更新于：2024-11-01

p38 MAPK x PDE4

更新于：2024-11-01

基本信息

关联

项与 p38 MAPK x PDE4 相关的药物

CBS-3595

靶点

PDE4 x p38 MAPK

作用机制

PDE4抑制剂 [+1]

在研机构

c-a-i-r biosciences GmbH [+1]

原研机构

Merckle GmbH

在研适应症

类风湿关节炎

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

CGH-2466

靶点

A1R x PDE4 x p38 MAPK

作用机制

A1R拮抗剂 [+2]

在研机构-

原研机构

Novartis AG

在研适应症-

非在研适应症

哮喘 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 p38 MAPK x PDE4 相关的临床结果

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100 项与 p38 MAPK x PDE4 相关的转化医学

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0 项与 p38 MAPK x PDE4 相关的专利（医药）

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项与 p38 MAPK x PDE4 相关的文献（医药）

2022-02-01·Toxicology and Applied Pharmacology3区 · 医学

Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein

3区 · 医学

Article

作者: Wang, Haitao ; Qiu, Shuqing ; Zhong, Jiahong ; Dong, Wenli ; Li, Mengfan ; Xu, Jiangping ; Li, Xing ; Qin, Yunyun

We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 μM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

2021-10-01·Traffic2区 · 生物学

Phosphatidic acid‐PKA signaling regulates p38 and ERK1/2 functions in ligand‐independent EGFR endocytosis

2区 · 生物学

Article

作者: Oyanadel, Claudia ; Cancino, Jorge ; Retamal, Claudio ; Venegas, Jaime ; Barra, Jonathan ; Du, Guangwei ; Jung, Juan ; Metz, Claudia ; Soza, Andrea ; González, Alfonso

AbstractLigand‐independent epidermal growth factor receptor (EGFR) endocytosis is inducible by a variety of stress conditions converging upon p38 kinase. A less known pathway involves phosphatidic acid (PA) signaling toward the activation of type 4 phosphodiesterases (PDE4) that decrease cAMP levels and protein kinase A (PKA) activity. This PA/PDE4/PKA pathway is triggered with propranolol used to inhibit PA hydrolysis and induces clathrin‐dependent and clathrin‐independent endocytosis, followed by reversible accumulation of EGFR in recycling endosomes. Here we give further evidence of this signaling pathway using biosensors of PA, cAMP, and PKA in live cells and then show that it activates p38 and ERK1/2 downstream the PKA inhibition. Clathrin‐silencing and IN/SUR experiments involved the activity of p38 in the clathrin‐dependent route, while ERK1/2 mediates clathrin‐independent EGFR endocytosis. The PA/PDE4/PKA pathway selectively increases the EGFR endocytic rate without affecting LDLR and TfR constitute endocytosis. This selectiveness is probably because of EGFR phosphorylation, as detected in Th1046/1047 and Ser669 residues. The EGFR accumulates at perinuclear recycling endosomes colocalizing with TfR, fluorescent transferrin, and Rab11, while a small proportion distributes to Alix‐endosomes. A non‐selective recycling arrest includes LDLR and TfR in a reversible manner. The PA/PDE4/PKA pathway involving both p38 and ERK1/2 expands the possibilities of EGFR transmodulation and interference in cancer.

2021-02-01·Phytotherapy Research2区 · 医学

Trigonelline induces browning in 3T3‐L1 white adipocytes

2区 · 医学

Article

作者: Choi, Minji ; Yun, Jong Won ; Mukherjee, Sulagna

Trigonelline, a major alkaloid component of fenugreek, has been demonstrated to have several biological activities, including antidiabetic and anticancer effects. This study aimed to examine the possible application of trigonelline as an anti‐obesity compound based on an investigation of its enhancement of lipid catabolism and induction of browning in white adipocytes. Trigonelline induces browning of 3T3‐L1 white adipocytes by enhancing the expressions of brown‐fat signature proteins and genes as well as beige‐specific genes, including Cd137, Cited1, Tbx1, and Tmem26. Trigonelline also improves lipid metabolism in white adipocytes by decreasing adipogenesis and lipogenesis as well as promotes lipolysis and fatty acid oxidation. Moreover, trigonelline increases the expression of Cox4, Nrf1, and Tfam genes that are responsible for mitochondrial biogenesis. Mechanistic studies revealed that the browning effect of trigonelline in 3T3‐L1 white adipocytes is mediated by activating β3‐AR and inhibiting PDE4, thereby stimulating the p38 MAPK/ATF‐2 signaling pathway. Considering its high bioavailability in humans and the results of this study, trigonelline may have potential as an anti‐obesity compound.