Last update 01 Nov 2024

Nrf2 x PDE4

Last update 01 Nov 2024

Basic Info

Related Targets

Nrf2PDE4

Drugs associated with Nrf2 x PDE4

RLV-147

Target

Nrf2 x PDE4

Mechanism

Nrf2 stimulants [+1]

Active Org.

Resolvex Pharmaceuticals Inc.

Originator Org.

Resolvex Pharmaceuticals Inc.

Active Indication

Inflammation

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Nrf2 x PDE4

100 Translational Medicine associated with Nrf2 x PDE4

0 Patents (Medical) associated with Nrf2 x PDE4

Literatures (Medical) associated with Nrf2 x PDE4

01 Nov 2024·International Journal of Biological Macromolecules

Fibroblast growth factor 1 (FGF1) improves glucose homeostasis, modulates gut microbial composition, and reduces inflammatory responses in rainbow trout (Oncorhynchus mykiss) fed a high-fat diet

Article

Author: Du, Yuyou ; Zhang, Qianqin ; Wang, Lixin ; Gao, Jiuwei ; Liu, Kexin ; Mo, Haolin ; Yu, Huixia ; Yao, Mingxing ; Li, Yang ; Yu, Jiajia

High-fat diets (HFDs) are widely used in aquaculture due to their lipid and protein-conserving effects, thereby reducing feed costs. However, prolonged feeding of HFD often leads to metabolic disorders in fish, such as disruption of hepatic lipid homeostasis, liver injury, and disruption of glucose homeostasis. Fibroblast growth factor 1 (FGF1) plays an essential role in controlling glucose levels in the body and dampening immune reactions. However, its impact on teleosts remains poorly researched. The therapeutic potential of recombinant FGF1 (rFGF1) was examined in a 6-week culture experiment involving rainbow trout (Oncorhynchus mykiss) that were fed an HFD. The results revealed that rFGF1 significantly reduced serum glucose levels and hepatic PEPCK and G6PC activities, but improved hepatic glycogen (P < 0.05), compared to the HFD + PBS group. Further experiments indicated that the inhibitory effect of rFGF1 on hepatic gluconeogenesis was mediated by the cAMP signaling pathway and was dependent on the high expression of PDE4. In addition, rFGF1 increased hepatic glycogen content, which involves the AKT-GSK3β axis. Despite this increase, rFGF1 did not lead to glycogen storage disease, as shown by reduced hepatic inflammation as a result of decreased GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), and elevated SOD (superoxide dismutase) in the rFGF1-treated group, accompanied by decreased il-1β, il-6, and xbp-1, and elevated nrf2 and number of hepatocyte autophagosomes. Alterations in gut microbes and short-chain fatty acids (SCFAs) were noted, indicating that rFGF1 caused a notable rise in intestinal Lactobacillus, acetic acid, and butyric acid levels. This study investigated the molecular mechanisms of rFGF1 on glucose metabolism and inflammatory responses in an HFD-fed rainbow trout model, providing new insights to improve the regulation of glucose metabolism in carnivorous fish.

01 Apr 2024·Inflammopharmacology

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

Article

Author: Abdel-Salam, Omar M E ; El Sayed, Nesrine S ; El-Shamarka, Marwa El-Sayed ; Farid, Heba A ; Sayed, Rabab H

AbstractParkinson’s disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3β and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation.Graphical Abstract

01 May 2023·Journal of dermatological science

Roflumilast enhances the melanogenesis and attenuates oxidative stress-triggered damage in melanocytes.

Article

Author: Chen, Bin ; Wu, Zhouwei ; Nie, Shu ; Chen, Zile ; Li, Yiting ; Xie, Yongyi

BACKGROUNDThe management of vitiligo is challenging due to limited treatment options, and therapeutic strategy varies according to the active or stable stage of vitiligo. PDE4 inhibitor has been used to treat various skin diseases, but the efficacy in vitiligo treatment is mixed.OBJECTIVEIn this study, we aimed to investigate whether roflumilast, a PDE4 inhibitor, induces melanogenesis and attenuates oxidative stress-triggered damage in melanocytes, and if so, what is the mechanism.METHODSMelanin content assay, qRT-PCR, western blotting, ELISA, immunofluorescence assays, immunohistochemistry, small interfering RNA, flow cytometry, and transmission electron microscopy were employed.RESULTSOur results demonstrated that roflumilast alone only slightly increased melanogenesis, however, the combination of roflumilast and forskolin could boost cAMP levels, hence promoting melanogenesis more significantly. Moreover, roflumilast attenuated H₂O₂-induced apoptosis and mitochondrial morphological changes in melanocytes by reducing ROS levels. Furthermore, roflumilast activated AhR/Nrf2 pathway via cAMP whereas AhR silencing blocked roflumilast-induced Nrf2 nuclear translocation and reversed the inhibitory effect of roflumilast on H₂O₂-induced ROS production. Finally, we observed that the lesional skin of active vitiligo patients exhibited higher PDE4 expression levels.CONCLUSIONroflumilast enhances the melanogenesis effect of forskolin and protects melanocytes from H₂O₂-induced apoptosis by cAMP/AhR/Nrf2-activated ROS inhibition, highlighting its therapeutic potential in vitiligo treatment.

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