different between groups.The intra/extracellular ratio of cGMP was similar in CC from obese and lean mice stimulated with BAY 58-2667.Mariana Gonçalves de Oliveira and Gabriela Reolon Passos contributed equally.

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“…For example, phosphodiesterase 5 (PDE5) inhibitors are commonly used in the clinical treatment of ED and ease the suffering of some patients. 32 However, for ED related to senility, diabetes, and nerve-damage, such treatments are not effective, 33 , 34 and the cost is high. PDE5-Is are mainly used to alleviate symptoms and cannot cure the condition, and their long-term safety is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

miR-195-5p Regulates the Phenotype Switch of CCSM Cells by Targeting Smad7

Zhang¹,

Zhang

Cong

et al. 2021

Sexual Medicine

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Introduction Phenotype switch refers to the process in which smooth muscle cells change from contractile type to synthetic type and acquire the ability of proliferation. Phenotypic transformation involves many changes of cell function, such as collagen deposition and fibrosis, which affect the normal erectile function of penis. Aim To investigate the role of miR-195-5p in regulating the Phenotype switch of the corpus cavernosum smooth muscle (CCSM) cells. Methods A small mother against decapentaplegic 7(Smad7) virus vector and a miR-195-5p mimics or an si-Smad7 viral vector and a miR-195-5p inhibitor were transfected into CCSM cells. The cells were obtained by primary culture of rat corpus cavernosum smooth muscle tissue. Real-time polymerase chain reaction (PCR) experiments, Western blotting, hematoxylin-eosin (HE) staining, transwell experiments, MTT assays, and flow cytometry were used to detect miR-195-5p, Smad7, phenotype switch markers of CCSM cells and related protein expression, as well as changes in cell morphology, migration, proliferation and apoptosis. Main Outcome Measure To study the regulation of miR-195-5p in CCSM cells by overexpression and silencing strategies. Results Overexpressed miR-195-5p promoted the transformation of CCSM cells from a contractile type to a synthetic type. Meanwhile, the migration ability and proliferation ability of CCSM cells increased, and the apoptosis rate decreased. The expression-silencing of miR-195-5p gave rise to the opposite effect. The results of the rescue experiment demonstrated that overexpressed Smad7 rescued the inhibitory of the switch of the CCSM cell phenotype from the contractile type to the synthesis type caused by overexpression of miR-195-5p alone. Moreover, the enhancement effect of the migration ability and proliferation ability of CCSM cells was also eliminated, and the apoptosis rate was increased. Silencing miR-195-5p and Smad7 at the same time resulted in the opposite effect. Conclusion miR-195-5p may regulate the phenotype switch of CCSM cells by targeting Smad7. Zhang J, Zhang X, Zhang J, et al. miR-195-5p Regulates the Phenotype Switch of CCSM Cells by Targeting Smad7. Sex Med 2021;9:100349.

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Practical Approaches to Treat ED in PDE5i Nonresponders

Cited by 13 publications

References 136 publications

Co‐overexpression of VEGF and Smad7 improved the therapeutic effects of adipose‐derived stem cells on neurogenic erectile dysfunction in the rat model

Co‐overexpression of VEGF and Smad7 improved the therapeutic effects of adipose‐derived stem cells on neurogenic erectile dysfunction in the rat model

Inhibition of multidrug resistance proteins by MK571 restored the erectile function in obese mice through cGMP accumulation

miR-195-5p Regulates the Phenotype Switch of CCSM Cells by Targeting Smad7

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