as-601245 and pyrazolanthrone

The article reviews the literature regarding the role of c-Jun-N-terminal kinases (JNK) and its inhibitors in brain damage in the settings of ischemia and reperfusion injury. The implication of JNK in signaling mechanisms involved in ischemia-reperfusion-induced cerebral injury are discussed. Described effects associated with JNK inhibition using synthetic and natural substances in experimental models of ischemic and reperfusion injury of the brain. Results of experimental studies demonstrated that JNK represent promising therapeutic targets for brain protection against ischemic stroke. However, multiple physiologic functions of various JNK family members do not allow for the systemic use of non-specific JNK inhibitors for therapeutic purposes. The authors conclude that the continuous search for selective inhibitors of JNK3 remains an important task.

Topics: Acetonitriles; Animals; Anthracenes; Benzothiazoles; Brain; Brain Ischemia; Gene Expression Regulation; Ginsenosides; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 10; Neuroprotective Agents; Oximes; Plant Extracts; Protein Kinase Inhibitors; Quinoxalines; Reperfusion Injury; Signal Transduction

c-Jun N-terminal kinase (JNK) plays an integral role in neuronal death in multiple cell lines following a wide variety of stimuli and in a number of physiological functions that may be involved in human disease, including CNS diseases. In the past decades, many researchers in this field have found and reinforced the concept that prolonged activation of JNK signalling can induce neuronal cell death by both a transcriptional induction of death-promoting genes and modulation of the mitochondrial apoptosis pathways. Data are emerging to extend the understanding of the JNK signalling and confirm the possibility that targeting JNK signalling may offer an effective therapy for pathological conditions in the near future. This review will focus on the pro-apoptotic role of JNK signalling and updated pharmacological inhibitors of this pathway.

Topics: Acetonitriles; Animals; Anthracenes; Apoptosis; Benzothiazoles; Carbazoles; Humans; Indole Alkaloids; Indoles; JNK Mitogen-Activated Protein Kinases; Neuroprotective Agents; Protein Kinase Inhibitors; Signal Transduction; Thiazoles

Topics: Acetonitriles; Animals; Anthracenes; Anti-Mullerian Hormone; Apoptosis; Benzothiazoles; Cell Line, Tumor; Cell Proliferation; Estradiol; Female; G2 Phase Cell Cycle Checkpoints; Granulosa Cell Tumor; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, SCID; Mitosis; Ovarian Neoplasms; RNA Interference; RNA, Small Interfering; Signal Transduction

c-Jun N-terminal kinase (JNK) pathway has been shown to be essential for cell cycle progression and mitosis. We previously showed that this pathway is activated in mitotic granulosa cells of follicles from transitional to antral stages. In this study, we, therefore, aimed to investigate whether this signaling pathway has any effect on in-vitro growth of murine preantral follicles and granulosa cell cycle control. Two structurally different pharmacologic JNK inhibitors, SP600125 and AS601245, were used in the experiments. First their inhibitory concentrations were determined in granulosa cells by Western blot analysis. Then preantral follicles isolated from immature and adult C57BL/6 mice were cultured in matrigel and standard culture plates for 6 days with these inhibitors. Spontaneously immortalized rat granulosa cells (SIGCs) were first synchronized at G1/S and G2/M stages of cell cycle and then treated with JNK inhibitors. Cell cycle progression was analyzed with Bromodeoxyuridine (BrdU) assay and flow cytometry analysis. Both inhibitors significantly inhibited phosphorylation of c-Jun in granulosa cells at 25, 50, and 100 μmol/L concentrations. Isolated preantral follicles cultured with these inhibitors exhibited arrested growth in culture in a dose-dependent manner. Cell cycle analyses showed that both inhibitors impair the progression of cell cycle at S phase and G2/M transition of granulosa cells. These results suggest that JNK pathway is essential for in vitro growth of preantral follicle growth and regulates both S phase and G2/M stages of cell cycle in granulosa cells.

Topics: Acetonitriles; Animals; Anthracenes; Benzothiazoles; Cell Cycle; Female; Granulosa Cells; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Ovarian Follicle; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction

Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Here, we report that treatment of T-ALL cells with JNK inhibitors led to cell cycle arrest and apoptosis and increased sensitivity to Fas-mediated apoptosis, whereas weak ectopic expression of MKK7-JNK1 fusion protein, which shows constitutive JNK activity, in T-ALL cells resulted in accelerated cell cycle progression and resistance to Fas-mediated apoptosis. The protein levels of c-Myc and Bcl-2 were reduced in the presence of JNK inhibitors but were enhanced with MKK7-JNK1. Small interfering RNA against JNK1, but not JNK2, exhibited similar effects to JNK inhibitors. These findings suggest that targeting JNK, especially JNK1 isoform, may have some important therapeutic implications in the treatment of T-ALL. Further exploration revealed that JNK protein and basal JNK activity in T-ALL cells showed aberrant subcellular localization, but no hyperactivation of JNK was observed. Thus, our work suggests that there might be novel mechanism(s) other than hyperactivation underlying the protumorigenic role of JNK activity.

Topics: Acetonitriles; Animals; Anthracenes; Apoptosis; Benzothiazoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Immunoblotting; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; MAP Kinase Kinase 7; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; RNA Interference; Transfection

In the present study the activation of p38 mitogen-activated protein kinase (p38-MAPK) and c-Jun N-terminal kinases (JNKs) by hyperthermia was investigated in the isolated perfused Rana ridibunda heart. Hyperthermia (42 degrees C) was found to profoundly stimulate p38-MAPK phosphorylation within 0.5 h, with maximal values being attained at 1 h [4.503(+/-0.577)-fold relative to control, P<0.01]. JNKs were also activated under these conditions in a sustained manner for at least 4 h [2.641(+/-0.217)-fold relative to control, P<0.01]. Regarding their substrates, heat shock protein 27 (Hsp27) was maximally phosphorylated at 1 h [2.261(+/-0.327)-fold relative to control, P<0.01] and c-Jun at a later phase [3 h: 5.367(+/-0.081)-fold relative to control, P<0.001]. Hyperthermia-induced p38-MAPK activation was found to be dependent on the Na+/H+ exchanger 1 (NHE1) and was also suppressed by catalase (Cat) and superoxide dismutase (SOD), implicating the generation of reactive oxygen species (ROS). ROS were also implicated in the activation of JNKs by hyperthermia, with the Na+/K+-ATPase acting as a mediator of this effect at an early stage and the NHE1 getting involved at a later time point. Finally, JNKs were found to be the principal mediators of the apoptosis induced under hyperthermic conditions, as their inhibition abolished poly(ADP-ribose) polymerase (PARP) cleavage after 4 h at 42 degrees C. Overall, to our knowledge, this study highlights for the first time the variable mediators implicated in the transduction of the hyperthermic signal in the isolated perfused heart of an ectotherm and deciphers a potential salutary effect of p38-MAPK as well as the fundamental role of JNKs in the induced apoptosis.

Topics: Acetonitriles; Animals; Anthracenes; Anura; Apoptosis; Benzothiazoles; Caspase 3; Catalase; Electrocardiography; Guanidines; Heat-Shock Proteins; Hyperthermia, Induced; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases; Myocardium; Ouabain; p38 Mitogen-Activated Protein Kinases; Perfusion; Phosphorylation; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-jun; Sulfones; Superoxide Dismutase; Time Factors