scholarly journals Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5688
Author(s):  
Serhii A. Liakhov ◽  
Igor A. Schepetkin ◽  
Olexander S. Karpenko ◽  
Hanna I. Duma ◽  
Nadiia M. Haidarzhy ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Biological Effects ◽  
Ischemia Reperfusion ◽  
Nuclear Factor Κb ◽  
Mechanistic Studies ◽  
Jnk Inhibitors ◽  
Inflammatory Drugs ◽  
Jnk Isoforms ◽  
Small Molecule Modulators ◽  
Derivatives Of

c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.

Human breast milk suppresses the transcriptional regulation of IL-1β-induced NF-κB signaling in human intestinal cells

2004 ◽  
Vol 287 (5) ◽  
pp. C1404-C1411 ◽  
Author(s):  
Ryoko Minekawa ◽  
Takashi Takeda ◽  
Masahiro Sakata ◽  
Masami Hayashi ◽  
Aki Isobe ◽  
...  
Keyword(s):  
Breast Milk ◽  
Pathogenic Bacteria ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nuclear Factor Κb ◽  
Protective Role ◽  
Intestinal Cells ◽  
Human Breast Milk ◽  
Human Breast ◽  
Activation Pathway

Neonatal necrotizing enterocolitis (NEC), which is a disease with a poor prognosis, is considered to be caused by the coincidence of intestinal ischemia-reperfusion injury and systemic inflammation due to the colonization of pathogenic bacteria. Interleukin (IL)-8, a proinflammatory cytokine, plays an important role in the pathophysiology of NEC. It was recently reported that IL-1β activates the IL-8 gene by regulating the transcriptional nuclear factor κB (NF-κB) signaling pathways in intestinal cells. The protective role of maternal milk in NEC pathogenesis has been reported in both human and animal studies. In this study, we show that human breast milk dramatically suppressed the IL-1β-induced activation of the IL-8 gene promoter by inhibiting the activation pathway of NF-κB. Moreover, we also show that human breast milk induced the production of IκBα. These results suggest that human breast milk could be protective and therapeutic in neonates with NEC by inhibiting the activation pathway of NF-κB.

Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB

2000 ◽  
Vol 279 (3) ◽  
pp. L528-L536 ◽  
Author(s):  
Scott D. Ross ◽  
Irving L. Kron ◽  
James J. Gangemi ◽  
Kimberly S. Shockey ◽  
Mark Stoler ◽  
...  
Keyword(s):  
Lung Function ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Nuclear Factor Κb ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Factor ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

A central role for nuclear factor-κB (NF-κB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-κB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-κB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-κB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-κB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-κB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower Pco2, reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-κB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-κB may be a promising therapy to reduce this injury and improve lung function.

Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury

2012 ◽  
Vol 22 (3) ◽  
pp. 1427-1432 ◽  
Author(s):  
Véronique Plantevin Krenitsky ◽  
Mercedes Delgado ◽  
Lisa Nadolny ◽  
Kiran Sahasrabudhe ◽  
Leticia Ayala ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Jnk Inhibitors

Nuclear factor-κB inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats

2005 ◽  
Vol 83 (6) ◽  
pp. 483-492 ◽  
Author(s):  
Eman El Eter ◽  
Hanan H Hagar ◽  
Ali Al-Tuwaijiri ◽  
Maha Arafa
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Thiobarbituric Acid ◽  
Nuclear Factor Κb ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Nuclear Factor ◽  
P53 Expression ◽  
Apoptotic Protein ◽  
Gastric Ischemia

Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n=7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-α (TNF-α). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and depleted reduced glutathione in gastric tissues. NF-κB translocation was also detected by electrophoretic mobility shift assay. Microscopically, gastric tissues subjected to I/R injury showed ulceration, hemorrhages, and neutrophil infiltration. Immunohistochemical studies of gastric sections revealed increased expression of p53 and Bcl-2 proteins. PDTC pretreatment reduced Evans blue extravasation, serum lactate dehydrogenase levels, gastric TNF-α levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-κB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-κB activation and pro-apoptotic protein p53 induction are involved in gastric I/R injury. PDTC protects against gastric I/R injury by an antioxidant, NF-κB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-κB, thus promoting cell survival. Key words: pyrrolidinedithiocarbamate, ischemia–reperfusion injury, gastric mucosa, nuclear factor-κB, inflammatory cytokines, oxidative stress.

IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

2007 ◽  
Vol 293 (4) ◽  
pp. H2248-H2253 ◽  
Author(s):  
Nancy C. Moss ◽  
William E. Stansfield ◽  
Monte S. Willis ◽  
Ru-Hang Tang ◽  
Craig H. Selzman
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Nuclear Factor Κb ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Artery Ligation ◽  
Cardiac Morbidity

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-κB (NF-κB) has been implicated as a key mediator of reperfusion injury. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated IκBα and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-κB activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.

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