Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase

Liu, Zehui; Hu, Qian; Wang, Wanyan; Lu, Sisi; Wu, Dang; Ze, Shuyin; He, Jiacheng; Huang, Ying; Chen, Wuyan; Xu, Yechun; Lü, Weiqiang; Huang, Jin

doi:10.1016/j.bcp.2020.114000

Cited by 17 publications

(6 citation statements)

References 60 publications

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“…On the other hand, using a panel of biochemical assays and structural biology approach, we identified that piperine, a main bioactive constituent of black pepper, as a potent inhibitor of DHODH. We characterized that piperine impairs T cell proliferation as well as reduced inflammation in MOG-induced EAE mouse model with lessened myelin and bold-brain barrier (BBB) destruction by targeting DHODH (161). Collectively, these natural products-derived DHODH inhibitors may represent promising treatment strategy across various diseases.…”

Section: Natural Product-derived Inhibitorsmentioning

confidence: 99%

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Wang

Cui

et al. 2021

Front. Oncol.

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Metabolic rewiring is considered as a primary feature of cancer. Malignant cells reprogram metabolism pathway in response to various intrinsic and extrinsic drawback to fuel cell survival and growth. Among the complex metabolic pathways, pyrimidine biosynthesis is conserved in all living organism and is necessary to maintain cellular fundamental function (i.e. DNA and RNA biosynthesis). A wealth of evidence has demonstrated that dysfunction of pyrimidine metabolism is closely related to cancer progression and numerous drugs targeting pyrimidine metabolism have been approved for multiple types of cancer. However, the non-negligible side effects and limited efficacy warrants a better strategy for negating pyrimidine metabolism in cancer. In recent years, increased studies have evidenced the interplay of oncogenic signaling and pyrimidine synthesis in tumorigenesis. Here, we review the recent conceptual advances on pyrimidine metabolism, especially dihydroorotate dehydrogenase (DHODH), in the framework of precision oncology medicine and prospect how this would guide the development of new drug precisely targeting the pyrimidine metabolism in cancer.

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Section: Natural Product-derived Inhibitorsmentioning

confidence: 99%

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Wang

Cui

et al. 2021

Front. Oncol.

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“…The nuclear receptor retinoic acid receptor-related orphan receptor γ-t (RORγt) is a key regulator of the development of T-helper 17 (Th17) cells and the production of IL-17, which are related to the pathology of a variety of human inflammatory and autoimmune disorders. , In this context, modulating Th17 cells via RORγt inhibition has been expected to be an attractive strategy for the management of IBD. − However, some of frontrunner clinical compounds were either discontinued or suspended for further development probably due to lack of efficacy in humans, which continuously promoted multitarget-directed compound design to increase therapeutic efficacy. Apart from RORγt, inhibition of human dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of pyrimidine de novo synthesis, blocks lymphocyte activation via metabolic stress and leads to reduction of pro-inflammatory cytokines, such as IL-17, IL-6, and TNF-α. − Thus, DHODH has been considered as an attractive target for the treatment of autoimmune diseases. DHODH inhibitors like leflunomide and its active metabolite teriflunomide have been approved for the treatment of rheumatoid arthritis (RA) and multiple sclerosis (MS). − However, the long elimination half-life of teriflunomide (approximately 2 weeks) is implicated with its observed hepatotoxicity in clinical practice and potential teratogenicity in animal study. − …”

Section: Introductionmentioning

confidence: 99%

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Chen

Liu

et al. 2021

J. Med. Chem.

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Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC 50 values of 0.110 μM for RORγt and of 0.297 μM for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.

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“…It has also been proved that piperine reduces in ammation by suppressing iNOS activity and activating the nuclear factor erythroid 2-related factor 2 (Nrf-2) / heme oxygenase-1 (HO-1) [29,30]. Recent study revealed that piperine decreased T-cell proliferation via dihydrooratate dehydrogenase inhibition, which provides a therapeutic strategy for MS disease [31]. Furthermore, piperine was effective in various animal models of neurological diseases such as Alzheimer [16,32], Parkinson [33,34], epilepsy [35] and local model of demyelination [30].…”

Section: Introductionmentioning

confidence: 99%

Piperine Improves Experimental Autoimmune Encephalomyelitis (EAE) in Lewis Rats Through its Neuroprotective, Anti-inflammatory, and Antioxidant Effects

et al. 2021

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In ammation, demyelination, glial activation, and oxidative damage are the most pathological hallmarks of multiple sclerosis (MS). Piperine, a main bioactive alkaloid of black pepper, possesses antioxidant, anti-in ammatory and neuroprotective properties whose therapeutic potential has been less studied in the experimental autoimmune encephalomyelitis (EAE) models. In this study, the e ciency of peprine on progression of EAE model and myelin repair mechanisms was investigated. EAE was induced in female Lewis rats and piperine and its vehicle were daily administrated intraperitoneally from day 8 to 29 post immunization. We found that peperine alleviated neurological de cits and EAE disease progression. Luxol fast blue and H&E staining and immuno-staining of lumbar spinal cord cross sections con rmed that piperine signi cantly reduced the extent of demyelination, in ammation and immune cell in ltration and inhibited microglia and astrocyte activation. Gene expression analysis in lumbar spinal cord showed that piperine treatment decreased the level of pro-in ammatory cytokines (TNF-α, IL-1β) and iNOS and enhanced IL-10, Nrf-2, HO-1and MBP expressions. Piperine supplementation also enhanced the total antioxidant capacity (FRAP) and reduced the level of oxidative stress marker (MDA) in the CNS of EAE rats. Finally, we found that piperine has anti-apoptotic and neuroprotective effect in EAE through reducing caspase-3 (apoptosis marker) and enhancing BDNF and NeuN expressing cells. This study strongly indicates that piperine has a bene cial effect on the EAE progression and could be considered as a potential therapeutic target for MS treatment. Upcoming clinical trials will provide the deep understanding of piperine's role for the treatment of the MS.

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Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase

Cited by 17 publications

References 60 publications

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Piperine Improves Experimental Autoimmune Encephalomyelitis (EAE) in Lewis Rats Through its Neuroprotective, Anti-inflammatory, and Antioxidant Effects

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