Positional scanning of natural product hispidol’s ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases

Hassan, Ahmed H.E.; Kim, Yang Soo; Gee, Min Sung; Park, Jong‐Hyun; Jeon, Hye Rim; Lee, Cheol Jung; Choi, Yeonwoo; Moon, Suyeon; Lee, Danbi; Lee, Jong Kil; Park, Ki Duk; Lee, Yong Sup

doi:10.1080/14756366.2022.2036737

Cited by 14 publications

(11 citation statements)

References 73 publications

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“…Here, our study found that EF could directly bind to MAO-B and inhibit its activity, indicating that the MAO-B inhibition might contribute to the anti-inflammatory and neuroprotective effects of EF on ischemic stroke. A recent study also discovered several highly selective MAO-B inhibitors and validated their anti-inflammatory effects in microglia, further supporting that MAO-B is a promising therapeutic target in neuroinflammation ( Hassan et al, 2022 ). Additionally, given that MAO-B is also a therapeutic target in Parkinson’s disease (PD), we proposed that EF might have potentials as a MAO-B inhibitor to treat PD, which needs further validation in preclinical rodent models of PD.…”

Section: Discussionmentioning

confidence: 85%

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

Zou

Gao

et al. 2022

Front. Pharmacol.

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Microglia are the resident macrophages in the brain, which play a critical role in post-stroke neuroinflammation. Accordingly, targeting neuroinflammation could be a promising strategy to improve ischemic stroke outcomes. Ethyl ferulate (EF) has been confirmed to possess anti-inflammatory properties in several disease models, including acute lung injury, retinal damage and diabetes-associated renal injury. However, the effects of EF on microglial activation and the resolution of post-stroke neuroinflammation remains unknown. Here, we found that EF suppressed pro-inflammatory response triggered by lipopolysaccharide (LPS) stimulation in primary microglia and BV2 cell lines, as well as post-stroke neuroinflammation in an in vivo transient middle cerebral artery occlusion (tMCAO) stroke model in C57BL/6 mice, consequently ameliorating ischemic brain injury. Furthermore, EF could directly bind and inhibit the activity of monoamine oxidase B (MAO-B) to reduce pro-inflammatory response. Taken together, our study identified a MAO-B inhibitor, Ethyl ferulate, as an active compound with promising potentials for suppressing post-stroke neuroinflammation.

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Section: Discussionmentioning

confidence: 85%

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

Zou

Gao

et al. 2022

Front. Pharmacol.

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“…MAOB, as a form of monoamine oxidase (MAO), catalyzes the oxidative deamination of biogenic amines and allogenic amines ( Hassan et al, 2022 ). In wild-type mice, pressure overload induced by transverse aortic constriction (TAC) leads to enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of Renshen-Fuzi herb pair for treating heart failure—Integrating a cardiovascular pharmacological assessment with serum metabolomics

Chen

Xie

et al. 2022

Front. Pharmacol.

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Background: Renshen-Fuzi herb pair (RS-FZ) is often used in the clinical treatment of heart failure (HF) and has a remarkable therapeutic effect. However, the mechanism of RS-FZ for treating HF remains unclear. In our study, we explored the mechanism of RS-FZ for treating HF.Methods: Evaluation of RS-FZ efficacy by cardiovascular pharmacology. Moreover, Global metabolomics profiling of the serum was detected by UPLC-QTOF/MS. Multivariate statistics analyzed the specific serum metabolites and corresponding metabolic pathways. Combining serum metabolomics with network pharmacology, animal experiments screened and validated the critical targets of RS-FZ intervention in HF.Results: RS-FZ significantly ameliorated myocardial fibrosis, enhanced cardiac function, and reduced the serum HF marker (brain natriuretic peptide) level in rats with HF. Through topological analysis of the “Metabolite-Target-Component” interaction network, we found that 79 compounds of RS-FZ directly regulated the downstream specific serum metabolites by acting on four critical target proteins (CYP2D6, EPHX2, MAOB, and ENPP2). The immunohistochemistry results showed that RS-FZ observably improved the expression of CYP2D6 and ENPP2 proteins while decreasing the expression of EPHX2 and MAOB proteins dramatically.Conclusion: The integrated cardiovascular pharmacological assessment with serum metabolomics revealed that RS-FZ plays a crucial role in the treatment of HF by intervening in CYP2D6, EPHX2, MAOB, and ENPP2 target proteins. It provides a theoretical basis for RS-FZ for treating HF.

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“…A molecular docking study was performed using the crystal structure of TMPRSS2 deposited in Protein Data Bank (PDB: 7MEQ) employing standard computational protocols as described in Supplementary Materials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Methodsmentioning

confidence: 99%

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Hassan,

El-Sayed,

Yamamoto

et al. 2023

Viruses

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Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10–12 triggered potential TMPRSS2 inhibition with low micromolar IC50 concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC50 value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.

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Positional scanning of natural product hispidol’s ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases

Cited by 14 publications

References 73 publications

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

The mechanism of Renshen-Fuzi herb pair for treating heart failure—Integrating a cardiovascular pharmacological assessment with serum metabolomics

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

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