Electroacupuncture reduces apoptotic index and inhibits p38 mitogen-activated protein kinase signaling pathway in the hippocampus of rats with cerebral ischemia/reperfusion injury

Electroacupuncture attenuates cerebral hypoxia and neuronal apoptosis induced by cerebral ischemia/reperfusion injury.To further identify the involved mechanisms,we assumed that electroacupuncture used to treat cerebral ischemia/reperfusion injury was associated with the p38 mitogen-activated protein kinase（MAPK） signaling pathway.We established rat models of cerebral ischemia/reperfusion injury using the modified Zea-Longa＇s method.At 30 minutes before model establishment,p38 MAPK blocker SB20358 was injected into the left lateral ventricles.At 1.5 hours after model establishment,electroacupuncture was administered at acupoints of Chize（LU5）,Hegu（LI4）,Zusanli（ST36）,and Sanyinjiao（SP6） for 20 minutes in the affected side.Results showed that the combination of EA and SB20358 injection significantly decreased neurologic impairment scores,but no significant differences were determined among different interventional groups.Hematoxylin-eosin staining also showed reduced brain tissue injuries.Compared with the SB20358 group,the cells were regularly arranged,the structures were complete,and the number of viable neurons was higher in the SB20358 ＋ electroacupuncture group.Terminal deoxynucleotidyl transferase（Td T）-mediated d UTP nick-end labeling assay showed a decreased apoptotic index in each group,with a significant decrease in the SB20358 ＋ electroacupuncture group.Immunohistochemistry revealed reduced phosphorylated p38 expression at 3 days in the electroacupuncture group and SB20358 ＋ electroacupuncture group compared with the ischemia/reperfusion group.There was no significant difference in phosphorylated p38 expression between the ischemia/reperfusion group and SB20358 group.These findings confirmed that the electroacupuncture effects on mitigating cerebral ischemia/reperfusion injury are possibly associated with the p38 MAPK signaling pathway.A time period of 3 days could promote the repair of ischemic cerebral nerves.

Inhibition of p38 mitogen-activated protein kinase may decrease intestinal epithelial cell apoptosis and improve intestinal epithelial barrier function after ischemia- reperf usion injury

AIM: To investigate the role of p38 mitogen-activated protein kinase in rat small intestine after ischemia-reperfusion (I/R)insult and the relationship between activation of p38 MAPK and apoptotic cell death of intestine.METHODS: Ninety Wistar rats were divided randomly into three groups, namely sham-operated group (C), I/R vehicle group (R) and SB203580 pre-treated group(S).In groups R and S, the superior mesenteric artery(SMA)was separated and occluded for 45 min, then released for reperfusion for0.25, 0.5, 1, 2, 6, 12 and 24 h. In group C, SMA was separated without occlusion. Plasma D-lactate levels were examined and histological changes were observed under a light microscope. The activity of p38 MAPK was determined by Western immunoblotting and apoptotic cells were detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUDP-biotin nick end labeling (TUNEL).RESULTS: Intestinal ischemia followed by reperfusion activated p38 MAPK, and the maximal level of activation (7.3-fold vs sham-operated group) was reached 30 min after I/R. Treatment with SB 203580, a p38 MAPK inhibitor,reduced intestinal apoptosis (26.72±3.39% vs62.50±3.08%in I/R vehicle, P＜0.01) and decreased plasma D-lactate level (0.78±0.15 mmol/L in I/R vehicle vs0.42±0.17 mmol/L in SB-treated group) and improved post-ischemic intestinal histological damage.CONCLUSION: p38 MAPK plays a crucial role in the signal transduction pathway mediating post-ischemic intestinal apoptosis, and inhibition of p38 MAPK may attenuate ischemia-reperfusion injury.

Physiological roles of mitogen-activated-protein-kinase-activated p38-regulated/activated protein kinase

Mitogen-activated protein kinases(MAPKs)are a family of proteins that constitute signaling pathways involved in processes that control gene expression,cell division, cell survival,apoptosis,metabolism,differentiation and motility.The MAPK pathways can be divided into conventional and atypical MAPK pathways.The first group converts a signal into a cellular response through a relay of three consecutive phosphorylation events exerted by MAPK kinase kinases,MAPK kinase,and MAPK.Atypical MAPK pathways are not organized into this three-tiered cascade.MAPK that belongs to both conventional and atypical MAPK pathways can phosphorylate both non-protein kinase substrates and other protein kinases.The latter are referred to as MAPK-activated protein kinases.This review focuses on one such MAPK-activated protein kinase,MAPK-activated protein kinase 5(MK5)or p38-regulated/activated protein kinase(PRAK).This protein is highly conserved throughout the animal kingdom and seems to be the target of both conventional and atypical MAPK pathways.Recent findings on the regulation of the activity and subcellular localization,bona fide interaction partners and physiological roles of MK5/PRAK are discussed.

Hippocampal activation of c-Jun N-terminal kinase,protein kinase B,and p38 mitogen-activated protein kinase in a chronic stress rat model of depression

Recent studies have shown that varied stress stimuli activate c-Jun N-terminal kinase （JNK）, protein kinase B （Akt）, and p38 mitogen-activated protein kinase （p38） signal transduction pathway, and also regulate various apoptotic cascades. JNK and p38 promote apoptosis, but Akt protects against apoptosis, in hippocampal neurons. However, changes in the transduction pathway in different regions of brain tissues in a chronic stress rat model of depression remain poorly understood. Results from this study showed that JNK phosphorylation levels were significantly greater in the stress group hippocampus compared with the control group （P 〈 0.05）. No significant difference in JNK phosphorylation levels was detected in the rat cerebral cortex between stress and control groups, and no significant difference in Akt and p38 phosphorylation levels was detected in the rat hippocampus and cerebral cortex between stress and control groups （P 〉 0.05）. These results suggested that the JNK signal pathway is activated by JNK phosphorylation and participates in pathophysiological changes in rat models of depression.

Inhibiting p38 mitogen-activated protein kinase attenuates cerebral ischemic injury in Swedish mutant amyloid precursor protein transgenic mice

Cerebral ischemia was induced using photothrombosis 1 hour after intraperitoneal injection of the p38 mitogen-activated protein kinase （MAPK） inhibitor $B239063 into Swedish mutant amyloid precursor protein （APP/SWE） transgenic and non-transgenic mice. The number of surviving neurons in the penumbra was quantified using Nissl staining, and the activity of p38 MAPKs was measured by western blotting. The number of surviving neurons in the penumbra was significantly reduced in APP/SWE transgenic mice compared with non-transgenic controls 7 days after cerebral ischemia, but the activity of p38 MAPKs was significantly elevated compared with the non-ischemic hemisphere in the APP/SWE transgenic mice. SB239063 prevented these changes. The APP/SWE mutation exacerbated ischemic brain injury, and this could be alleviated by inhibiting p38 MAPK activity.

INVOLVEMENT OF p38 MITOGEN-ACTIVATED PROTEIN KINASE IN E.coli-INDUCED U937 APOPTOSIS

Objective To investigate whether the effect of E. coli on U937 cell fines apoptosis is mediated via p38 mitogen-activated protein kinase （MAPK） activation. Methods The U937 cell lines were treated with E. coli at different time or together with SB203580, an inhibitor for p38. Cell apoptosis was analyzed by flow cytometry, p38 activities were detected by Western blotting. Results E. coli induced apoptosis in cultured U937 cell lines in a time-dependent manner. The phosphorylation of p38 was induced after 10 minutes infection, reached the peak after 20 minutes, and started to decline after 30 minutes. In contrast, the level of total p38 protein was not changed in whole experimental period. Inhibition of p38 with SB203580 significantly inhibited E. coli induced apoptosis in U937 cells. Conclusion The activation of the p38 MAPK in U937 cell lines by E. coli is a major pathway to mediate the apoptosis.

Functional study of p38 mitogen-activated protein kinase based on cell-penetrating peptide delivery system

Objective p38 Mitogen-activated protein kinase （MAPK） is a crossing center of various pathways. In this study, protein transduction system based on human immunodeficiency virus （HIV）-1 transactivator of transcription （TAT）, which is an efficient delivery peptide of the foreign proteins into cells, was employed to study p38 MAPK functions in eukaryotic cells. Methods p38 And its dominant negative form, p38AF, were constructed into pET-His-TAT vector correctly to verify that the recombinant plasmids were well-founded through restriction enzyme digestion and DNA sequencing. The two proteins, His-TAT-p38 and His-TAT-p38AF, were expressed and purified in Escherichia coli by SDS-PAGE. Then they were incubated with ECV304 cells respectively and readily transduced into cells in a time-dependent and dose-dependent manner. The cells were stimulated by sorbitol. Activating transcription factor （ATF） 2 phosphorylation level was checked using Western blot to assess the activity of endogenous p38. Results Compared with controls, it was found that His-TAT-p38 increased the level ofATF2 phosphorylation in sorbitol-stimulated ECV304 cells, while His-TAT-p38AF inhibited it, indicating p38 MAPK protein delivery system based on TAT was constructed successfully. TAT-p38 and its dominant negative form possessed high biological activity after transduction into ECV304 cells by TAT protein delivery system. The results showed that p38AF fused with TAT could inhibit the transduction of endogenous p38 signal pathway in part, and other pathway might regulate p38 phosphorylation. Conclusions Our study provides a novel pathway to inhibit p38 signal pathway and establish a new method to study p38 function.

Interleukin-1 beta up-regulates tissue inhibitor of matrix metalloproteinase-1 mRNA and phosphorylation of c-jun N-terminal kinase and p38 in hepatic stellate cells

AIM： To study the relationship between interleukin-lbeta （IL-1β） up-regulating tissue inhibitor of matrix metalloproteinase-1 （TIMMP-1） mRNA expression and phosphorylation of both c-jun N-terminal kinase （INK） and p38 in rat heffatic stellate cells （HSC）. METHODS： RT-PCR was performed to measure the expression of TIMMP-1 mRNA in rat HSC. Western blot was performed to measure IL-1β-induced JNK and p38 activities in rat HSC. RESULTS： TIMMP-1 mRNA expression （1.191± 0.079） was much higher after treatment with IL-1β （10 ng/mL） for 24 h than in control group （0.545±0.091） （P〈0.01）. IL-1β activated INK and p38 in a time-dependent manner. After stimulation with IL-1β for 0, 5, 15, 30, 60 and 120 min, the INK activity was 0.982±0.299, 1.501±0.720, 2.133±0.882, 3.360±0.452, 2.181±0.789, and 1.385 ± 0.368, respectively. There was a significant difference in JNK activity at 15 min （P〈 0.01）, 30 min （P〈 0.01） and 60 min （P〈0.01） in comparison to that at 0 min. The p38 activity was 1.061±0.310, 2.050±0.863, 2.380±0.573, 2.973±0.953, 2.421±0.793, and 1.755 ± 0.433 at the 6 time points （0, 5, 15, 30, 60 and 120 min） respectively. There was a significant difference in p38 activity at 5 min （P〈0.05）, 15 min （P〈0.01）, 30 min （P〈0.01） and 60 min （P〈0.01） compared to that at 0 min. TIMMP-1 mRNA expression trended to decrease in 3 groups pretreated with different concentrations of SP600125 （10 μmol/L, 1.022±0.113; 20 μmol/L, 0.869±0.070; 40 μmol/L, 0.666±0.123）. Their decreases were all significant （P〈0.05, P〈0.01, P〈0.01） in comparison to control group （without SP600125 treatment, 1.163±0.107）. In the other 3 groups pretreated with different concentrations of SB203580 （10 μmol/L, 1.507±0.099; 20 μmol/L, 1.698±0.107; 40 μmol/L, 1.857±0.054）, the expression of TIMMP-1 mRNA increased. Their levels were higher than those in the control group （without SB203580 treatment, 1.027 ± 0.061） with a significant statistical significance （P〈 0.01）. CONCLUSION： IL-1β has a direct action on hepatic fibrosis by up-regulating TIMMP-1 mRNA expression in ratessionin in rate HSC.JNK and p38 mitogen-activated protein kinases （MAPKs） are involved in IL-1β-induced TIMMP-1 gene expression, and play a distinct role in this process, indicating that p38 and .INK pathways cooperatively mediate TIMP-1 mRNA expression in rat HSC.

N-methyl-D-aspartate receptor effects on p38 mitogen activated protein kinase and its role in a rat model of diabetic neuropathic pain

BACKGROUND： Activated N-methyl-D-aspartate （NMDA） receptor is involved in the formation of chronic neuropathic pain, and its antagonist, ketamine, exhibits effective amelioration of diabetic neuropathic pain （DNP）. However, the mechanisms of NMDA receptor participation in the formation and maintenance of DNP remain poorly understood. OBJECTIVE： To evaluate the role NMDA receptor plays in DNP and effects on p38 mitogen activated protein kinase （p38 MAPK） in a rat model of DNP. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Human Embryonic Stem Cell Research Institute of Yunyang Medical College Affiliated Taihe Hospital between July 2005 and September 2007. MATERIALS： Streptozotocin was provided by Sigma, USA; p38 MAPK inhibitor （SB203580） was provided by Shanghai KangChen Biotech, China; NMDA receptor antagonist （MK-801） was purchased from Shanghai Yope Biotech, China. METHODS： A total of 128 healthy, Wistar rats of clean grade, aged 3 months and weighing 180- 220 g, were randomly assigned to 4 groups： control, DNP model, p38 MAPK, and NMDA receptor. Each group contained 32 rats. DNP was established in all groups except for the control group by intraperitoneal injection of streptozocin （65 mg/kg）. Subsequently, 1 mg/kg SB203580 and 1 mg/kg MK-801 were injected once each week via intraperitoneal injection in the p38 MAPK and NMDA receptor groups, respectively. MAIN OUTCOME MEASURES： At the end of 2, 4, 6, and 8 weeks following streptozotocin injection, mechanical withdrawal threshold was measured in 8 animals from each group following von Frey filament stimulation. The rats were anesthetized and nerve conduction velocity of the left sciatic nerve was measured. Subsequently, the right sciatic nerve, the lumbar segment of the spinal cord, and dorsal root ganglia were removed from the L3-6 segment for microscopic examination, p38 MAPK expression was determined using immunohistochemistry and Western blot analysis. Expression of NMDA receptor 1 mRNA in dorsal root ganglion and spinal cord neurons was detected using RT-PCR. RESULTS： Mechanical withdrawal threshold and nerve conduction velocity were significantly reduced, and p38 MAPK and NMDA receptor 1 mRNA expression in the spinal cord and dorsal root ganglia were significantly increased, in the model, p38 MAPK, and NMDA receptor groups compared with the control group at all time points （P 〈 0.05）. At 4-8 weeks following successful DNP model establishment, SB203580 and MK-801 increased mechanical withdrawal threshold, accelerated nerve conduction velocity, and attenuated p38 MAPK expression, compared with the model group. The NMDA receptor group exhibited downregulated mRNA expression of NMDA receptor 1 compared with the model and p38 MAPK groups （P 〈 0.05）. CONCLUSION： NMDA receptor was highly expressed in the brains of DNP rats and was involved in DNP development via activation of the p38 MAPK signal pathway.

Involvement of ERK1/2 and p38 MAPK in up-regulation of 14-3-3 protein induced by hydrogen peroxide preconditioning in PC12 cells

Objective To investigate the protective effects of hydrogen peroxide preconditioning （HPP） on the pheochromocytoma （PC12） cells treated with 1-methyl-4-phenylpyridinium （MPP^＋） and to explore the potential mechanisms. Methods The viability and apoptosis of PC 12 cells were determinded by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay and 4′,6′-diamidino-2-phenylindole （DAPI） staining, respectively. The expressions of 14-3-3 protein and phospholylated p38 mitogen-activated protein kinase （MAPK） were determined by Western blot. Enzyme-linked immunosorbent assay （ELISA） was used to measure the activity of extracellular signal-regulated protein kinase 1/2 （ERK1/2）. Results The cell viability decreased and the number of apoptotic cells increased dramatically in MPP^＋ group compared with that in Control group. HPP induced a significant increase in cell viability and a marked decrease in population of apoptotic cells of the MPP^＋- treated PC 12 cells, accompanied with up-regulation of 14-3-3 protein and increase of ERK 1/2 and p38 MAPK activities. The 14-3-3 protein expression was positively correlated with the phosphorylation of ERK1/2. Furthermore, inhibition of the ERK1/2 with PD98059 abolished the 14-3-3 protein up-regulation in PC 12 cells induced by HPP. Conclusion HPP protects PC 12 cells against MPP＋ toxicity by up-regulating 14-3-3 protein expression through the ERK1/2 and p38 MAPK signaling pathways.

Stress kinase inhibition modulates acute experimental pancreatitis

AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.

Cross-talk between Smad4 and P38 Proteins in Non-small Cell Lung Cancer

Objective： Impaired signal transduction is associated with tumorigenesis and progression of various kinds of human cancers. Transforming growth factor （TGF）-beta/Smad and ras-mitogen activated protein kinase （MAPK） are two major signal transduction pathways for adjusting cell proliferation and differentiation. Little is known about TGF-beta/Smad4 in non-small cell lung cancer （NSCLC）. Hereby, we investigated the expression of Smad4 in NSCLC, its correlation with MAPK proteins （including p38, ERK1 and JNK1 proteins） and their clinical significance in NSCLC. Methods： The expressions of Smad4, p38, ERK1 and JNK1 were detected at protein level with Western blotting and immunohistochemistry, at transcription level with RT-PCR. Statistical analysis was performed for the comparisons of expressions of Smad4, p38, ERK1 and JNK1, and their correlation with various clinicopathological parameters and the prognosis of NSCLC. Results： The levels of protein and mRNA expression of Smad4 in lung cancer tissues were significantly lower than in normal tissues （P〈0.05）. All these four proteins were associated with TNM staging. There was a strongly negative correlation between p38 and Smad4. Expressions of Smad4, p38 and JNK1, as well as tumor differentiation and staging were significantly correlated with the prognosis of NSCLC by univariate analysis. By multivariate analysis, only Smad4, p38, tumor differentiation and staging were correlated with the prognosis. Taken together, the negative expression of p38 and positive expression of Smad4 were associated with a better prognosis of NSCLC. Conclusion： Smad4 could be of vital importance for the initiation and development of NSCLC. The expression of Smad4 might be inhibited by p38, supporting a cross-talk between main proteins of TGF-beta/Smad and ras-MAPK signal transduction pathways. Smad4 and p38 could be possible prognostic factors for NSCLC.

Effect of oxymatrine on the p38 mitogen-activated protein kinases signalling pathway in rats with CCl4 induced hepatic fibrosis

Background Recent studies have suggested that p38 mitogen-activated protein kinases （MAPK） signalling pathway plays an important role in hepatic fibrosis. This study explored the antifibrotic effect of oxymatrine on tetrachloromethane induced liver fibrosis in rats and its modulation on the p38 MAPK signalling pathway. Methods One hundred and twenty healthy male Sprague-Dawley rats were randomly assigned to six groups： normal （n=20）, induced fibrosis （n=20）, colchicine （n=20） and three treatment groups of oxymatrine （n=20x3）. We obesrved changes in deposition of collagen, hyaluronic acid （HA）, laminin （LN）, collagen type IV （CIV）, procollagen III （PCIll） and hydroxyproline （Hyp）, a-smooth muscle actin （α-SMA） and phosphor-p38 （pp38）. Results The relative indicators of changes in histopathology, HA, LN, CIV, PCIII, Hyp, a-SMA and pp38 were raised significantly in the induced fibrosis group （P〈0.01 vs normal group）. The semiquantitative hepatic fibrosis staging scores of middle dose group and high dose group were decreased （P 〈0.05 and P 〈0.01 respectively vs the induced fibrosis group）, as was the average area of collagen in rats＇ liver, the concentrations of serum HA, LN, CIV, PCIII and liver tissue homogenate Hyp. The gene expression of α-SMA mRNA was considerably decreased in the treated animals, as was the protein espression of pp38 protein. Conclusions Oxymatrine is effective in reducing the production and deposition of collagen in the liver tissue of experimental rats in ways which relate to modulating the fibrogenic signal transduction via p38 MAPK signalling pathway.

Role of p38 mitogen-activated protein kinases in cardioprotection of morphine preconditioning

Background p38 mitogen-activated protein kinases （MAPK） in ischemic preconditioning （IPC） may be essential to cardioprotection. We assessed whether protective effect of morphine-induced preconditioning （MPC） on myocardial ischemia and reperfusion injury in rat hearts involved p38 MAPK activation.Methods Male Spargue-Dawley rats （weighing 300--350 g） were randomly assigned to 1 of the following 8 groups： control （CON, saline vehicle, n=9）, SB 203580 （SB, a p38 MAPK inhibitor, n=6）, MPC （n=6）, IPC （n=9）, SB＋MPC, SB＋IPC, MPC＋SB, and IPC＋SB （n=6）. Infarct sizes （IS）, a percentage of the area at risk （AAR）, were determined by triphenyltetrazolium （TTC） staining. Hssue samples were processed from the entire AAR of left ventricle for the determination of p38 MAPK protein expression （5 hearts/group）. The bands representing the proteins were visualized using an enhanced chemiluminescence detection system. Results The IS/AAR was significantly reduced by I PC （12.9±1.6）% or MPC （25.3±2.9）% compared to the control （52.7±5.5）%. SB 203580 administered prior to preconditioning abolished the effect of IPC （SB＋IPC： （43.8±2.6）%, P〉0.05 vs CON, P〈0.01 vs IPC）, but not MPC （SB＋MPC： （30.7±0.9）%, P〈0.01 vs CON, P〉0.05 vs MPC）. Treatment with SB 203580 prior to sustained ischemia diminished the protective effect of both MPC （MPC＋SB： （42.4±2.9）%, P〉0.05 vs CON） and IPC （IPC＋SB： （52.0±2.5）%, P〉0.05 vs CON） on IS/AAR. In the IPC group, phospho-p38 MAPK protein increased significantly within 5 minutes into ischemia and remained elevated at 30 minutes into reperfusion, while phospho-p38 MAPK protein in the MPC group only increased significantly at 30 minutes into reperfusion.Conclusion The activation of p38 MAPK just acts as a mediator of MPC,whereas it acts as both a trigger and a mediator in IPC.

Proliferation of renal mesangial cells induced by very low density lipoprotein is mediated by p42/44 mitogen activated protein kinase

Background The plasma concentration of very low density lipoprotein （VLDL） is negatively correlated to renal function in glomerular diseases. Effects of VLDL on renal function have been partially attributed to the proliferation of mesangial cells. This study examined the potential role of the p42/44 mitogen activated protein kinase （MAPK） in mesangial cell proliferation induced by VLDL. Methods Mesangial cells were treated with VLDL at different concentrations or for different time. The cell cycle of the mesangial cells was analyzed by Xl-r assay and flow-cytometry; MAPK activity was also assayed. In some experiments, cells were treated with VLDL together with or without 0.1 pmol/L PD 98059. Results Ten to 500 μg/ml VLDL stimulated the proliferation of mesangial cells cultured in vitro in a concentration-dependent manner. The effect was associated with an increase in p42/44 MAPK activity. Increased proliferation of mesangial cells by VLDL was significantly attenuated by PD98059, a specific p42/44 MAPK inhibitor. Conclusion These results indicate that the p42/44 MAPK pathway is an important regulator of mesangial cell proliferation and of renal functions.

p38α MAPK pathway:A key factor in colorectal cancer therapy and chemoresistance

Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38α MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38α pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38α pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38α MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.

Inflammation-and stress-related signaling pathways in hepatocarcinogenesis

It has been established that cancer can be promoted and exacerbated by inflammation.Hepatocellular carcinoma(HCC) is the fifth most common cancer worldwide,and its long-term prognosis remains poor.Although HCC is a complex and heterogeneous tumor with several genomic mutations,it usually develops in the context of chronic liver damage and inflammation,suggesting that understanding the mechanism(s) of inflammation-mediated hepatocarcinogenesis is essential for the treatment and prevention of HCC.Chronic liver damage induces a persistent cycle of necroinflammation and hepatocyte regeneration,resulting in genetic mutations in hepatocytes and expansion of initiated cells,eventually leading to HCC development.Recently,several inflammation-and stress-related signaling pathways have been identified as key players in these processes,which include the nuclear factor B,signal transducer and activator of transcription,and stress-activated mitogen-activated protein kinase pathways.Although these pathways may suggest potential therapeutic targets,they have a wide range of functions and complex crosstalk occurs among them.This review focuses on recent advances in our understanding of the roles of these signaling pathways in hepatocarcinogenesis.

The involvement of p38 MAPK in transforming growth factor β1-induced apoptosis in murine hepatocytes

We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.

Reactive oxygen species: A double-edged sword in oncogenesis

Reactive oxygen species (ROS) are molecules or ions formed by the incomplete one-electron reduction of oxygen. Ofinterest, it seems that ROS manifest dual roles, cancer promoting or cancer suppressing, in tumorigenesis. ROS participate simultaneously in two signaling pathways that have inverse functions in tumorigenesis, Ras-Raf-MEK1/2-ERK1/2 signaling and the p38 mitogen-activated protein kinases (MAPK) pathway. It is well known that Ras-Raf-MEK1/2-ERK1/2 signaling is related to oncogenesis, while the p38 MAPK pathway contributes to cancer suppression, which involves oncogene-induced senescence, inflammationinduced cellular senescence, replicative senescence, contact inhibition and DNA-damage responses. Thus, ROS may not be an absolute carcinogenic factor or cancer suppressor. The purpose of the present review is to discuss the dual roles of ROS in the pathogenesis of cancer, and the signaling pathway mediating their role in tumorigenesis.