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    Tocris drugs sl327
    PTPN11 D61G overexpression induces learning and memory and LTP deficits that can be reversed by MEK inhibition a. AAV– PTPN11 D61G infection results in overexpression of SHP2 D61G . Anti–SHP2 immunohistochemistry shows robust overexpression of SHP2 in the hippocampus of AAV– PTPN11 D61G –infused brains (left) compared with AAV– GFP infused brains (right). Full-length blots/gels are presented in Supplementary Figure 11 . b. PTPN11 D61G overexpression increases basal Erk activity (phospho–Erk level) and prevents further Erk activation in response to TBS. Left , Representative immunoblot showing p–Erk (upper) and total Erk (lower) in PTPN11 D61G –expressing slices and GFP –expressing slices. Slices were prepared 1 h after TBS. Right , Bar graph displays normalized p–Erk levels (mean ± s.e.m.). CTL, control without TBS. c. MEK inhibitor <t>SL327</t> reverses spatial memory deficits in PTPN11 D61G –overexpressing mice in the Morris water maze. Quadrant occupancy analysis for the probe trial reveals that PTPN11 D61G /veh mice showed no preference for the target quadrant (target vs. other quadrants, Dunnett’s Multiple Comparison Test after one-way ANOVA, P > 0.05). PTPN11 D61G /veh mice also spent significantly less time in the target quadrant compared with GFP /veh mice. SL327 treatment significantly increased the time spent in the target quadrant in PTPN11 D61G -expressing mice compared with vehicle-treated PTPN11 D61G mice ( PTPN11 D61G /SL327, 37.25 ± 3.50 %, n=10, unpaired two-tailed t-test, t = 2.335, * P
    Drugs Sl327, supplied by Tocris, used in various techniques. Bioz Stars score: 90/100, based on 3 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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    Tocris sl327 toxicity sl327
    Histological and electron microscopy assesment of pERK expression in P7 mouse forebrain following 30 min HI A and B , distribution of normal pERK immunoreactivity in the forebrain of sham animal ( A ) and an animal with unilateral carotid occlusion ( B ). C and G , increased pERK immunoreactivity in untreated animals at 15 min following 30 min HI ( C ). Response was ablated with the application of MEK inhibitor <t>SL327</t> (133 μg/g BW) ( G ). D and E , schematic summary of white matter pERK‐IR in naive ( D ) and after a 30 min HI insult ( E ). Light microscopy overview at the intersection between hippocampus (top), thalamus (left) and cerebral cortex (right), coronal section at mid‐parietal level ( D and E ). Note the faint pERK‐IR in control animal with carotid occlusion only ( D , Ctrl), and the strong increase of expression in fibre tracts in external capsule (ec), fornix (fx), cortico‐thalamic fibres (ct), and descending tracts of the internal capsule (ic) at 1 h recovery following HI ( E ). F and H , electron microscopy of the internal capsule, at 15 min recovery following HI. Early pERK reactivity is located to the axons only. Arrows point to pERK positive clusters within adjacent axons. Scale bar ( A–C, G ): 1.5 mm [Color figure can be viewed at http://wileyonlinelibrary.com ]
    Sl327 Toxicity Sl327, supplied by Tocris, used in various techniques. Bioz Stars score: 95/100, based on 6 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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    PKC-mediated ADP secretion and subsequent P2Y 12 activation are essential for thrombin-induced p70S6K phosphorylation. Washed platelets were incubated with vehicle (0.2% DMSO), BIM I (10 μmol L −1 ), <t>U0126</t> (10 μmol L −1 ), PD98059 (50 μmol L −1 ), VU 0155069 (10 μmol L −1 ), VU 0364739 HCl (10 μmol L −1 ), MRS 2279 (10 μmol L −1 ), AR-C 66096 (1 μmol L −1 ), abciximab (10 μg mL −1 ), or RGDS (1 mmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ) for 15 min (A, B). Washed platelets were incubated with vehicle (0.2% DMSO) or BIM I (10 μmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ), ADP (10 μmol L −1 ), or both for 15 min (C). Phosphorylation of the indicated proteins was assessed by Western blotting of either whole cell lysates or immunoprecipitates (IP). Membranes were reprobed for α-tubulin to confirm equal loading. The bar graphs depict quantification of pTSC2 at Ser939 and Thr1462 (ratio phosphorylated/loading control) and pp70S6K at Thr389 (ratio phosphorylated/total) expressed as a percentage of the maximal signal induced by thrombin in vehicle conditions. * P
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    Tocris erk1 2 inhibitor sl327
    PKC-mediated ADP secretion and subsequent P2Y 12 activation are essential for thrombin-induced p70S6K phosphorylation. Washed platelets were incubated with vehicle (0.2% DMSO), BIM I (10 μmol L −1 ), <t>U0126</t> (10 μmol L −1 ), PD98059 (50 μmol L −1 ), VU 0155069 (10 μmol L −1 ), VU 0364739 HCl (10 μmol L −1 ), MRS 2279 (10 μmol L −1 ), AR-C 66096 (1 μmol L −1 ), abciximab (10 μg mL −1 ), or RGDS (1 mmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ) for 15 min (A, B). Washed platelets were incubated with vehicle (0.2% DMSO) or BIM I (10 μmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ), ADP (10 μmol L −1 ), or both for 15 min (C). Phosphorylation of the indicated proteins was assessed by Western blotting of either whole cell lysates or immunoprecipitates (IP). Membranes were reprobed for α-tubulin to confirm equal loading. The bar graphs depict quantification of pTSC2 at Ser939 and Thr1462 (ratio phosphorylated/loading control) and pp70S6K at Thr389 (ratio phosphorylated/total) expressed as a percentage of the maximal signal induced by thrombin in vehicle conditions. * P
    Erk1 2 Inhibitor Sl327, supplied by Tocris, used in various techniques. Bioz Stars score: 89/100, based on 9 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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    Schematic of a proposed mechanism underlying the neuroprotective effects of PYP against PFOS exposure in frontal cortical neurons. The expression level of GRP78 by PFOS exposure is mediated by phosphorylation of JNK linked to CaMKII. PYP downregulates the JNK-mediated increase in ER stress by PFOS via the activation of TrkB receptor-linked <t>ERK1/2</t> signaling. Thus, PYP protects frontal cortical neurons from ER stress caused by PFOS-induced calcium dysregulation.
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    Tocris α amino
    Schematic of a proposed mechanism underlying the neuroprotective effects of PYP against PFOS exposure in frontal cortical neurons. The expression level of GRP78 by PFOS exposure is mediated by phosphorylation of JNK linked to CaMKII. PYP downregulates the JNK-mediated increase in ER stress by PFOS via the activation of TrkB receptor-linked <t>ERK1/2</t> signaling. Thus, PYP protects frontal cortical neurons from ER stress caused by PFOS-induced calcium dysregulation.
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    Tocris erk kinase mek1 2
    Schematic of a proposed mechanism underlying the neuroprotective effects of PYP against PFOS exposure in frontal cortical neurons. The expression level of GRP78 by PFOS exposure is mediated by phosphorylation of JNK linked to CaMKII. PYP downregulates the JNK-mediated increase in ER stress by PFOS via the activation of TrkB receptor-linked <t>ERK1/2</t> signaling. Thus, PYP protects frontal cortical neurons from ER stress caused by PFOS-induced calcium dysregulation.
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    Image Search Results


    PTPN11 D61G overexpression induces learning and memory and LTP deficits that can be reversed by MEK inhibition a. AAV– PTPN11 D61G infection results in overexpression of SHP2 D61G . Anti–SHP2 immunohistochemistry shows robust overexpression of SHP2 in the hippocampus of AAV– PTPN11 D61G –infused brains (left) compared with AAV– GFP infused brains (right). Full-length blots/gels are presented in Supplementary Figure 11 . b. PTPN11 D61G overexpression increases basal Erk activity (phospho–Erk level) and prevents further Erk activation in response to TBS. Left , Representative immunoblot showing p–Erk (upper) and total Erk (lower) in PTPN11 D61G –expressing slices and GFP –expressing slices. Slices were prepared 1 h after TBS. Right , Bar graph displays normalized p–Erk levels (mean ± s.e.m.). CTL, control without TBS. c. MEK inhibitor SL327 reverses spatial memory deficits in PTPN11 D61G –overexpressing mice in the Morris water maze. Quadrant occupancy analysis for the probe trial reveals that PTPN11 D61G /veh mice showed no preference for the target quadrant (target vs. other quadrants, Dunnett’s Multiple Comparison Test after one-way ANOVA, P > 0.05). PTPN11 D61G /veh mice also spent significantly less time in the target quadrant compared with GFP /veh mice. SL327 treatment significantly increased the time spent in the target quadrant in PTPN11 D61G -expressing mice compared with vehicle-treated PTPN11 D61G mice ( PTPN11 D61G /SL327, 37.25 ± 3.50 %, n=10, unpaired two-tailed t-test, t = 2.335, * P

    Journal: Nature neuroscience

    Article Title: Mechanism and treatment for the learning and memory deficits associated with mouse models of Noonan syndrome

    doi: 10.1038/nn.3863

    Figure Lengend Snippet: PTPN11 D61G overexpression induces learning and memory and LTP deficits that can be reversed by MEK inhibition a. AAV– PTPN11 D61G infection results in overexpression of SHP2 D61G . Anti–SHP2 immunohistochemistry shows robust overexpression of SHP2 in the hippocampus of AAV– PTPN11 D61G –infused brains (left) compared with AAV– GFP infused brains (right). Full-length blots/gels are presented in Supplementary Figure 11 . b. PTPN11 D61G overexpression increases basal Erk activity (phospho–Erk level) and prevents further Erk activation in response to TBS. Left , Representative immunoblot showing p–Erk (upper) and total Erk (lower) in PTPN11 D61G –expressing slices and GFP –expressing slices. Slices were prepared 1 h after TBS. Right , Bar graph displays normalized p–Erk levels (mean ± s.e.m.). CTL, control without TBS. c. MEK inhibitor SL327 reverses spatial memory deficits in PTPN11 D61G –overexpressing mice in the Morris water maze. Quadrant occupancy analysis for the probe trial reveals that PTPN11 D61G /veh mice showed no preference for the target quadrant (target vs. other quadrants, Dunnett’s Multiple Comparison Test after one-way ANOVA, P > 0.05). PTPN11 D61G /veh mice also spent significantly less time in the target quadrant compared with GFP /veh mice. SL327 treatment significantly increased the time spent in the target quadrant in PTPN11 D61G -expressing mice compared with vehicle-treated PTPN11 D61G mice ( PTPN11 D61G /SL327, 37.25 ± 3.50 %, n=10, unpaired two-tailed t-test, t = 2.335, * P

    Article Snippet: Drugs SL327 (Tocris) was dissolved in DMSO (16 mg/ml) and was injected intraperitoneally once daily, 30 min before the water maze experiment at a dose of 32mg/kg.

    Techniques: Over Expression, Inhibition, Infection, Immunohistochemistry, Activity Assay, Activation Assay, Expressing, CTL Assay, Mouse Assay, Two Tailed Test

    PTPN11 D61G overexpression enhances excitatory synaptic function through increased Ras-Erk signaling a. AMPA receptor-mediated currents were measured at the peak of the currents at − 65 mV, and NMDA currents were measured 50 ms after onset at + 40 mV. The average of 15 traces is shown. Scale, 100 pA and 40 ms. b. Group data showing the increased AMPA:NMDA current ratio in AAV– PTPN11 D61G mice compared with AAV- GFP mice. SL327 treatment (1 μM, 1 h) significantly reversed the AMPA:NMDA current ratio in the PTPN11 D61G group without affecting GFP –expressing mice. Two-way ANOVA, interaction between viral treatment and drug, F 1, 31 = 10.53, ** P

    Journal: Nature neuroscience

    Article Title: Mechanism and treatment for the learning and memory deficits associated with mouse models of Noonan syndrome

    doi: 10.1038/nn.3863

    Figure Lengend Snippet: PTPN11 D61G overexpression enhances excitatory synaptic function through increased Ras-Erk signaling a. AMPA receptor-mediated currents were measured at the peak of the currents at − 65 mV, and NMDA currents were measured 50 ms after onset at + 40 mV. The average of 15 traces is shown. Scale, 100 pA and 40 ms. b. Group data showing the increased AMPA:NMDA current ratio in AAV– PTPN11 D61G mice compared with AAV- GFP mice. SL327 treatment (1 μM, 1 h) significantly reversed the AMPA:NMDA current ratio in the PTPN11 D61G group without affecting GFP –expressing mice. Two-way ANOVA, interaction between viral treatment and drug, F 1, 31 = 10.53, ** P

    Article Snippet: Drugs SL327 (Tocris) was dissolved in DMSO (16 mg/ml) and was injected intraperitoneally once daily, 30 min before the water maze experiment at a dose of 32mg/kg.

    Techniques: Over Expression, Mass Spectrometry, Mouse Assay, Expressing

    ERKi regulates NP cells i n vivo in the developing rat brain. ( A ) Injection of brain permeable SL327 compound resulted in more BrdU+ proliferative cell in the VZ/SVZ of the embryonic brain. ( B ) The number of Tbr2+ intermediate progenitor cells was also significantly increased by SL327 injection. ( C ) The number of ASCL1+ cells was significantly reduced by SL327 injection. ( D ) The number of DCX+ neuroblasts was also significantly reduced by SL327 injection. ( E ) The number of GFAP+ astrocytes was not affected by SL327 injection. In all the panels representative sections were shown in the left two images, the quantification of the number of positive cells was shown in the right bar graph. All bar graphs represent Mean ± s.d., n = 6. LV, lateral ventricle. *P

    Journal: Scientific Reports

    Article Title: Cell type-dependent Erk-Akt pathway crosstalk regulates the proliferation of fetal neural progenitor cells

    doi: 10.1038/srep26547

    Figure Lengend Snippet: ERKi regulates NP cells i n vivo in the developing rat brain. ( A ) Injection of brain permeable SL327 compound resulted in more BrdU+ proliferative cell in the VZ/SVZ of the embryonic brain. ( B ) The number of Tbr2+ intermediate progenitor cells was also significantly increased by SL327 injection. ( C ) The number of ASCL1+ cells was significantly reduced by SL327 injection. ( D ) The number of DCX+ neuroblasts was also significantly reduced by SL327 injection. ( E ) The number of GFAP+ astrocytes was not affected by SL327 injection. In all the panels representative sections were shown in the left two images, the quantification of the number of positive cells was shown in the right bar graph. All bar graphs represent Mean ± s.d., n = 6. LV, lateral ventricle. *P

    Article Snippet: For developing brain study groups of three pregnant Sprague Dawley rats were injected intraperitoneally (i.p.) with SL327 compound (Tocris Bioscience, Bristol, UK) or DMSO control daily for 3 days from embryonic day 18 to 20.

    Techniques: Injection

    Histological and electron microscopy assesment of pERK expression in P7 mouse forebrain following 30 min HI A and B , distribution of normal pERK immunoreactivity in the forebrain of sham animal ( A ) and an animal with unilateral carotid occlusion ( B ). C and G , increased pERK immunoreactivity in untreated animals at 15 min following 30 min HI ( C ). Response was ablated with the application of MEK inhibitor SL327 (133 μg/g BW) ( G ). D and E , schematic summary of white matter pERK‐IR in naive ( D ) and after a 30 min HI insult ( E ). Light microscopy overview at the intersection between hippocampus (top), thalamus (left) and cerebral cortex (right), coronal section at mid‐parietal level ( D and E ). Note the faint pERK‐IR in control animal with carotid occlusion only ( D , Ctrl), and the strong increase of expression in fibre tracts in external capsule (ec), fornix (fx), cortico‐thalamic fibres (ct), and descending tracts of the internal capsule (ic) at 1 h recovery following HI ( E ). F and H , electron microscopy of the internal capsule, at 15 min recovery following HI. Early pERK reactivity is located to the axons only. Arrows point to pERK positive clusters within adjacent axons. Scale bar ( A–C, G ): 1.5 mm [Color figure can be viewed at http://wileyonlinelibrary.com ]

    Journal: The Journal of Physiology

    Article Title: Extracellular signal‐regulated kinase 2 has duality in function between neuronal and astrocyte expression following neonatal hypoxic–ischaemic cerebral injury

    doi: 10.1113/JP275649

    Figure Lengend Snippet: Histological and electron microscopy assesment of pERK expression in P7 mouse forebrain following 30 min HI A and B , distribution of normal pERK immunoreactivity in the forebrain of sham animal ( A ) and an animal with unilateral carotid occlusion ( B ). C and G , increased pERK immunoreactivity in untreated animals at 15 min following 30 min HI ( C ). Response was ablated with the application of MEK inhibitor SL327 (133 μg/g BW) ( G ). D and E , schematic summary of white matter pERK‐IR in naive ( D ) and after a 30 min HI insult ( E ). Light microscopy overview at the intersection between hippocampus (top), thalamus (left) and cerebral cortex (right), coronal section at mid‐parietal level ( D and E ). Note the faint pERK‐IR in control animal with carotid occlusion only ( D , Ctrl), and the strong increase of expression in fibre tracts in external capsule (ec), fornix (fx), cortico‐thalamic fibres (ct), and descending tracts of the internal capsule (ic) at 1 h recovery following HI ( E ). F and H , electron microscopy of the internal capsule, at 15 min recovery following HI. Early pERK reactivity is located to the axons only. Arrows point to pERK positive clusters within adjacent axons. Scale bar ( A–C, G ): 1.5 mm [Color figure can be viewed at http://wileyonlinelibrary.com ]

    Article Snippet: SL327 toxicity SL327 (Tocris, Bristol, UK), a MEK1/2 inhibitor (Atkins et al . ) proved to be toxic when dissolved in DMSO (data not shown), and therefore, was dissolved in 100% EtOH instead.

    Techniques: Electron Microscopy, Expressing, Hi-C, Light Microscopy

    Ipsilateral ERK phosphorylation Dose response for SL327 inhibition of pERK immunoreactivity (optical luminosity value (OLV)), applied 20 min before a 30 min HI insult in hemispheric regions ipsilateral to carotid occlusion. A , CTX 12–2 dorsal cerebral cortex (12 to 2 o'clock segment), CTX 2–4 middle cerebral cortex (2 to 4 o'clock segment). B , PYRI: pyriform cortex, HIP: hippocampus. C , THAL: thalamus, STR; striatum. Increasing the dose of SL327 from 15 to 30 μg/g BW correlates to an 80% reduction in immunoreactivity.

    Journal: The Journal of Physiology

    Article Title: Extracellular signal‐regulated kinase 2 has duality in function between neuronal and astrocyte expression following neonatal hypoxic–ischaemic cerebral injury

    doi: 10.1113/JP275649

    Figure Lengend Snippet: Ipsilateral ERK phosphorylation Dose response for SL327 inhibition of pERK immunoreactivity (optical luminosity value (OLV)), applied 20 min before a 30 min HI insult in hemispheric regions ipsilateral to carotid occlusion. A , CTX 12–2 dorsal cerebral cortex (12 to 2 o'clock segment), CTX 2–4 middle cerebral cortex (2 to 4 o'clock segment). B , PYRI: pyriform cortex, HIP: hippocampus. C , THAL: thalamus, STR; striatum. Increasing the dose of SL327 from 15 to 30 μg/g BW correlates to an 80% reduction in immunoreactivity.

    Article Snippet: SL327 toxicity SL327 (Tocris, Bristol, UK), a MEK1/2 inhibitor (Atkins et al . ) proved to be toxic when dissolved in DMSO (data not shown), and therefore, was dissolved in 100% EtOH instead.

    Techniques: Inhibition

    Schedule of experimental procedures A , WT (C57/Bl6) mice underwent 30 min hypoxic–ischaemic (HI) insult and were then killed at 15 min post‐hypoxia for pERK immunoreactivity evaluation. B , pERK immunoreactivity was assessed at multiple time points up to 48 h post‐insult to P7 WT mice. C , a dose response of SL327, controlled to vehicle alone, was administered 20 min prior to 30 min HI and pERK immunoreactivity was assessed at 15 min post‐insult. D , WT mice were subject to either 30 min or 60 min HI, with 133 μg/g SL327 or EtOH (vehicle) administered either 20 min prior to or 60 min post‐insult. Brain histology was assessed at 48 h. E , inhibition of neuronal pERK immunoreactivity was confirmed at 15 min post‐HI in synapsin‐cre driven ERK tg mutant mice compared to littermate WT controls. F , brain histology was assessed at 48 h after 30 min HI in synapsin‐cre driven ERK tg mutant mice and littermate WT controls. G , brain histology was assessed at 48 h after 30 min HI in GFAP‐cre driven ERK tg mutant mice and littermate WT controls. H , saline or LPS was injected at 12 h prior to 30 min HI in both synapsin‐cre and GFAP‐cre driven ERK tg mutant mice and littermate WT controls. Brain histology was assessed at 48 h.

    Journal: The Journal of Physiology

    Article Title: Extracellular signal‐regulated kinase 2 has duality in function between neuronal and astrocyte expression following neonatal hypoxic–ischaemic cerebral injury

    doi: 10.1113/JP275649

    Figure Lengend Snippet: Schedule of experimental procedures A , WT (C57/Bl6) mice underwent 30 min hypoxic–ischaemic (HI) insult and were then killed at 15 min post‐hypoxia for pERK immunoreactivity evaluation. B , pERK immunoreactivity was assessed at multiple time points up to 48 h post‐insult to P7 WT mice. C , a dose response of SL327, controlled to vehicle alone, was administered 20 min prior to 30 min HI and pERK immunoreactivity was assessed at 15 min post‐insult. D , WT mice were subject to either 30 min or 60 min HI, with 133 μg/g SL327 or EtOH (vehicle) administered either 20 min prior to or 60 min post‐insult. Brain histology was assessed at 48 h. E , inhibition of neuronal pERK immunoreactivity was confirmed at 15 min post‐HI in synapsin‐cre driven ERK tg mutant mice compared to littermate WT controls. F , brain histology was assessed at 48 h after 30 min HI in synapsin‐cre driven ERK tg mutant mice and littermate WT controls. G , brain histology was assessed at 48 h after 30 min HI in GFAP‐cre driven ERK tg mutant mice and littermate WT controls. H , saline or LPS was injected at 12 h prior to 30 min HI in both synapsin‐cre and GFAP‐cre driven ERK tg mutant mice and littermate WT controls. Brain histology was assessed at 48 h.

    Article Snippet: SL327 toxicity SL327 (Tocris, Bristol, UK), a MEK1/2 inhibitor (Atkins et al . ) proved to be toxic when dissolved in DMSO (data not shown), and therefore, was dissolved in 100% EtOH instead.

    Techniques: Mouse Assay, Inhibition, Mutagenesis, Injection

    Effect of SL327 on αMβ2+ microglial activation, astroglial activation, neuronal tissue loss (Nissl body presence) and TUNEL+ cell death, when applied 20 min before ( A , C , E , G ) or 1 h post ( B , D , F , H , I ) 30 or 60 min HI Assessment at ×20 microscopy field magnification (mean + SEM over 3 fields). A and B , the levels of CD11b+ microglia are significantly decreased in the SL327 group in white matter (EC) as well as in most grey matter regions (STR, CTX, HIP). E and F , Nissl score was decreased in pre‐treated animals. Cortex was particularly spared compared to vehicle alone. G and H , this trend to decrease is observed with number of TUNEL+ cells. SL327 treated pups have a reduction in dying cells compared to EtOH treated animals, significantly so in pre‐treated STR and HIP. C and D , extent of gliosis and reactive (GFAP+) astrocyte activation was unaffected by the application of SL327. * P

    Journal: The Journal of Physiology

    Article Title: Extracellular signal‐regulated kinase 2 has duality in function between neuronal and astrocyte expression following neonatal hypoxic–ischaemic cerebral injury

    doi: 10.1113/JP275649

    Figure Lengend Snippet: Effect of SL327 on αMβ2+ microglial activation, astroglial activation, neuronal tissue loss (Nissl body presence) and TUNEL+ cell death, when applied 20 min before ( A , C , E , G ) or 1 h post ( B , D , F , H , I ) 30 or 60 min HI Assessment at ×20 microscopy field magnification (mean + SEM over 3 fields). A and B , the levels of CD11b+ microglia are significantly decreased in the SL327 group in white matter (EC) as well as in most grey matter regions (STR, CTX, HIP). E and F , Nissl score was decreased in pre‐treated animals. Cortex was particularly spared compared to vehicle alone. G and H , this trend to decrease is observed with number of TUNEL+ cells. SL327 treated pups have a reduction in dying cells compared to EtOH treated animals, significantly so in pre‐treated STR and HIP. C and D , extent of gliosis and reactive (GFAP+) astrocyte activation was unaffected by the application of SL327. * P

    Article Snippet: SL327 toxicity SL327 (Tocris, Bristol, UK), a MEK1/2 inhibitor (Atkins et al . ) proved to be toxic when dissolved in DMSO (data not shown), and therefore, was dissolved in 100% EtOH instead.

    Techniques: Activation Assay, TUNEL Assay, Microscopy

    PKC-mediated ADP secretion and subsequent P2Y 12 activation are essential for thrombin-induced p70S6K phosphorylation. Washed platelets were incubated with vehicle (0.2% DMSO), BIM I (10 μmol L −1 ), U0126 (10 μmol L −1 ), PD98059 (50 μmol L −1 ), VU 0155069 (10 μmol L −1 ), VU 0364739 HCl (10 μmol L −1 ), MRS 2279 (10 μmol L −1 ), AR-C 66096 (1 μmol L −1 ), abciximab (10 μg mL −1 ), or RGDS (1 mmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ) for 15 min (A, B). Washed platelets were incubated with vehicle (0.2% DMSO) or BIM I (10 μmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ), ADP (10 μmol L −1 ), or both for 15 min (C). Phosphorylation of the indicated proteins was assessed by Western blotting of either whole cell lysates or immunoprecipitates (IP). Membranes were reprobed for α-tubulin to confirm equal loading. The bar graphs depict quantification of pTSC2 at Ser939 and Thr1462 (ratio phosphorylated/loading control) and pp70S6K at Thr389 (ratio phosphorylated/total) expressed as a percentage of the maximal signal induced by thrombin in vehicle conditions. * P

    Journal: Journal of Thrombosis and Haemostasis

    Article Title: Protein kinase C and P2Y12 take center stage in thrombin-mediated activation of mammalian target of rapamycin complex 1 in human platelets

    doi: 10.1111/jth.12552

    Figure Lengend Snippet: PKC-mediated ADP secretion and subsequent P2Y 12 activation are essential for thrombin-induced p70S6K phosphorylation. Washed platelets were incubated with vehicle (0.2% DMSO), BIM I (10 μmol L −1 ), U0126 (10 μmol L −1 ), PD98059 (50 μmol L −1 ), VU 0155069 (10 μmol L −1 ), VU 0364739 HCl (10 μmol L −1 ), MRS 2279 (10 μmol L −1 ), AR-C 66096 (1 μmol L −1 ), abciximab (10 μg mL −1 ), or RGDS (1 mmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ) for 15 min (A, B). Washed platelets were incubated with vehicle (0.2% DMSO) or BIM I (10 μmol L −1 ) for 15 min before stimulation with thrombin (0.2 U mL −1 ), ADP (10 μmol L −1 ), or both for 15 min (C). Phosphorylation of the indicated proteins was assessed by Western blotting of either whole cell lysates or immunoprecipitates (IP). Membranes were reprobed for α-tubulin to confirm equal loading. The bar graphs depict quantification of pTSC2 at Ser939 and Thr1462 (ratio phosphorylated/loading control) and pp70S6K at Thr389 (ratio phosphorylated/total) expressed as a percentage of the maximal signal induced by thrombin in vehicle conditions. * P

    Article Snippet: AR-C 66096 tetrasodium salt, bisindolylmaleimide I (BIM I), H89, MRS 2279, PD98059, rapamycin, SL 327, SQ 22536, U0126, U46619, VU 0155069, VU 0364739 hydrochloride, and wortmannin were from Tocris (Avonmouth, UK).

    Techniques: Activation Assay, Incubation, Western Blot

    Schematic of a proposed mechanism underlying the neuroprotective effects of PYP against PFOS exposure in frontal cortical neurons. The expression level of GRP78 by PFOS exposure is mediated by phosphorylation of JNK linked to CaMKII. PYP downregulates the JNK-mediated increase in ER stress by PFOS via the activation of TrkB receptor-linked ERK1/2 signaling. Thus, PYP protects frontal cortical neurons from ER stress caused by PFOS-induced calcium dysregulation.

    Journal: Marine Drugs

    Article Title: Phycoerythrin Peptide from Pyropia yezoensis Alleviates Endoplasmic Reticulum Stress Caused by Perfluorooctane Sulfonate-Induced Calcium Dysregulation

    doi: 10.3390/md16020044

    Figure Lengend Snippet: Schematic of a proposed mechanism underlying the neuroprotective effects of PYP against PFOS exposure in frontal cortical neurons. The expression level of GRP78 by PFOS exposure is mediated by phosphorylation of JNK linked to CaMKII. PYP downregulates the JNK-mediated increase in ER stress by PFOS via the activation of TrkB receptor-linked ERK1/2 signaling. Thus, PYP protects frontal cortical neurons from ER stress caused by PFOS-induced calcium dysregulation.

    Article Snippet: JNK inhibitor (SP600125; 10 µM), CaMKII inhibitor (KN62; 10 µM), TrkB receptor antagonist (cyclotraxin B; 200 nM), PI3K inhibitor ( ; 20 µM), and ERK1/2 inhibitor (SL327; 10 µM) were obtained from Tocris Bioscience (Minneapolis, MN, USA) and were incubated for 30 min prior to PYP or PFOS treatments.

    Techniques: Expressing, Activation Assay