Reno-protective effects of Phosphodiesterase 5 inhibitors

Coşkuner, Enis Rauf; Ozkan, Burak

doi:10.1007/s10157-021-02051-6

Cited by 14 publications

(8 citation statements)

References 72 publications

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“…PDE5 is also a negative regulator for cGMP-dependent natriuresis. Moreover, it increases renin synthesis by degrading cGMP in juxtaglomerular cells [ 17 ].…”

Section: Pde5 Physiological Rolementioning

confidence: 99%

“…Coskuner and coauthor [ 17 ] and Afsar et al [ 182 ] thoroughly investigated the renoprotective benefits of PDE5-Is in kidney-related clinical conditions, such as diabetic or nephrotoxic nephropathy, renal ischemia/reperfusion injury, renovascular hypertension and chronic kidney disease. Most reported preclinical studies highlighted a promising potential of PDE5-Is to improve renal function and histopathological changes via collaborative mechanisms, including antioxidative, anti-inflammatory, anti-apoptotic, antifibrotic pathways along with suppression of DNA damage and improving renal blood flow, NOS levels, endothelial function and mitochondrial biogenesis.…”

Section: Pde5 As a Drug Target For Disease Treatmentmentioning

confidence: 99%

“…A plethora of preclinical and clinical studies were conducted over the past 20 years to evaluate the role of PDE5-Is either as a single treatment or in combination therapy for various FDA-approved or emerging clinical conditions. These studies have been extensively discussed in several previous reviews [ 17 , 23 , 76 , 122 , 123 , 283 , 284 , 285 , 286 , 287 ]; thus, we herein present an update of the clinical trials status of PDE5-Is in the past five years (summarized in Table 2 ). Focus was mainly directed to registered trials in (accessed on 1 August 2023) that are complete with published results.…”

Section: Recent Update On Clinical Trials Involving Pde5 Inhibitorsmentioning

confidence: 99%

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Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

ElHady,

El-Gamil,

Abdel-Halim

et al. 2023

Pharmaceuticals

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Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.

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“…PDE5 is also a negative regulator for cGMP-dependent natriuresis. Moreover, it increases renin synthesis by degrading cGMP in juxtaglomerular cells [ 17 ].…”

Section: Pde5 Physiological Rolementioning

confidence: 99%

Section: Pde5 As a Drug Target For Disease Treatmentmentioning

confidence: 99%

Section: Recent Update On Clinical Trials Involving Pde5 Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

ElHady,

El-Gamil,

Abdel-Halim

et al. 2023

Pharmaceuticals

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“…Phosphodiesterase (PDE) enzymes are responsible for the regulation of cAMP and cGMP levels in the cell through their degradation to AMP and GMP (Tzoumas et al, 2020 ). PDE-5 is one of the PDE subtypes expressed in various smooth muscle cells involving the kidneys (renal vessels, glomeruli, medullary collecting tubules, cortical tubules) (Coskuner and Ozkan, 2021 ). It has been reported that PDE-5 inhibitors could protect against kidney injury of various etiologies (Afsar et al, 2015 , Coskuner and Ozkan, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…PDE-5 is one of the PDE subtypes expressed in various smooth muscle cells involving the kidneys (renal vessels, glomeruli, medullary collecting tubules, cortical tubules) (Coskuner and Ozkan, 2021 ). It has been reported that PDE-5 inhibitors could protect against kidney injury of various etiologies (Afsar et al, 2015 , Coskuner and Ozkan, 2021 ). PDE-5 inhibitors improve renal functions by different mechanisms, including vasodilation and increased renal blood flow via NO/cGMP signaling, inhibition of oxidative stress, inflammation, and renal cell apoptosis (Georgiadis et al, 2020 , Coskuner and Ozkan, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of renal nitric oxide and eNOS/iNOS expression by tadalafil participates in the mitigation of amphotericin B–induced renal injury: Down-regulation of NF-κB/iNOS/caspase-3 signaling

Abdel-Rahman,

Messiha,

Ali

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Amphotericin B (AmB)–induced acute kidney injury (AKI) is a common health problem having an undesirable impact on its urgent therapeutic utility for fatal systemic fungal infections. Tadalafil (TAD), a phosphodiesterase-5 (PDE-5) inhibitor, has been observed to have a wide range of pharmacological actions, including nephroprotection. The study’s objective was to examine the possible underlying protective mechanism of TAD against AmB-induced nephrotoxicity. Experimentally, animals were divided randomly into four groups: control, TAD (5 mg/kg/day; p.o.), AmB (18.5 mg/kg/day; i.p.), and TAD+AmB groups. Sera and tissue samples were processed for biochemical, molecular, and histological analyses. The biochemical investigations showed that TAD significantly ameliorated the increase of kidney function biomarkers (creatinine, urea, CysC, KIM-1) in serum, renal nitric oxide (NO), lipid peroxidation (MDA), and inflammatory cytokines (TNF-α, IL-6) in AmB-treated rats. Meanwhile, TAD significantly retarded AmB-induced decrease in serum magnesium, sodium, potassium, and renal glutathione content. Molecular analysis revealed that TAD reduced AmB-induced imbalance in the protein expression of eNOS/iNOS, which explains its regulatory effect on renal NO content. These results were also supported by the down-regulation of nuclear NF-κB p65 and cleaved caspase-3 protein expressions, as well as the improvement of histological features by TAD in AmB-treated rats. Therefore, it can be suggested that TAD could be a promising candidate for renoprotection against AmB-induced AKI. That could be partly attributed to its regulatory effect on renal eNOS/iNOS balance and NO, the inhibition of NF-κB p65 nuclear translocation, its downstream inflammatory cytokines and iNOS, and ultimately the inhibition of caspase-3-induced renal apoptosis.

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PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

Zhang,

Huang,

Feng

et al. 2024

Interdisciplinary Medicine

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Phosphodiesterase‐5 (PDE5) inhibitors are used clinically for the treatment of erectile dysfunction, pulmonary arterial hypertension, and other urological diseases. Emerging evidences have suggested the therapeutic capacity of PDE5 inhibitors as the repurposed drugs in oncology. However, the essential immune function of PDE5 inhibitors against cancer in tumor microenvironment (TME) remains unclear. This review aimed to summarize the recent advances regarding the repurposing of PDE5 inhibitors as anti‐cancer agents for cancer management to enhance the anti‐tumor immune response by mediating various immune cells, which included the myeloid‐derived suppressor cells, macrophages, T cells, fibroblasts, and natural killer cells in TME. Moreover, artificial intelligence (AI), as a new approach, is composed of traditional machine learning and deep learning methods and could be potentially used to identify the targets of immune cells in TME and predict the efficacy for repurposed drug toward malignancies. In summary, these endeavors provide novel insights into the comprehensive strategies for PDE5 inhibitors mediating immune cells against cancer and AI‐based approach for future drug repurposing exploration.

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Reno-protective effects of Phosphodiesterase 5 inhibitors

Cited by 14 publications

References 72 publications

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

Regulation of renal nitric oxide and eNOS/iNOS expression by tadalafil participates in the mitigation of amphotericin B–induced renal injury: Down-regulation of NF-κB/iNOS/caspase-3 signaling

PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

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