Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study

Mohamed, Doaa I.; Ezzat, Samar F.; Elayat, Wael M.; El-Kharashi, Omnyah A.; El-Kareem, Hanaa F. Abd; Nahas, Hebatallah H. Abo; Abdel-Wahab, Basel A.; Alshawwa, Samar Zuhair; Saleh, Asmaa; Helmy, Yosra A.; Khairy, Eman; Saied, Essa M.

doi:10.3390/ph15070832

Cited by 20 publications

(15 citation statements)

References 101 publications

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“…To explore whether the observed anti-inflammatory activity of this class of compounds could be a result of their ability to target Cyclooxygenases enzymes, extensive molecular docking studies were performed using MOE software. Computational analysis affirmed the ability to assess the binding affinity of small molecules (ligand) toward the active pocket of the targeted protein (receptor) and offer valuable information to explain the mode of action of pharmacological compounds [ 97 , 98 , 99 , 100 , 101 , 102 ]. To examine the binding mode of mono N3-substituted and N1, N3-disubstituted-2-thohydantoins, compounds 5 and 7 were selected to explore their binding affinity toward the active pocket of COX1 and COX-2 enzymes.…”

Section: Methodsmentioning

confidence: 99%

“…The X-ray structures of COX-1 (PDB code: 3KK6 ) and COX-2 (PDB code: 3LN1 ) were acquired from the protein databank RCSB ( , accessed on 1 June 2022) [ 103 , 104 ]. The preparation of COX1 and 2 proteins, 3D-structures of compounds 5 and 7 , and the molecular modelling study were achieved utilizing the MOE program as previously reported [ 97 , 98 , 99 , 100 , 101 , 102 ]. The docking protocol was adjusted to Triangle Matcher placement and the scoring function to London dG.…”

Section: Methodsmentioning

confidence: 99%

“…The p value was used to establish the relevance of the data; p > 0.05 is regarded non-significant, whereas p < 0.05 is considered significant. For statistical assessment, we used GraphPad prism software Incorporation (San Diego, CA, USA, 2007) [ 101 , 102 ].…”

Section: Methodsmentioning

confidence: 99%

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Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

et al. 2022

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Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term application. Toward this aim, the present study reported the design, synthesis, and characterization of a set of novel 1,3-disubstituted-2-thiohydantoins derivatives. The anti-inflammatory activity of synthesized compounds was assessed against murine leukemia cell line (RAW264.7) by evaluating the cytotoxicity activity and their potency to prevent nitric oxide (NO) production. The results revealed that the synthesized compounds possess a considerable cytotoxic activity together with the ability to reduce the NO production in murine leukemia cell line (RAW264.7). Among synthesized compounds, compound 7 exhibited the most potent cytotoxic activity with IC50 of 197.68 μg/mL, compared to celecoxib drug (IC50 value 251.2 μg/mL), and demonstrated a significant ability to diminish the NO production (six-fold reduction). Exploring the mode of action responsible for the anti-inflammatory activity revealed that compound 7 displays a significant and dose-dependent inhibitory effect on the expression of pro-inflammatory cytokines IL-1β. Furthermore, compound 7 demonstrated the ability to significantly reduce the expression of the inflammatory cytokines IL-6 and TNF-α at 50 μg/mL, as compared to Celecoxib. Finally, detailed molecular modelling studies indicated that compound 7 exhibits a substantial binding affinity toward the binding pocket of the cyclooxygenase 2 enzyme. Taken together, our study reveals that 1,3-disubstituted-2-thiohydantoin could be considered as a promising scaffold for the development of potent anti-inflammatory agents.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

et al. 2022

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“…Draw tool was used to construct the structure of the target compounds 3c and 4 . Then, the protonated 3D structure of target ligands 3c and 4 , the preparation of VEGFR2, and the docking studies were performed using MOE software as previously reported [ 35 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. The validity of the applied protocol was evaluated by performing a molecular docking of the original inhibitor to affirm the main interactions that exist in the reported crystal structure.…”

Section: Methodsmentioning

confidence: 99%

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

et al. 2022

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Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.

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“…Liver tissue sections were examined, and staging and grading of liver were graded according to the Supplementary Tables S1 and S2 [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

Vitamin D and Swimming Exercise Prevent Obesity in Rats under a High-Fat Diet via Targeting FATP4 and TLR4 in the Liver and Adipose Tissue

Kolieb

Maher

Shalaby

et al. 2022

IJERPH

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The prevalence of obesity has risen in the last decades, and it has caused massive health burdens on people’s health, especially metabolic and cardiovascular issues. The risk of vitamin D insufficiency is increased by obesity, because adipose tissue alters both the requirements for and bioavailability of vitamin D. Exercise training is acknowledged as having a significant and long-term influence on body weight control; the favorable impact of exercise on obesity and obesity-related co-morbidities has been demonstrated via various mechanisms. The current work illustrated the effects of vitamin D supplementation and exercise on obesity induced by a high-fat diet (HFD) and hepatic steatosis in rats and explored how fatty acid transport protein-4 (FATP4) and Toll-like receptor-4 antibodies (TLR4) might be contributing factors to obesity and related hepatic steatosis. Thirty male albino rats were divided into five groups: group 1 was fed a normal-fat diet, group 2 was fed an HFD, group 3 was fed an HFD and given vitamin D supplementation, group 4 was fed an HFD and kept on exercise, and group 5 was fed an HFD, given vitamin D, and kept on exercise. The serum lipid profile adipokines, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were analyzed, and the pathological changes in adipose and liver tissues were examined. In addition, the messenger–ribonucleic acid (mRNA) expression of FATP4 and immunohistochemical expression of TLR4 in adipose and liver tissues were evaluated. Vitamin D supplementation and exercise improved HFD-induced weight gain and attenuated hepatic steatosis, along with improving the serum lipid profile, degree of inflammation, and serum adipokine levels. The expression of FATP4 and TLR4 in both adipose tissue and the liver was downregulated; it was noteworthy that the group that received vitamin D and was kept on exercise showed also improvement in the histopathological picture of this group. According to the findings of this research, the protective effect of vitamin D and exercise against obesity and HFD-induced hepatic steatosis is associated with the downregulation of FATP4 and TLR4, as well as a reduction in inflammation.

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Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study

Cited by 20 publications

References 101 publications

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

Vitamin D and Swimming Exercise Prevent Obesity in Rats under a High-Fat Diet via Targeting FATP4 and TLR4 in the Liver and Adipose Tissue

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