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PubMed2001

Neurotrophic signaling in normal and degenerating rodent retinas.

Several types of insult cause up-regulation of neurotrophic factors and their receptors in the retina resulting in decreased photoreceptor cell death from subsequent injury. This phenomenon is more prominent in rats than in mice and neurotrophic factors are more efficacious in rats than mice. If up-regulation of neurotrophic factor receptors on photoreceptor cells early in the course of degenerations contributes to neurotrophic factor survival-promoting activity, it may also increase the ability to detect neurotrophic factor-induced signaling in photoreceptors, particularly in rats. In this study, these hypotheses were investigated by performing immunohistochemical staining for the phosphorylated form of extracellular receptor kinase (pERK) or c-fos after intravitreous injection of neurotrophic factors in wild type rats or mice, or those with inherited retinal degenerations. In both rats and mice either early or late in the course of degeneration, or in wild type animals, intravitreous injection of brain-derived neurotrophic factor, ciliary neurotrophic factor, or fibroblast growth factor-2 caused immunostaining for pERK and c-fos in cells of the inner retina, particularly Müller cells, but not in photoreceptors. These data add to the mounting evidence suggesting that neurotrophic factors act indirectly through Müller cells to promote photoreceptor survival.

Animals↗
PubMed2005

Cyclic AMP alleviates endoplasmic stress and programmed cell death induced by lipopolysaccharides in human endothelial cells.

The possible protection provided by enhancement of the cAMP signal in the process of lipopolysaccharide (LPS)-induced endothelial cell death has been addressed, with special emphasis on the endoplasmic initiation of caspase-12-mediated apoptosis. Human umbilical vein endothelial cells were challenged with LPS to reduce viability after 12 h to less than 20% that of the control. Cell death was preceded by ultrastructural disintegration at the endoplasmic reticulum, PERK-phosphorylation, degradation of caspase-12-like protein and cleavage of caspase 9, resulting in apoptosis through the activation of caspase 3. Treatment with a cell-permeable cAMP analogue led to a dose-dependent reduction of cell death over time, mitigated endoplasmic reticulum disturbances, reduced phosphorylation of PERK, and the degradation of caspases 12, 9 and 3. The selective inhibition of caspase 9 completely supplanted the anti-apoptotic effects obtained by cAMP, while being without any influence on caspase 12 degradation. The data suggest that cAMP positively modulates early endoplasmic alterations and caspase activation in LPS-induced apoptosis.

Apoptosis↗
PubMed2005

Overexpression of ERp29 in the thyrocytes of FRTL-5 cells.

It was previously reported that the up-regulation of ERp29 mRNA depends on the levels of thyroid stimulating hormone (TSH) in the thyrocytes of FRTL-5 cells. In order to investigate the putative new function of ERp29 as an endoplasmic molecular (ER) chaperone, an ERp29-overexpressing FRTL-5 cell line was established. This cell line had approximately three times the levels of ERp29 protein and an enhanced level of thyroglobulin (Tg) secretion. The results showed both enhanced ERp29 expression and an interaction with the other ER chaperones such as GRP94, BiP, ERp72 and calnexin. In addition, ERp29 enhanced the expression of PKR-like ER kinase (PERK), which is a transmembrane protein located in the ER membrane. These findings suggest that ERp29 assists in protein folding as well as in the secretion of the secretory/plasma membrane proteins under close co-operation with other ER chaperones and the ER stress signaler, PERK.

Animals↗
PubMed2004

Eukaryotic initiation factor 2-associated glycoprotein, p67, shows differential effects on the activity of certain kinases during serum-starved conditions.

Phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 is the major regulatory step in the initiation of protein synthesis in mammals. P67, a cellular glycoprotein, protects phosphorylation of eIF2alpha from kinases. P67 has five conserved amino acid residues at the D251, D262, H331, E364, and E459 positions. To determine the roles of these conserved amino acid residues in eIF2alpha phosphorylation during serum-starved conditions, we constitutively expressed D251A, D262A, H331A, E364A, and E459A mutants in rat tumor hepatoma cells. We find that the point mutants D251A, H331A, and E364A lower the levels of eIF2alpha phosphorylation. These low levels of phosphorylation decrease when serum-starved cells are grown in medium containing serum. To understand the mechanism of action of the p67 mutants in eIF2alpha phosphorylation during serum-starvation, we performed detailed biochemical analyses with the D251A mutant. We find that neither the O-GlcNAc modification on the D251A mutant nor the binding of D251A mutant with eIF2gamma has significant effects on eIF2alpha phosphorylation during serum-starved conditions. However, the D251A mutant inhibits p67's activity to suppress the activity of ERK1/2. Our data suggest that both p67 and the D251A mutant bind to ERK1, thus strengthening the idea that p67 regulates the activity of ERK1. During serum-starvation conditions, both PKR and PERK are phosphorylated and the D251A mutant shows increased stability of PERK as well as a slight decrease in its activity. Altogether, our data provide evidence to suggest that p67 modulates the expression and activity of certain eIF2alpha-specific kinases.

Blotting, Western↗
PubMed2004

Extracellular calcium-sensing receptor transactivates the epidermal growth factor receptor by a triple-membrane-spanning signaling mechanism.

Activation of the extracellular calcium-sensing receptor (CaR) stimulates mitogen-activated protein kinases to upregulate the synthesis and secretion of parathyroid hormone related peptide (PTHrP) from cells expressing the CaR heterologously or endogenously. The current experiments demonstrate that this occurs because CaR activation "transactivates" the EGF receptor (EGFR). Time dependent increases in tyrosine phosphorylation of the EGFR after addition of extracellular calcium ([Ca2+]o, 3 mM) occurred in stably CaR-transfected HEK293 cells but not in non-transfected HEK293 cells. AG1478, an EGFR kinase inhibitor, prevented the CaR-mediated increases of pERK and PTHrP release, while AG1296, a PDGFR kinase inhibitor, had no effect. Inhibitors of matrix metalloproteinase and heparin bound-EGF prevented the CaR-mediated increases of pERK and PTHrP, consistent with a "triple-membrane-spanning signaling" requirement for transactivation of the EGFR by the CaR. Proximal and distal signal transduction cascades activated by the CaR may reflect transactivation of the EGFR by the extracellular calcium-sensing receptor.

Cell Line↗
PubMed2005

Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway.

In the broadest sense, cellular stress describes conditions wherein cells encounter and react to a 'non-normal' state. Perturbations may originate through both extracellular and intracellular means. Whereas transient levels of stress are expected to occur on a regular basis, a series of checks and balances ensures that cells are well equipped to maintain a homeostatic state. In the case of supra-physiological stress signaling, cellular challenges are more severe, and programmed cell death may be the best option for the organism. The ability of a cell, and by extension, an organism, to adequately manage cellular stress is fundamental--a question of life or death. The endoplasmic reticulum (ER) is exquisitely poised to sense and respond to cellular stresses including those that result from metabolic and/or protein folding imbalances. In response to stress originating from within the ER, the PERK and Ire1 protein kinases, along with other proximal signaling molecules, initiate a program of transcriptional and translational regulation termed the unfolded protein response. A consequence of ER stress is the accumulation of reactive oxygen species that promotes a state of oxidative stress. PERK signaling, via activation of the Nrf2 and ATF4 transcription factors, coordinates the convergence of ER stress with oxidative stress signaling. Here we discuss progress regarding the signaling pathways involved in these cellular stresses and the implications of the intersection between the two signaling pathways.

Activating Transcription Factor 6↗
PubMed2005

The protective effect of dantrolene on ischemic neuronal cell death is associated with reduced expression of endoplasmic reticulum stress markers.

The endoplasmic reticulum (ER) plays an important role in ischemic neuronal cell death. In order to determine the effect of dantrolene, a ryanodine receptor antagonist, on ER stress response and ischemic brain injury, we investigated changes in ER stress-related molecules, that is phosphorylated form of double-stranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), phosphorylated form of eukaryotic initiation factor 2alpha (p-eIF2alpha), activating transcription factor-4 (ATF-4), and C/EBP-homologous protein (CHOP), as well as terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in the peri-ischemic area and ischemic core region of rat brain after transient middle cerebral artery occlusion (MCAO). In contrast to the cases treated with vehicle, the infarct volume and TUNEL-positive cells were significantly reduced at 24 h of reperfusion by treatment with dantrolene. The immunoreactivities for p-PERK, p-eIF2alpha, ATF-4, and CHOP were increased at the ischemic peripheral region after MCAO, which were partially inhibited by dantrolene treatment. The present results suggest that dantrolene significantly decreased infarct volume and provided neuroprotective effect on rats after transient MCAO by reducing ER stress-mediated apoptotic signal pathway activation in the ischemic area.

Activating Transcription Factor 4↗
PubMed2006

Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke.

After ischemia, endoplasmic reticulum (ER) stress pathways are activated that include unfolded protein response (UPR) and protein synthesis inhibition (PSI). Both of these mechanisms aim to restore ER functioning mainly by inhibition of translation and increased processing of excess proteins in ER. We were interested in the role of these pathways during spontaneous recovery after transient middle cerebral artery occlusion (MCAO) in rats. The spontaneous recovery of rats was assessed with a limb-placing test. The expression of ER-stress-related genes (IRE1, ATF6, GRP78, eif2alpha, ATF4, PERK) was studied by using in situ hybridization in different brain areas on post-operative days 2, 7, 14 and 28. Elevated signals were detected in striatum contralateral to the lesion on days 2 (PERK and IRE1) and 14 post-ischemia (IRE1). Gene expression was elevated on day 7 in the striatum ipsilateral to the lesion (ATF6 and GRP78) and on day 14 (GRP78) post-ischemia. Furthermore, elevated levels of GRP78 were detected on day 14 after ischemia in the ipsilateral sensorimotor cortex. These results suggest that altered gene expression related to unfolded protein response may be more long lasting than expected following focal cerebral ischemia. In addition, these results show that the response to ER stress differs ipsi- and contralaterally after MCAO in rats. Since these differences are detected in both hemispheres only in areas adjacent to the lesion, UPR may contribute to spontaneous recovery after MCAO in rats.

Animals↗
PubMed2026

Eucalyptol mitigates isoproterenol-induced myocardial injury in rats via activation of p38 MAPK/JNK signaling, suppression of ER stress, and modulation of apoptotic pathway.

BACKGROUND: Myocardial injury (MI), a subset of cardiovascular diseases, remains a leading cause of deaths globally, driven by pathological inflammation, oxidative stress, and apoptosis. Despite advances in interventional cardiology, high relapse rates and therapeutic limitations underscore the urgent need for novel pharmacological agents. Phytochemicals, with their multi-target approach and favorable safety profiles, offer promising alternatives for mitigating ischemic injury. METHODS: The cardioprotective effects of 1,8-cineole, a monoterpene derived from Eucalyptus species, was investigated in a rat model of isoproterenol-induced myocardial injury. Serum levels of cardiac enzymes (creatine kinase (CK), lactate dehydrogenase (LDH)) and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were quantified. Preliminary histopathological analysis was performed to assess the extent of myocardial damage. Key molecular mechanisms were evaluated via western blotting and immunohistochemistry, examining pathways related to inflammation (NF-κB), apoptosis (Bcl-2/Bax, caspase-3), endoplasmic reticulum (ER) stress (GRP78, CHOP, PERK-eIF2α), and antioxidant defense (GSH, SOD, CAT). RESULTS: Our results demonstrate that 1,8-cineole significantly reduced the levels of serum cardiac enzymes (CK-MB, LDH), and histopathological damage. Mechanistically, 1,8-cineole also suppressed pro-inflammatory cytokine release (TNF-α, IL-6, and IL-1β) via inhibition of the NF-κB pathway. Furthermore, it attenuated cardiomyocyte apoptosis by modulating Bcl-2/Bax expression and inhibiting caspase-3 activation. Additionally, 1,8-cineole alleviated ER stress by downregulating GRP78, CHOP, and PERK-eIF2α signaling. Importantly, we identified enhanced Nrf2 nuclear translocation and subsequent upregulation of antioxidant enzymes (GSH, SOD, CAT) as key contributors to its cytoprotective effects. CONCLUSIONS: 1,8-Cineole exhibits potent cardio-protection in experimental myocardial injury by targetinginflammation, apoptosis, ER stress, and oxidative stress through modulation of p38 MAPK/JNK, suppression of inflammatory markers (TNF-α, IL-6, IL-1β) and apoptotic markers (Bax, p53). Its natural origin, bioavailability, and multi-mechanistic effectiveness make it a promising candidate for translational development as an adjunct therapy for myocardial injury.

Animals↗
PubMed2005

Quantitative measurement of events in the mammalian unfolded protein response.

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response. IRE1, PERK, ATF6, BiP, EDEM, lipid-linked oligosaccharides (LLOs), and XBP1 directly or indirectly participate in this process. This article provides methods used in our laboratory to quantitatively measure the accumulation of mRNAs encoding BiP and EDEM; splicing of XBP-1; cleavage of ATF6; inhibition of protein synthesis by PERK; and extension of LLOs under control and stress conditions.

Activating Transcription Factor 6↗
PubMed2003

Secreted phospholipases A2 induce the expression of chemokines in microvascular endothelium.

Acute respiratory distress syndrome (ARDS) is characterized by alterations in microvascular permeability. In ARDS secreted phospholipase A(2) (sPLA(2)) IB and IIA are found to be highly upregulated. In this study, we therefore investigated the influence of exogenously added sPLA(2)-IB and sPLA(2)-IIA on the production of chemokines and adhesion molecules in lung microvascular endothelial cells (LMVEC). Treatment of LMVEC with sPLA(2)s resulted in a significant increase in the production of chemokines and adhesion molecules due to an increased expression of their mRNA and in an enhanced release of oleic acid. The upregulation of chemokines and adhesion molecules by LPS was stronger in the presence of sPLA(2). Activation of NF-kappaB occurred upon stimulation with sPLA(2). Moreover the MAPkinase pERK seems to be involved since a specific pERK inhibitor, e.g., U0126, but not a p38Kinase inhibitor, e.g., SB203580 prevented sPLA(2)-induced chemokine upregulation. Our data therefore suggest that LMVEC are a highly sensitive target for the direct action of extracellular sPLA(2)s.

Cell Adhesion Molecules↗
PubMed2002

Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response.

CHOP is a non-ER localized transcription factor that is induced by a variety of adverse physiological conditions including ER stress. Accumulation of unfolded proteins in the ER activates an unfolded protein response pathway that targets both ER resident chaperones (e.g. BiP) and CHOP. Hence, it is unclear if CHOP induction during ER stress occurs through the ER stress response element that is conserved in both CHOP and ER chaperone promoters, or through a separate regulatory pathway conserved among different CHOP inducing cellular stress conditions. We identified a bona fide ER stress element in the hamster CHOP promoter and found that similar transcription complexes containing NF-Y bound to both the CHOP and BiP ER stress response elements. In addition, we demonstrated for the first time the importance of the C/EBP-ATF composite site for CHOP regulation during ER stress. Activation of the ER transmembrane eIF2alpha kinase, PERK, induced ATF4 protein expression, direct binding to the composite site in CHOP promoter, and as a consequence, CHOP protein induction. We propose that this eIF2alpha-kinase/ATF4/C/EBP-ATF composite site pathway is conserved for CHOP regulation during various cellular stress conditions including ER stress. Our data indicate that both the ERSE and the PERK-ATF4 pathways converge on the CHOP promoter during ER stress and provide insights into the similarities and differences between CHOP and ER chaperone expression during normal and stress conditions.

Animals↗
PubMedDate not supplied

Endoplasmic reticulum: a primary target in various acute disorders and degenerative diseases of the brain.

Changes in neuronal calcium activity in the various subcellular compartments have divergent effects on affected cells. In the cytoplasm and mitochondria, where calcium activity is normally low, a prolonged excessive rise in free calcium levels is believed to be toxic, in the endoplasmic reticulum (ER), in contrast, calcium activity is relatively high and severe stress is caused by a depletion of ER calcium stores. Besides its role in cellular calcium signaling, the ER is the site where membrane and secretory proteins are folded and processed. These calcium-dependent processes are fundamental to normal cell functioning. Under conditions of ER dysfunction unfolded proteins accumulate in the ER lumen, a signal responsible for activation of the unfolded protein response (UPR) and the ER-associated degradation (ERAD). UPR is characterized by activation of two ER-resident kinases, PKR-like ER kinase (PERK) and IRE1. PERK induces phosphorylation of the eukaryotic initiation factor (eIF2alpha), resulting in a shut-down of translation at the initiation step. This stress response is needed to block new synthesis of proteins that cannot be correctly folded, and thus to protect cells from the effect of unfolded proteins which tend to form toxic aggregates. IRE1, on the other hand, is turned after activation into an endonuclease that cuts out a sequence of 26 bases from the coding region of xbp1 mRNA. Processed xbp1 mRNA is translated into the respective protein, an active transcription factor specific for ER stress genes such as grp78. In acute disorders and degenerative diseases, the ER calcium pool is a primary target of toxic metabolites or intermediates, such as oxygen free radicals, produced during the pathological process. Affected neurons need to activate the entire UPR to cope with the severe form of stress induced by ER dysfunction. This stress response is however hindered under conditions where protein synthesis is suppressed to such an extent that processed xbp1 mRNA is not translated into the processed XBP1 protein (XBP1(proc)). Furthermore, activation of ERAD is important for the degradation of unfolded proteins through the ubiquitin/proteasomal pathway, which is impaired in acute disorders and degenerative diseases, resulting in further ER stress. ER functioning is thus impaired in two different ways: first by the direct action of toxic intermediates, produced in the course of the pathological process, hindering vital ER reactions, and second by the inability of cells to fully activate UPR and ERAD, leaving them unable to withstand the severe form of stress induced by ER dysfunction.

Acute Disease↗
PubMed1993

The Casebeer system for predictable keratorefractive surgery. One-year evaluation of 205 consecutive eyes.

PURPOSE: This study documents the results of current radial keratotomy (RK) surgical technology, using the Casebeer keratorefractive system. These results are contrasted to those of the Prospective Evaluation of Radial Keratotomy (PERK) keratorefractive system, developed approximately 12 years ago. METHODS: Two hundred five consecutive surgical procedures were examined, which was the first year of experience with RK for one of the authors (TPW). All procedures fit within the Casebeer nomograms. Enhancement procedures were performed following the Casebeer system nomograms. RESULTS: Follow-up for 100% of patients was achieved. Postoperative cycloplegic refractions yielded an average of +0.27 +/- 0.58 diopters (D) of residual refractive correction (range, -0.88 to +2.50 D). One year postoperatively, 20/25 or better uncorrected visual acuity was achieved in 86% of patients and 20/40 or better uncorrected visual acuity was achieved in 99% of patients. Bothersome but not incapacitating side effects, such as glare, starbursting, and fluctuating vision, have been commonly observed with RK. CONCLUSION: The Casebeer system for keratorefractive surgery, which is easy to learn, can yield an extremely accurate surgical result. The major reason for increased accuracy compared with the PERK system is the surgeon's ability to titrate the primary surgical procedure with enhancement operations. Although RK is by no means a perfect surgical technique, side effects tend to be relatively minimal, and patient satisfaction tends to be extremely high.

Adult↗
PubMed1988

Prospective evaluation of radial keratotomy. Photokeratoscope corneal topography.

Preoperative and postoperative corneascope photographs of 368 myopic patients undergoing radial keratotomy in the Prospective Evaluation of Radial Keratotomy (PERK) study were optically scanned and digitized. A high-resolution scanning system was developed in order to quantify the preoperative and postoperative corneal shape accurately. Careful analysis of the 72 data points in the nine representative rings demonstrated that corneal topography is best represented by radius of curvature from the center to the periphery. The normal myopic cornea flattens approximately +0.28 mm from the center to the periphery, demonstrating the cornea's aspheric nature. More highly myopic patients in the PERK population (-4.50 to -8.00 diopters [D]) demonstrated corneas that are 0.08 to 0.10 mm steeper than the less myopic population (-2.00 to -3.12 D). Optical zone, patient age, and gender are all correlated to changes in corneal topography after radial keratotomy. In more myopic populations, men have corneas which are flatter than those of women by 0.09 to 0.11 mm in all rings represented on corneoscopy. Highly myopic males also experience more corneal flattening after 3.0-mm optical zone radial keratotomy. Regardless of the optical zone used in radial keratotomy, the resulting corneal topography flattens in all rings. However, the ratio of millimeters of radius of curvature change to diopters of correction is consistent for each ring. The dioptric change observed after radial keratotomy corresponds closely with the millimeters of flattening at the respective rings being examined. The central rings flatten 0.166-mm radius of curvature per diopter of refractive alteration obtained. The largest degree of corneal flattening occurs centrally, 0.72 mm, in the more highly myopic patients who underwent 3-mm optical zone radial keratotomy. The use of smaller optical zones in radial keratotomy produces larger changes in the radius of curvature and, consequently, in the amount of refraction than when larger optical zones are used. When compared with younger patients, older patients with 3.0, 3.5, and 4.0 optical zone radial keratotomies experience more central and peripheral corneal flattening. This study of the corneal topography of the myopic population demonstrates that the refractive change resulting from radial keratotomy is related to alterations in corneal topography. The use of similar modifications of the corneal surface may be effective for newer refractive surgical procedures.

Adult↗
PubMed1994

Spectacle and contact lens wearing six years after radial keratotomy in the Prospective Evaluation of Radial Keratotomy Study.

BACKGROUND: Patients in the Prospective Evaluation of Radial Keratotomy (PERK) Study stated that a major reason for obtaining radial keratotomy was to see without dependence on corrective lenses. The authors examined lens-wearing patterns 6 years after surgery. METHODS: Of the 435 patients in the PERK Study, the authors analyzed the responses of 328 (75.4%) who elected to have surgery on both eyes, who completed a questionnaire at 6 years, and for whom visual acuity and cycloplegic refraction were available. RESULTS: Sixty-four percent (106/167) of patients younger than 40 years of age and 38% (64/161) of patients older than 40 years of age wore no lenses for distance or near vision. The proportion of time lenses were worn increased with age for those who wore them for close work only (from 18% younger than 40 years of age to 25% older than 40 years of age) and decreased with age for those who wore them for distance only (from 41% to 27%). The authors examined the visual acuity and refractive error criteria for patients to be free of distance lenses. Of the 359 patients who saw 20/20 or better uncorrected in one or both eyes, 77% (n = 198) wore no distance correction, whereas of the 53 patients who saw 20/25 to 20/40 in both eyes or their best eye, only 34% (n = 18) wore no distance correction. Of the 72 patients with a residual refractive error of +/- 0.50 diopters (D) in both eyes, 85% (n = 61) wore no distance correction, whereas of the 87 patients with +/- 1.00 D in both eyes, only 39% (n = 34) wore no distance correction. Of the 328 patients, 60% (n = 197) were highly satisfied with the results of surgery, and satisfaction was primarily predicted by having a visual acuity 20/20 or better in at least one eye and not wearing spectacles for distance vision. Before surgery, 57% of patients reported worrying about their eyesight and 47% reported restrictions in activities because of their eyes; these rates dropped to 31% and 9%, respectively, at 6 years. Of the 328 patients, 74% (n = 243) said their preoperative goals were completely met and 94% (n = 308) said they would have radial keratotomy again. CONCLUSION: The use of 20/40 uncorrected visual acuity and a residual refractive error of +/- 1.00 D were insensitive criteria for evaluating distance spectacle independence. The ability to function without lenses increased substantially only when patients had an uncorrected visual acuity of 20/20 or better in at least one eye, and a refractive error within +/- 0.50 D.

Adult↗
PubMed2003

Activation of extracellular signal-regulated kinases (ERK) during reperfusion of ischemic spinal cord.

The extracellular signal-regulated kinases (ERK) participate in numerous signaling pathways and are abundantly expressed in the CNS. It has been proposed that ERK activation promotes survival in models of neuronal injury. Inhibition of MEK, the upstream kinase that activates ERK, however, leads to neuroprotection in models of cerebral ischemia and trauma, suggesting that in this context ERK activation contributes to cellular damage. The effect of ischemia and reperfusion on activity and expression of ERK was investigated using a reversible model of rabbit spinal cord ischemia. Active ERK was observed in nai;ve animals, which decreased during 15 to 60 min of ischemia. Upon reperfusion, a robust activation of ERK was observed in animals occluded for 60 min that remained permanently paraplegic. Immunohistochemical analyses revealed increased staining of phosphorylated ERK (pERK) in glial cells and faint nuclear staining in motor neurons of animals occluded for 60 min and reperfused for 18 h. In contrast ERK activity did not increase in animals occluded for 15 min that regained motor function. No evidence of increased pERK immunoreactivity in motor neurons or nuclear translocation was noted in these animals. ERK1 was demonstrated to be identical to a p46 c-Jun/ATF-2 kinase previously shown to be activated by reperfusion after a 60-min occlusion. The results suggest that activation of ERK during reperfusion of ischemic spinal cord participates in the cellular pathways leading to neuronal damage.

Activating Transcription Factor 2↗
PubMed2001

Antitumor activities of a newly synthesized shikonin derivative, 2-hyim-DMNQ-S-33.

2- or 6-(1-hydroxyiminoalkyl)-5,8-dimethoxy-1, 4-naphthoquinone(2- or 6-hyim-DMNQ) derived from the roots of Lithospermum erythrorhizon was synthesized for the evaluation of antitumor activities. Among those derivatives, 2-hyim-DMNQ-S33 was found to be a potent anticancer agent. This compound suppressed the proliferation of Radiation Induced Fibrosarcoma (RIF) cells in a dose-dependent manner. 2-hyim-DMNQ-S33 significantly prolonged the survival time by 239% as compared with Sarcoma 180 tumor-bearing control mice in vivo. We found that the compound significantly suppressed phosphorylation of extracellular signal-regulated kinase (pERK) and activated c-jun-N-terminal kinase (JNK) and protein kinase C (PKC)-alpha following 4 h-treatment. These findings indicate that 2-hyim-DMSQ-S33 exerts antitumor activities by regulating pERK, JNK and PKC-alpha.

Animals↗