c-Jun N-terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor-β, toll-like receptors, interferon-γ, and autophagy, as well as compensatory JNK-dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK-mediated cancer cell survival. There is a focus on the specific "Yin and Yang" functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.

• Klíčová slova
• JNK, c-Jun N-terminal kinase, cancer, cell survival, chemoresistance, tumor development,
• MeSH
• autofagie MeSH
• chemorezistence MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• lidé MeSH
• MAP kinasový signální systém * MeSH
• nádory enzymologie   patologie   MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• JNK mitogenem aktivované proteinkinasy MeSH

c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context- and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment.

• Klíčová slova
• JNK, SP60012, cancer, cancer therapy, selective inhibitors, tumour,
• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• inhibitory proteinkinas chemická syntéza   chemie   farmakologie   MeSH
• JNK mitogenem aktivované proteinkinasy antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• proliferace buněk účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• inhibitory proteinkinas MeSH
• JNK mitogenem aktivované proteinkinasy MeSH

The exact signaling leading to neurological dysfunction in neurodegenerative diseases is currently unknown. We hypothesize that the c-Jun N-terminal kinase (JNK) signaling pathway is a potential therapeutic target for neurodegenerative diseases. This postulate rests on extensive data from cell and animal experimental studies, demonstrating that JNK signaling plays a crucial role in the pathogenesis of neurodegenerative diseases. The sustained activation of JNK leads to synaptic dysfunction and even neuronal apoptosis, ultimately resulting in memory deficits and neurodegeneration. JNK phosphorylates the amyloid precursor protein and tau, ultimately resulting in the formation of extraneuronal senile plaques and intraneuronal neurofibrillary tangles. Our hypothesis could be validated by investigating the cerebral cortex of elderly chimpanzees injected with phosphorylated JNK or transgenic pig and chimpanzee models established using gene editing technology including CRISPR. This hypothesis provides clues for further understanding the molecular mechanisms of neurodegenerative diseases and the development of potential target therapeutic drugs.

• Klíčová slova
• Alzheimer's disease, JNK, amyloid beta, neurodegenerative diseases, tau,
• MeSH
• Alzheimerova nemoc genetika   MeSH
• amyloidní beta-protein * metabolismus   MeSH
• amyloidový prekurzorový protein beta * genetika   metabolismus   MeSH
• fosforylace MeSH
• genový targeting * MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozková kůra metabolismus   patologie   MeSH
• neurodegenerativní nemoci patologie   MeSH
• neurony metabolismus   MeSH
• Pan troglodytes MeSH
• prasata MeSH
• proteiny tau metabolismus   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein * MeSH
• amyloidový prekurzorový protein beta * MeSH
• JNK mitogenem aktivované proteinkinasy MeSH
• proteiny tau MeSH

• Klíčová slova
• JNK, cancer development, chemoresistance, hypoxia-inducible factors, immune evasion,
• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• chemorezistence účinky léků   MeSH
• inhibitory proteinkinas chemie   farmakologie   MeSH
• JNK mitogenem aktivované proteinkinasy antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• úvodníky MeSH
• Názvy látek
• antitumorózní látky MeSH
• inhibitory proteinkinas MeSH
• JNK mitogenem aktivované proteinkinasy MeSH

After reaching metaphase II, in vitro matured oocytes undergo the complex processes referred to as oocyte aging. Under our culture conditions, some aged oocytes remained at the stage of metaphase II, some underwent spontaneous parthenogenetic activation and others underwent cellular death, either through apoptosis (fragmentation) or lysis. We investigated the effect of c-Jun N-terminal kinases (JNK) and p38 Mitogen-activated protein kinase (p38 MAPK) inhibition on pig oocyte aging and the activity of JNK and p38 MAPK during the aging period. Inhibition of JNK protected the oocytes from fragmentation (0% fragmented oocytes under JNK inhibition vs. 26% fragmented oocytes in the control group). Inhibition of p38 MAPK had no effect on fragmentation. Inhibition of JNK also had an influence on spontaneous parthenogenetic activation of aged oocytes. The ratio of activated JNK to total JNK decreased during aging of oocytes. However, exit from MII had no effect on it. The ratio of activated p38 MAPK to total p38 MAPK did not change significantly. The phosphorylated form of JNK is present in fragmented and activated oocytes, while lysed oocytes lack the active form of JNK. Based on our data, we can conclude that JNK plays an active role in fragmentation of pig oocytes and that p38 MAPK is not involved in this process.

• MeSH
• anthraceny farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• JNK mitogenem aktivované proteinkinasy antagonisté a inhibitory   metabolismus   fyziologie   MeSH
• kultivované buňky MeSH
• metafáze účinky léků   fyziologie   MeSH
• mitogenem aktivované proteinkinasy p38 antagonisté a inhibitory   metabolismus   fyziologie   MeSH
• oocyty účinky léků   enzymologie   metabolismus   MeSH
• prasata * metabolismus   fyziologie   MeSH
• pyrazoly farmakologie   MeSH
• stadium rýhování vajíčka účinky léků   enzymologie   metabolismus   MeSH
• stárnutí buněk fyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anthraceny MeSH
• inhibitory enzymů MeSH
• JNK mitogenem aktivované proteinkinasy MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• pyrazoly MeSH

The study aimed to determine the effects of protease-activated receptor-2 (PAR-2) on glial scar formation after spinal cord injury (SCI) in Sprague-Dawley (SD) rats and the underlying mechanisms. Rivlin and Tator's acute extradural clip compression injury (CCI) model of severe SCI was established in this study. Animals were divided into four groups: 1) sham group (laminectomy only); 2) model group, treated with normal saline; 3) PAR-2 inhibitor group; 4) PAR-2 activator group. Enhanced GFAP and vimentin expression were the markers of glial scar formation. To determine whether JNK was involved in the effects of PAR-2 on GFAP and vimentin expression, we administered anisomycin (a JNK activator) in the presence of PAR-2 inhibitor and SP600125 (a JNK inhibitor) in the presence of PAR-2 activator. At 1, 7, 14 and 28 day after SCI, Basso, Beattie, and Bresnahan (BBB) locomotor score test was used to assess the locomotor functional recovery; immunofluorescence and western blot analysis were used to assess the expression level of GFAP, vimentin and p-JNK. Double immunofluorescence staining with GFAP and tubulin beta was used to assess the glial scar formation and the remaining neurons. Results suggested that PAR-2 is involved in glial scar formation and reduces neurons residues which can cause a further worsening in the functional outcomes after SCI via JNK signaling. Therefore, it may be effective to target PAR-2 in the treatment of SCI.

• MeSH
• anisomycin farmakologie   MeSH
• anthraceny farmakologie   MeSH
• jizva metabolismus   patologie   prevence a kontrola   MeSH
• krysa rodu Rattus MeSH
• MAP kinasový signální systém účinky léků   fyziologie   MeSH
• poranění míchy metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• receptor PAR-2 antagonisté a inhibitory   biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anisomycin MeSH
• anthraceny MeSH
• pyrazolanthrone MeSH Prohlížeč
• receptor PAR-2 MeSH

Mycotoxins have been shown to activate multiple mechanisms that may potentially lead to the progression of Alzheimer's disease (AD). Overexpression/aberrant cleavage of amyloid precursor protein (APP) and hyperphosphorylation of tau (P-tau) is hallmark pathologies of AD. Recent advances suggest that the neurotoxic effects of mycotoxins involve c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor-1α (HIF-1α) signaling, which are closely linked to the pathogenesis of AD. Due to the high toxicity and broad contamination of T-2 toxin, we assessed how T-2 toxin exposure alters APP and P-tau formation in BV2 cells and determined the underlying roles of HIF-1α and JNK signaling. The findings revealed that T-2 toxin stimulated the expression of HIF-1α and hypoxic stress factors in addition to increasing the expression of APP and P-tau. Additionally, HIF-1α acted as a "brake" on the induction of APP and P-tau expression by negatively regulating these proteins. Notably, T-2 toxin activated JNK signaling, which broke this "brake" to promote the formation of APP and P-tau. Furthermore, the cytoskeleton was an essential target for T-2 toxin to exert cytotoxicity, and JNK/HIF-1α participated in this damage. Collectively, when the T-2 toxin induces the production of APP and P-tau, JNK might interfere with HIF-1α's protective function. This study will provide clues for further research on the neurotoxicity of mycotoxins.

• Klíčová slova
• Amyloid precursor protein, Hypoxia-inducible factor-1α, T-2 toxin, Tau, c-Jun N-terminal kinase,
• MeSH
• amyloidový prekurzorový protein beta * metabolismus   MeSH
• buněčné linie MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus   genetika   MeSH
• fosforylace účinky léků   MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• myši MeSH
• proteiny tau * metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• T-2 toxin * toxicita   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidový prekurzorový protein beta * MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa * MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• JNK mitogenem aktivované proteinkinasy MeSH
• proteiny tau * MeSH
• T-2 toxin * MeSH

Cellular senescence leads to decreased tissue regeneration and inflammation and is associated with diabetes, neurodegenerative diseases, and tumorigenesis. However, the mechanisms of cellular senescence are not fully understood. Emerging evidence has indicated that c-Jun N-terminal kinase (JNK) signaling is involved in the regulation of cellular senescence. JNK can downregulate hypoxia inducible factor-1α to accelerate hypoxia-induced neuronal cell senescence. The activation of JNK inhibits mTOR activity and triggers autophagy, which promotes cellular senescence. JNK can upregulate the expression of p53 and Bcl-2 and accelerates cancer cell senescence; however, this signaling also mediates the expression of amphiregulin and PD-LI to achieve cancer cell immune evasion and prevents their senescence. The activation of JNK further triggers forkhead box O expression and its target gene Jafrac1 to extend the lifespan of Drosophila. JNK can also upregulate the expression of DNA repair protein poly ADP-ribose polymerase 1 and heat shock protein to delay cellular senescence. This review discusses recent advances in understanding the function of JNK signaling in cellular senescence and includes a comprehensive analysis of the molecular mechanisms underlying JNK-mediated senescence evasion and oncogene-induced cellular senescence. We also summarize the research progress in anti-aging agents that target JNK signaling. This study will contribute to a better understanding of the molecular targets of cellular senescence and provides insights into anti-aging, which may be used to develop drugs for the treatment of aging-related diseases.

• Klíčová slova
• Anti-aging, Cell senescence, Hypoxia, JNK, PARP1,
• MeSH
• hypoxie MeSH
• JNK mitogenem aktivované proteinkinasy * metabolismus   MeSH
• lidé MeSH
• MAP kinasový signální systém MeSH
• signální transdukce * MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• JNK mitogenem aktivované proteinkinasy * MeSH

Mitogen-activated protein kinases (MAPKs) were extensively studied in cancer-derived cell lines; however, studies in non-transformed human cells are scarce. In the current paper, we studied the effect of SB203580, a pharmacological inhibitor of p38 MAPK, on activation and inhibition of p38 MAPK transduction partway in primary human hepatocytes (in vitro model of differentiated cells) in comparison with several tumor cell lines (proliferating non-differentiated in vitro model). In addition, we analyzed the effect of SB203580 on extracellular-regulated protein kinase (ERK) and c-jun-N-terminal kinase (JNK) pathways both in primary human hepatocytes and tumor cell lines employing primary antibodies detecting phosphorylated kinases. We show that SB203580 activates ERK and JNK in primary cultures of human hepatocytes. The levels of ERK-P(Thr202/Tyr204), JNK-P(Thr183/Tyr185) and c-Jun-P(Ser63/73), a target down-stream protein of JNK, were increased by SB203580. In contrast, SB203580 activated ERK but not JNK in HepG2, HL-60, Saos-2 and HaCaT human cancer cell lines. We tested, whether the effects of SB203580 are due to metabolism. Using liquid chromatography/mass spectrometry, we found one minor metabolite in human liver microsomes but not in HepG2 cells. These data imply that biotransformation could be responsible for the effects of SB203580 in human hepatocytes. This study is the first report on the effects of MAPK activators (sorbitol, anisomycin, EGF) and MAPK inhibitors in primary human hepatocytes. We observed differential effects of these compounds in primary human hepatocytes and in cancer cells, implying the cell-type specificity and the essential differences between the role and function of MAPKs in normal and cancer cells.

• MeSH
• aktivace enzymů účinky léků   MeSH
• buněčné linie MeSH
• extracelulárním signálem regulované MAP kinasy metabolismus   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• HL-60 buňky MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• imidazoly metabolismus   farmakologie   MeSH
• inhibitory enzymů metabolismus   farmakologie   MeSH
• interakce mezi receptory a ligandy účinky léků   MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 antagonisté a inhibitory   MeSH
• pyridiny metabolismus   farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• extracelulárním signálem regulované MAP kinasy MeSH
• imidazoly MeSH
• inhibitory enzymů MeSH
• JNK mitogenem aktivované proteinkinasy MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• pyridiny MeSH
• SB 203580 MeSH Prohlížeč

SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.

• MeSH
• anthraceny metabolismus   farmakologie   MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• cytochrom P-450 CYP1A2 genetika   MeSH
• hepatocyty enzymologie   MeSH
• hmotnostní spektrometrie MeSH
• inhibitory proteinkinas farmakologie   MeSH
• jaterní mikrozomy metabolismus   MeSH
• JNK mitogenem aktivované proteinkinasy antagonisté a inhibitory   MeSH
• kultivované buňky MeSH
• lidé MeSH
• polychlorované dibenzodioxiny antagonisté a inhibitory   MeSH
• receptory aromatických uhlovodíků agonisté   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anthraceny MeSH
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• inhibitory proteinkinas MeSH
• JNK mitogenem aktivované proteinkinasy MeSH
• polychlorované dibenzodioxiny MeSH
• pyrazolanthrone MeSH Prohlížeč
• receptory aromatických uhlovodíků MeSH