The Roles of c-Jun N-Terminal Kinase (JNK) in Infectious Diseases

Chen, Jing; Ye, Chao; Wan, Chao; Li, Gang; Peng, Lianci; Peng, Yuanyi; Fang, Rendong

doi:10.3390/ijms22179640

Cited by 26 publications

(28 citation statements)

References 126 publications

(160 reference statements)

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“…JNK, p38 MAPK, and ERK5 are the major subfamilies of MAPK. JNK, also known as stress-activated protein kinase (SAPK), is functionally similar to p38 MAPK, as both can be activated by various inflammatory cytokines and play important roles in stress responses related to conditions such as inflammation and apoptosis [39]. ERK5 mainly regulates cell growth and differentiation and is mediated by the upstream Ras/Raf signal protein, transmitting stimulatory signals to the nucleus and thereby regulating the proliferation, differentiation, and apoptosis of macrophages [40].…”

Section: Mapk Signaling Pathwaymentioning

confidence: 99%

Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses

Fang

et al. 2022

Nutrients

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In this study, a 100 g sample of Saxifraga atrata was processed to separate 1.3 g of 11-O-(4′-O-methylgalloyl)-bergenin (Fr1) after 1 cycle of MCI GEL® CHP20P medium pressure liquid chromatography using methanol/water. Subsequently, COX-2 affinity ultrafiltration coupled with reversed-phase liquid chromatography was successfully used to screen for potential COX-2 ligands in this target fraction (Fr1). After 20 reversed-phase liquid chromatography runs, 74.1 mg of >99% pure 11-O-(4′-O-methylgalloyl)-bergenin (Fr11) was obtained. In addition, the anti-inflammatory activity of 11-O-(4′-O-methylgalloyl)-bergenin was further validated through molecular docking analyses which suggested it was capable of binding strongly to ALOX15, iNOS, ERBB2, SELE, and NF-κB. As such, the AA metabolism, MAPK, and NF-κB signaling pathways were hypothesized to be the main pathways through which 11-O-(4′-O-methylgalloyl)-bergenin regulates inflammatory responses, potentially functioning by reducing pro-inflammatory cytokine production, blocking pro-inflammatory factor binding to cognate receptors and inhibiting the expression of key proteins. In summary, affinity ultrafiltration-HPLC coupling technology can rapidly screen for multi-target bioactive components and when combined with molecular docking analyses, this approach can further elucidate the pharmacological mechanisms of action for these compounds, providing valuable information to guide the further development of new multi-target drugs derived from natural products.

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Section: Mapk Signaling Pathwaymentioning

confidence: 99%

Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses

Fang

et al. 2022

Nutrients

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“…JNK, also known as stress‐activated protein kinase (SAPK), plays an important role in a variety of biological and pathological processes including cell cycle, apoptosis infection, reproduction, and cellular stress. 81 , 82 …”

Section: Kinase Groupsmentioning

confidence: 99%

“…JNKs family JNK, also known as stress-activated protein kinase (SAPK), plays an important role in a variety of biological and pathological processes including cell cycle, apoptosis infection, reproduction, and cellular stress. 81,82 There are three drugs targeting JNKs family in the PKIDB or in FDA approved drugs 5 : bentamapimod, pexmetinib, and tanzisertib. Bentamapimod is a specific c-JNK inhibitor, which increases the sensitivity of many tumors to chemotherapeutic drugs.…”

Section: 33mentioning

confidence: 99%

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Pang

Wang

Qin

et al. 2022

MedComm

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Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and C dc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

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“…Despite the multifaceted role of JNKs in cell signaling, JNK has still been viewed as a promising target for several disease areas ( Lai et al, 2020 ; Yung and Giacca, 2020 ; Abdelrahman et al, 2021 ). Our interest comes from its role in mediating inflammatory and immunological responses ( Lai et al, 2020 ; Chen et al, 2021 ). Indeed, JNK inhibition has been demonstrated to downregulate the production of several proinflammatory transcription factors and cytokines ( Kaminska et al, 2009 ; Lai et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors

et al. 2022

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The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNK represents an attractive target for therapeutic intervention. Herein, a panel of novel tryptanthrin oxime analogs were synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses (IC50). Several compounds exhibited submicromolar JNK binding affinity, with the most potent inhibitor being 6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high JNK1-3 binding affinity (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of selected compounds in the JNK3 catalytic site that were in agreement with the experimental JNK3 binding data. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems.

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The Roles of c-Jun N-Terminal Kinase (JNK) in Infectious Diseases

Cited by 26 publications

References 126 publications

Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses

Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors

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