Therapeutic effect of rupatadine against <scp>l</scp>-arginine-induced acute pancreatitis in rats: role of inflammation

Mohamed, Mervat Z.; Mohammed, Hanaa H.; Khalaf, Hanaa Mohamed

doi:10.1139/cjpp-2021-0330

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…RUP previously alleviated ROS-induced hepatocyte and intestinal apoptosis (Mohamed and Mohammed 2021). Besides, the anti-oxidant activity of RUP was demonstrated in rats with acute pancreatitis and diabetic nephropathy as well as in allergic rhinitis in patients (Hafez et al 2020;Kahveci et al 2021;Mohamed et al 2022). Based on these findings, the anti-oxidant activity of RUP could be postulated to prevent ROS-induced fibrosis.…”

Section: Discussionmentioning

confidence: 89%

A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories

2023

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Hepatic fibrosis is one of the major worldwide health concerns which requires tremendous research due to the limited outcomes of the current therapies. The present study was designed to assess, for the first time, the potential therapeutic effect of rupatadine (RUP) in diethylnitrosamine (DEN)-induced liver fibrosis and to explore its possible mechanistic actions. For the induction of hepatic fibrosis, rats were treated with DEN (100 mg/kg, i.p.) once weekly for 6 consecutive weeks, and on the 6th week, RUP (4 mg/kg/day, p.o.) was administered for 4 weeks. Treatment with RUP ameliorated changes in body weights, liver indices, liver function enzymes, and histopathological alterations induced by DEN. Besides, RUP amended oxidative stress, which led to the inhibition of PAF/NF-κB p65-induced inflammation, and, subsequently, prevention of TGF-β1 elevation and HSCs activation as indicated by reduced α-SMA expression and collagen deposition. Moreover, RUP exerted significant anti-fibrotic and anti-angiogenic effects by suppressing Hh and HIF-1α/VEGF signaling pathways. Our results highlight, for the first time, a promising anti-fibrotic potential of RUP in rat liver. The molecular mechanisms underlying this effect involve the attenuation of PAF/NF-κB p65/TGF-β1 and Hh pathways and, subsequently, the pathological angiogenesis (HIF-1α/VEGF). Graphical abstract

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Section: Discussionmentioning

confidence: 89%

A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories

2023

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“…Although the results of the RP-treated cells were not further examined in this study, a recent in vivo study has demonstrated that RP exhibits important anti-inflammatory and anti-apoptotic effects against l -arginine-induced acute pancreatitis by reducing the expression of nuclear factor kappa-B (NF-κB) and caspase 3, with the latter playing a crucial role in the apoptosis cascade that is anticipated upon p53 activation. 62 , 63 A confluence of the anti-apoptotic effects due to caspase 3 downregulation and the pro-apoptotic effects due to MDM2 inhibition could contribute to the near-basal/down-regulated levels of BAX , CDKN1A , and DDB2 expression in the RP-treated U87 cell lines. Despite the relatively low IC 50 dose, the same mechanism might not be as effective in the SH-SY5Y cell lines, hence the increased BAX and DDB2 expression but the decreased level of CDKN1A expression.…”

Section: Discussionmentioning

confidence: 99%

Targeting MDM2–p53 Axis through Drug Repurposing for Cancer Therapy: A Multidisciplinary Approach

Ghafoor,

Yildiz

2023

ACS Omega

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Cancer remains a major cause of morbidity and mortality worldwide, and while current therapies, such as chemotherapy, immunotherapy, and cell therapy, have been effective in many patients, the development of novel therapeutic options remains an urgent priority. Mouse double minute 2 (MDM2) is a key regulator of the tumor suppressor protein p53, which plays a critical role in regulating cellular growth, apoptosis, and DNA repair. Consequently, MDM2 has been the subject of extensive research aimed at developing novel cancer therapies. In this study, we employed a machine learningbased approach to establish a quantitative structure−activity relationship model capable of predicting the potential in vitro efficacy of small molecules as MDM2 inhibitors. Our model was used to screen 5883 FDA-approved drugs, resulting in the identification of promising hits that were subsequently evaluated using molecular docking and molecular dynamics simulations. Two antihistamine drugs, cetirizine (CZ) and rupatadine (RP), exhibited particularly favorable results in the initial in silico analyses. To further assess their potential use as the activators of the p53 pathway, we investigated the antiproliferative capability of the abovementioned drugs on human glioblastoma and neuroblastoma cell lines. Both the compounds exhibited significant antiproliferative effects on the abovementioned cell lines in a dose-dependent manner. The half-maximal inhibitory concentration (IC 50 ) of CZ was found to be 697.87 and 941.37 μM on U87 and SH-SY5Y cell lines, respectively, while the IC 50 of RP was found to be 524.28 and 617.07 μM on the same cell lines, respectively. Further investigation by quantitative reverse transcriptase polymerase chain reaction analysis revealed that the CZ-treated cell lines upregulate the expression of the p53-regulated genes involved in cell cycle arrest, apoptosis, and DNA damage response compared to their respective vehicle controls. These findings suggest that CZ activates the p53 pathway by inhibiting MDM2. Our results provide compelling preclinical evidence supporting the potential use of CZ as a modulator of the MDM2−p53 axis and its plausible repurposing for cancer treatment.

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“…4). Although the results of RP-treated cells were not further examined in this study, a recent in vivo study has demonstrated that RP exhibits important anti-in ammatory and anti-apoptotic effects against l-arginine-induced acute pancreatitis by reducing the expression of nuclear factor kappa-B (NF-κB) and caspase 3, the latter playing a crucial role in the apoptosis cascade which is anticipated upon p53 activation [58,59]. A con uence of anti-apoptotic effects due to caspase 3 downregulation and pro-apoptotic effects due to MDM2 inhibition could contribute to the near-basal/down-regulated levels of BAX, CDKN1A, and DDB2 expression in RP-treated U87 cell lines.…”

Section: Discussionmentioning

confidence: 99%

Targeting MDM2-p53 Axis Through Drug Repurposing for Cancer Therapy: a Multidisciplinary Approach

Ghafoor

Yıldız

2023

Preprint

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Purpose The purpose of this study was to identify potential small molecule inhibitors from a pool of FDA approved drugs that holds a potency against MDM2 and investigate their potential use as a modulator of MDM2-p53 axis to activate the p53 pathway in vitro for further use in drug repurposing studies.Methods In this study, machine learning-based approach to establish a quantitative structure-activity relationship model for predicting the potential in vitro efficacy of small molecules as MDM2 inhibitors. The developed model was used to screen 5883 FDA-approved drugs, resulting in the identification of promising hits that were subsequently evaluated using molecular docking and molecular dynamics simulations. Promising hits were further investigated for their cytotoxicity and anti-proliferative properties in vitro via MTT assay on glioblastoma and neuroblastoma cell lines. The expression of BAX, CDKN1A, and DDB2, three p53-regulated genes were investigated in drug treated cell lines to confirm the activation of the p53 in the former cell lines.Results Two antihistamine drugs, cetirizine (CZ) and rupatadine (RP), exhibited particularly favorable results in the initial in silico analyses. Both compounds exhibited significant antiproliferative effects on the former cell lines in a dose-dependent manner. Further investigation by quantitative reverse transcriptase PCR revealed CZ-treated but not RP-treated cell lines to upregulate the expression of p53-regulated genes.Conclusion These findings suggest that CZ activates the p53 pathway by inhibiting MDM2. Our results provide compelling preclinical evidence supporting the potential use of CZ as a modulator of the MDM2-p53 axis and its plausible repurposing for cancer treatment.

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Therapeutic effect of rupatadine against l-arginine-induced acute pancreatitis in rats: role of inflammation

Cited by 6 publications

References 37 publications

A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories

A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories

Targeting MDM2–p53 Axis through Drug Repurposing for Cancer Therapy: A Multidisciplinary Approach

Targeting MDM2-p53 Axis Through Drug Repurposing for Cancer Therapy: a Multidisciplinary Approach

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