Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

El-Deen, Reham M.; Heeba, Gehan H.; Abdel‐latif, Rania G.; Khalifa, Mohamed M.

doi:10.1111/fcp.12530

Cited by 8 publications

(6 citation statements)

References 65 publications

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“…Mechanistically, miR-137-3p is directly bound to the 3′-UTR of PDE4D, a cAMP-specific phosphodiesterase, and subsequently increased hepatic cAMP level and PKA activity, thereby activating the downstream AMPK α pathway. Consistently, other findings also proved that the treatment with PDE inhibitors could protect against HFD-induced NAFLD [ 55 , 56 ]. Beyond AMPK α , many other downstream targets of miR-137-3p have been proposed.…”

Section: Discussionsupporting

confidence: 75%

MicroRNA-137-3p Improves Nonalcoholic Fatty Liver Disease through Activating AMPKα

Sheng

et al. 2021

Analytical Cellular Pathology

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Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide and can develop to nonalcoholic steatohepatitis and later hepatic cirrhosis with a high prevalence to hepatocellular carcinoma. Oxidative stress and chronic hepatic inflammation are implicated in the pathogenesis of NAFLD. MicroRNA-137-3p (miR-137-3p) are associated with oxidative stress and inflammation; however, its role and mechanism in NAFLD remain unclear. Mice were fed with a high-fat diet (HFD) for 24 weeks to establish the NAFLD model. To overexpress or suppress hepatic miR-137-3p expression, mice were intraperitoneally injected with the agomir, antagomir, or respective controls of miR-137-3p at a dose of 100 mg/kg weekly for 6 consecutive weeks before the mice were sacrificed. To validate the involvement of AMP-activated protein kinase alpha (AMPKα) or cAMP-specific phosphodiesterase 4D (PDE4D), HFD mice were intraperitoneally injected with 20 mg/kg compound C or 0.5 mg/kg rolipram every other day for 8 consecutive weeks before the mice were sacrificed. Hepatic miR-137-3p expression was significantly decreased in mice upon HFD stimulation. miR-137-3p agomir alleviated, while miR-137-3p antagomir facilitated HFD-induced oxidative stress, inflammation, and hepatic dysfunction in mice. Mechanistically, we revealed that miR-137-3p is directly bound to the 3 ′ -untranslated region of PDE4D and subsequently increased hepatic cAMP level and protein kinase A activity, thereby activating the downstream AMPKα pathway. In summary, miR-137-3p improves NAFLD through activating AMPKα and it is a promising therapeutic candidate to treat NAFLD.

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Section: Discussionsupporting

confidence: 75%

MicroRNA-137-3p Improves Nonalcoholic Fatty Liver Disease through Activating AMPKα

Sheng

et al. 2021

Analytical Cellular Pathology

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“…Blood samples were collected by cardiac puncture and centrifuged for 10 min to obtain serum. After that, rats were sacrificed by decapitation and the livers were collected rinsed extensively in cold PBS and preserved for histopathological examination, oxidative stress, and inflammatory markers [13]. TC, TGs, HDL, LDL, VLDL, AST, ALP, ALT, and AI bilirubin were measured as described previously [14] while CRI calculated using formula [15].…”

Section: Hfd-induced Hyperlipidemiamentioning

confidence: 99%

Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways

Irshad

Khan

Shah

et al. 2021

Fundamemntal Clinical Pharma

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Hyperlipidemia is worth-mentioning risk factor in quickly expanding atherosclerosis, myocardial infarction, and stroke. This study attempted to determine effectiveness of selected pyrimidine derivatives: 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9), and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hyperlipidemia. In silico results revealed that SR-5, SR-8, SR-9, and SR-10 exhibited high affinity with 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) possessing binding energy values of −8.2, −8.4, −8.6, and −9.5 Kcal/mol, respectively, and moderate (<−8 Kcal/mol) against other selected targets. In vivo findings showed that test drugs (25 and 50 mg/Kg) significantly decreased HFD rat total cholesterol, triglycerides, low-density lipoprotein, very-low-density lipoprotein, atherogenic index, coronary risk index, alkaline phosphatase, aspartate transaminase, alanine transaminase, and bilirubin and increased high-density lipoprotein (p < 0.05, p < 0.01, p < 0.001 vs HFD group). In animal liver tissues, SR-5, SR-8, SR-9, and SR-10 inhibited HMGCoA reductase enzyme, enhanced glutathione-s-transferase, reduced glutathione, catalase levels, improved cellular architecture in histopathological examination, and decreased expression of inflammatory markers: cyclo-oxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in immunohistochemistry and enzyme-linked immunosorbent assay molecular investigations. This study indicates that SR-5, SR-8, SR-9, and SR-10 exhibit antihyperlipidemic action, mediated possibly through HMGCoA inhibition, hepatoprotection, antioxidant, and anti-inflammatory pathways.

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“…This result is in accordance with earlier studies that have reported the anti-inflammatory properties of Cilo in different experimental models of testicular injury [ 11 , 21 ]. Furthermore, the protective effect of Cilo against diclofenac-induced renal toxicity [ 37 ], high-fat-diet-induced nonalcoholic fatty liver [ 38 ], and cyclophosphamide-induced cardiac damage [ 39 ] has been partially attributed to its ability to diminish the level of inflammatory markers. Milrinone also dramatically decreases TNF-α levels, which contributes to its ameliorative effect against ischemia-reperfusion testicular injury [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Further, the potent anti-inflammatory properties of PTX have been documented in various illnesses [ 44 ]. PTX decreased TNF-α and NF-κB in cerebral ischemia reperfusion [ 45 ], high-fat-diet-induced nonalcoholic fatty liver [ 38 ], and diclofenac-induced acute renal injury [ 37 ] models. Importantly, the decline in NF-κB and TNF-α expression was more pronounced in CIS rats treated with 20 mg of Cilo compared to either the TDF or the PTX group.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways

Othman

Habib

Zahran

et al. 2023

IJMS

Self Cite

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Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa β, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage.

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Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

Cited by 8 publications

References 65 publications

MicroRNA-137-3p Improves Nonalcoholic Fatty Liver Disease through Activating AMPKα

MicroRNA-137-3p Improves Nonalcoholic Fatty Liver Disease through Activating AMPKα

Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways

Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways

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