Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors

Ahmed, Wesam S.; Geethakumari, Anupriya M.; Biswas, Kabir H.

doi:10.1016/j.biopha.2020.111128

Cited by 67 publications

(49 citation statements)

References 104 publications

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“…PDE-5 inhibitors have been widely used for treating ED. 31,32 Our previous study reported that chronic PDE-5 inhibitor administration was effective for refractory ED. 11,33 Because GJG decreased PDE-5 expression, GJG might be effective for other types of ED.…”

Section: Discussionmentioning

confidence: 99%

Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats

et al. 2022

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Background: A platinum-containing anti-cancer agent, oxaliplatin (L-OHP), is known to induce peripheral neuropathy, including erectile dysfunction (ED) as a side effect, while Gosha-jinki-gan (GJG) is a traditional Japanese herbal medicine mainly used for peripheral neuropathy. Aim: To investigate the effect of GJG on L-OHP-induced ED in rats. Methods: Twelve-week-old male Wister/ST rats were categorized into the following groups: Sham, Sham+GJG, L-OHP, and L-OHP+GJG (each n = 10). The L-OHP and L-OHP+GJG groups were injected intravenously with L-OHP (4 mg/ kg) for 2 consecutive days in the first week. Statistical significance was determined using Bonferroni's multiple comparison test. Outcomes: At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation. Western blot analysis was used to assess the neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) levels, and quantitative polymerase chain reaction was used to assess the expression of phosphodiesterase-5 (PDE-5) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1. Results: The ICP/MAP ratio of L-OHP rats (0.34 § 0.06) was significantly lower than that of Sham rats (0.67 § 0.03, P < .01), however, the ICP/MAP ratio of L-OHP+GJG rats (0.55 § 0.01) was significantly higher than that of L-OHP rats (P < .01). There were no significant differences in the nNOS and eNOS protein expression between both groups (P > .05). GJG administration significantly decreased PDE-5 and NADPH oxidase-1 messenger RNA expressions in the L-OHP+GJG group. Clinical Translation: This animal model study suggests that GJG might be effective for erectile function in cancer survivors.Strengths & limitations: Our study identified that GJG had no notable side effects in the treated group. Further investigation of the cavernous nerve would also help elucidate the mechanism of GJG effect, which is a limitation of this study. Conclusion: We found that GJG administration improved L-OHP-induced ED by improving transcriptional

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Section: Discussionmentioning

confidence: 99%

Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats

et al. 2022

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“…Currently available Food Drug Administration (FDA)-approved PDE5 inhibitors include sildenafil, tadalafil, vardenafil, and avanafil; non-FDA approved PDE5 inhibitors include lodenfil, udenafil, and mirodenafil (Ahmed et al 2021 ). PDE5 inhibitors prevent cGMP degradation by interfering with the binding of cGMP to the catalytic site of PDE5, consequently prolonging the action of the NO/cGMP signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The PDE superfamily consists of at least 11 isoforms, namely PDE1–PDE11. Among these isoforms, PDE5 hydrolyzes cGMP and is expressed in various organs and tissues, including the vascular smooth muscle cells, lung, penile corpus cavernosum, brain, kidney, cardiac myocytes, and gastrointestinal tract (Ahmed et al 2021 ). Nitric oxide (NO) activates soluble guanylyl cyclase (sGC), which in turn increases cGMP production.…”

Section: Introductionmentioning

confidence: 99%

Mirodenafil ameliorates skin fibrosis in bleomycin-induced mouse model of systemic sclerosis

Roh

Jeong

Lee

et al. 2021

Animal Cells and Systems

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Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Despite the recent advances in the pathogenesis and treatment of SSc, effective therapies for fibrosis caused by SSc have not yet been established. In this study, we investigated the potential role of mirodenafil, a potent phosphodiesterase 5 (PDE5) inhibitor, in the treatment of fibrosis in SSc. We used a bleomycin (BLM)-induced SSc mouse model to mimic the typical features of fibrosis in human SSc and examined the dermal thickness to assess the degree of skin fibrosis after staining with hematoxylin and eosin or Masson’s trichrome stains. The effect of mirodenafil on the expression of profibrotic genes was also analyzed by treating fibroblasts with transforming growth factor (TGF)-β and mirodenafil. We showed that mirodenafil ameliorated dermal fibrosis and downregulated the protein levels of fibrosis markers including COL1A1 and α-SMA in the BLM-induced SSc mouse model. Further, using mouse embryonic fibroblasts and human lung fibroblasts, we demonstrated that the expression of collagen and profibrotic genes was reduced by treatment with mirodenafil. Finally, we showed that mirodenafil inhibited TGF-β-induced phosphorylation of Smad2/3 in fibroblasts, which suggested that this drug may ameliorate fibrosis by suppressing the TGF-β/Smad signaling pathway. Our findings suggest that mirodenafil possesses a therapeutic potential for treating fibrosis in SSc.

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“…Furthermore, phosphodiesterase five inhibitors have been associated with a lower risk of developing colorectal cancer. [60,61] Protooncogene tyrosine-protein kinase ROS (ROS1), an enzyme synthesized by a gene ROS1, that is involved in sending signals in cells and cell growth, so its inhibition can counteract tumoral development. [62] Others ITCs predicted targets are dihydrofolate reductase, coagulation factor X, serine/threonine-protein kinase pknB, and serine-protein kinase ATM.…”

Section: Target Profiling and Prediction Of Activity Type Of Isothiocyanatesmentioning

confidence: 99%

Chemoinformatic Analysis of Isothiocyanates: Their Impact in Nature and Medicine

Guerrero-Alonso

Antúnez-Mojica

Medina-Franco

2021

Molecular Informatics

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Isothiocyanates (ITCs) have a significant impact on food and natural product chemistry. Several dietary components and food chemicals contain the isothiocyanate moiety. In addition, many ITCs interact with macromolecules of biological relevance, making these compounds relevant for potential therapeutic applications and disease prevention. However, there is a lack of systematic analysis of ITCs in chemical and biological databases. Herein, we conducted a comprehensive analysis of ITCs present in public domain databases, including natural products, food chemicals, macromolecular targets of drugs, and the Protein Data Bank. A total of 154 ITCs were found, which can be classified into seven categories: acyclic, cyclic, polycyclic, aromatic, polyaromatic, indolic, and glycosylated. 24 ITCs were reported in 18 vegetable sources, mainly in cruciferous vegetables (Brassica oleracea L.). Calculated properties of pharmaceutical relevance indicated that 11 % of the 154 ITCs would be suitable to be orally absorbed and 48 % permeate the blood-brain-barrier. It was also found that seven molecular targets have been co-crystallized with ITCs and the most frequent is the macrophage migration inhibitory factor. It is expected that this work will contribute to the sub-disciplines of natural products and food informatics.

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Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors

Cited by 67 publications

References 104 publications

Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats

Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats

Mirodenafil ameliorates skin fibrosis in bleomycin-induced mouse model of systemic sclerosis

Chemoinformatic Analysis of Isothiocyanates: Their Impact in Nature and Medicine

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