FR 236924

FR 236924 is a selective activator of PKC-ε [1].

PKC is a monomeric Ca2+- and phospholipid-dependent Ser/Thr protein kinase and plays an important role in growth factor-activated signaling and malignant transformation.

FR 236924 (DCP-LA) is a selective PKC-ε activator. In PC-12 cells, DCP-LA (10 nM-100 μM) activated PKC in a concentration dependent way with the maximal effect at 100 nM. In the cell-free system, DCP-LA (100 μM) significantly activated PKC-ε and exhibited >7-fold potency over other PKC isozymes (α,βI, βII, γ, δ, μ, η and ζ), suggesting that DCP-LA was a selective PKC-ε activator. DCP-LA exhibited the maximal effect on PKC-ε at 100 μM. The activation of PKC-ε induced by DCP-LA (100 μM) was inhibited by dioleoyl-phosphatidylserine in a concentration dependent way, suggesting that DCP-LA might bound to the phosphatidylserine binding site on PKC-ε. However, dioleoyl-phosphatidylserine increased DCP-LA (100 μM)-induced PKC-ε activation in a concentration dependent way, suggesting a different activation mechanism [1]. In Xenopus oocytes expressing α7 receptors, FR236924 (10 μM) induced a persistent increased α7 receptor responses to 144% via a PKC pathway. In rat hippocampal slices, FR236924 (10 nM to 10 μM) facilitated hippocampal neurotransmission [2].

In the hippocampus of rats, FR236924 induced glutamate release and facilitated hippocampal synaptic transmission through PKC [3].

References:
[1].  Kanno T, Yamamoto H, Yaguchi T, et al. The linoleic acid derivative DCP-LA selectively activates PKC-epsilon, possibly binding to the phosphatidylserine binding site. J Lipid Res, 2006, 47(6): 1146-1156.
[2].  Tanaka A, Nishizaki T. The newly synthesized linoleic acid derivative FR236924 induces a long-lasting facilitation of hippocampal neurotransmission by targeting nicotinic acetylcholine receptors. Bioorg Med Chem Lett, 2003, 13(6): 1037-1040.
[3].  Yamamoto S, Kanno T, Nagata T, et al. The linoleic acid derivative FR236924 facilitates hippocampal synaptic transmission by enhancing activity of presynaptic alpha7 acetylcholine receptors on the glutamatergic terminals. Neuroscience, 2005, 130(1): 207-213.

TeA is a key virulence factor for Alternaria alternata (Fr.) Keissler infection of its host.[Pubmed:28324684]

Plant Physiol Biochem. 2017 Jun;115:73-82.

A toxin-deficient mutant strain, HP001 mutant of Alternaria alternata, whose mycelium is unable to infect its host, produces little tenuazonic acid (TeA) toxin. How TeA plays a role in initiating host infection by A. alternata remains unclear. In this research we use Imaging-PAM based on chlorophyll fluorescence parameters and transmission electron microscopy to explore the role of TeA toxin during the infection process of A. alternata. Photosystem II damage began even before wild type mycelium infected the leaves of its host, croftonweed (Ageratina adenophora). Compared with the wild type, HP001 mutant produces morphologically different colonies, hyphae with thinner cell walls, has higher reactive oxygen species (ROS) content and lower peroxidase activity, and fails to form appressoria on the host surface. Adding TeA toxin allows the mutant to partially recover these characters and more closely resemble the wild type. Additionally, we found that the mutant is able to elicit disease symptoms when its mycelium is placed on leaves whose epidermis has been manually removed, which indicates that TeA may be determinant in the fungus recognition of its plant host. Lack of TeA toxin appears responsible for the loss of pathogenicity of the HP001 mutant. As a key virulence factor, TeA toxin not only damages the host plant but also is involved in maintaining ROS content, host recognition, inducing appressoria to infect the host and for allowing completion of the infection process.

Vessel Patency at 24 Hours and Its Relationship With Clinical Outcomes and Infarct Volume in REVASCAT Trial (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset).[Pubmed:28292867]

Stroke. 2017 Apr;48(4):983-989.

BACKGROUND AND PURPOSE: Higher rates of target vessel patency at 24 hours were noted in the thrombectomy group compared with control group in recent randomized trials. As a prespecified secondary end point, we aimed to assess 24-hour revascularization rates by treatment groups and occlusion site as they related to clinical outcome and 24-hour infarct volume in REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset). METHODS: Independent core laboratory adjudicated vessel status according to modified arterial occlusive lesion classification at 24 hours on computed tomographic/magnetic resonance (94.2%/5.8%) angiography and 24-hour infarct volume on computed tomography were studied (95/103 patients in the thrombectomy group versus 94/103 in the control group, respectively). Complete revascularization was defined as modified arterial occlusive lesion grade 3. Its effect on clinical outcome was analyzed by ordinal logistic regression. RESULTS: Complete revascularization was achieved in 70.5% of the solitaire group and in 22.3% of the control group (P<0.001). Significant differences in complete revascularization rates were found for terminus internal carotid artery, M1, and tandem occlusions (all P<0.001) but not for M2 occlusions. In the thrombectomy group, 2 out of 63 patients (3.1%) with modified Thrombolysis in Cerebral Infarction 2b/3 after thrombectomy showed arterial reocclusion (modified arterial occlusive lesion grade 0/1) at 24 hours. Complete revascularization was associated with improved outcome in both thrombectomy (adjusted odds ratio, 4.5; 95% confidence interval, 1.9-10.9) and control groups (adjusted odds ratio, 2.7; 95% confidence interval, 1.0-6.7). Revascularization (modified arterial occlusive lesion grade 2/3) was associated with smaller infarct volumes in either treatment arm. CONCLUSIONS: Complete revascularization at 24 hours is a powerful predictor of favorable clinical outcome, whereas revascularization of any type results in reduced infarct volume in both thrombectomy and control groups. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

The CAM-ICU has now a French "official" version. The translation process of the 2014 updated Complete Training Manual of the Confusion Assessment Method for the Intensive Care Unit in French (CAM-ICU.fr).[Pubmed:28365244]

Anaesth Crit Care Pain Med. 2017 Oct;36(5):297-300.

INTRODUCTION: Delirium is common in Intensive-Care-Unit (ICU) patients but under-recognized by bed-side clinicians when not using validated delirium-screening tools. The Confusion-Assessment-Method for the ICU (CAM-ICU) has demonstrated very good psychometric properties, and has been translated into many different languages though not into French. We undertook this opportunity to describe the translation process. MATERIAL AND METHODS: The translation was performed following recommended guidelines. The updated method published in 2014 including introduction letters, worksheet and flowsheet for bed-side use, the method itself, case-scenarios for training and Frequently-Asked-Questions (32 pages) was translated into French language by a neuropsychological researcher who was not familiar with the original method. Then, the whole method was back-translated by a native English-French bilingual speaker. The new English version was compared to the original one by the Vanderbilt University ICU-delirium-team. Discrepancies were discussed between the two teams before final approval of the French version. RESULTS: The entire process took one year. Among the 3692 words of the back-translated version of the method itself, 18 discrepancies occurred. Eight (44%) lead to changes in the final version. Details of the translation process are provided. CONCLUSIONS AND RELEVANCE: The French version of CAM-ICU is now available for French-speaking ICUs. The CAM-ICU is provided with its complete training-manual that was challenging to translate following recommended process. While many such translations have been done for other clinical tools, few have published the details of the process itself. We hope that the availability of such teaching material will now facilitate a large implementation of delirium-screening in French-speaking ICUs.

[Comparing study on the hyoid bone position after treatment of class malocclusion using improved appliance FR ].[Pubmed:28317354]

Hua Xi Kou Qiang Yi Xue Za Zhi. 2016 Aug 1;34(4):369-374.

OBJECTIVE: This study aims to compare the changes of hyoid bone position before and after treatment of Angle class malocclusion using improved appliance FR . METHODS: Forty patients with Angle class malocclusion were chosen and divided into two groups, namely, experimental and control. Each group had 20 patients. The young patients in the experi-mental group were treated using improved appliance FR , whereas those in the control group were treated using classic appliance FR . The hyoid bone position of the two groups were comparatively analyzed using an X-ray film before and after treatment. RESULTS: Compared with the condition before treatment, the condition after treatment showed that the hyoid bone position of young patients with Angle class malocclusion treated using improved appliance FR , H-FH, H-S, H-Ptm, and Ar-H-Me exhibited an increased angle (P<0.01), whereas the hyoid bone position of those treated using H-MP and H-Gn showed a decreased angle (P<0.01). The hyoid bone position of young patients with Angle class malocclusion treated using classic appliance FR , H-FH, H-S, and H-Ptm had an increased angle (P<0.05). Moreover, the hyoid bone position of those treated using Ar-H-Me had an increased angle (P<0.01), and the hyoid bone position of those treated using H-MP and H-RGn had a decreased angle (P<0.05). CONCLUSIONS: Compared with the hyoid bone position before treatment, the hyoid bone position after treatment of the young patients with Angle class malocclusion treated using improved appliance FR may move backward and downward, and the mandibular and hyoid bone position may move through clockwise rotation. The mandibular and hyoid bone position of young patients with Angle class malocclusion treated using classic appliance FR obtained a large angle by moving clockwise. The man-dibular bone moves backward and downward, thereby improving the hyoid bone in backward and upward directions. This condition makes a significant difference in treating the hyoid bone position of young patients with functional Angle class malocclusion..

The linoleic acid derivative DCP-LA selectively activates PKC-epsilon, possibly binding to the phosphatidylserine binding site.[Pubmed:16520488]

J Lipid Res. 2006 Jun;47(6):1146-56.

This study examined the effect of 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis-double bonds, on protein kinase C (PKC) activity. In the in situ PKC assay with reverse-phase high-performance liquid chromatography, DCP-LA significantly activated PKC in PC-12 cells in a concentration-dependent (10 nM-100 microM) manner, with the maximal effect at 100 nM, and the DCP-LA effect was blocked by GF109203X, a PKC inhibitor, or a selective inhibitor peptide of the novel PKC isozyme PKC-epsilon. Furthermore, DCP-LA activated PKC in HEK-293 cells that was inhibited by the small, interfering RNA against PKC-epsilon. In the cell-free PKC assay, of the nine isozymes examined here, DCP-LA most strongly activated PKC-epsilon, with >7-fold potency over other PKC isozymes, in the absence of dioleoyl-phosphatidylserine and 1,2-dioleoyl-sn-glycerol; instead, the DCP-LA action was inhibited by dioleoyl-phosphatidylserine. DCP-LA also activated PKC-gamma, a conventional PKC, but to a much lesser extent compared with that for PKC-epsilon, by a mechanism distinct from PKC-epsilon activation. Thus, DCP-LA serves as a selective activator of PKC-epsilon, possibly by binding to the phosphatidylserine binding site on PKC-epsilon. These results may provide fresh insight into lipid signaling in PKC activation.

The linoleic acid derivative FR236924 facilitates hippocampal synaptic transmission by enhancing activity of presynaptic alpha7 acetylcholine receptors on the glutamatergic terminals.[Pubmed:15561436]

Neuroscience. 2005;130(1):207-13.

The present study aimed at understanding the effect of FR236924, a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis-double bonds, on hippocampal synaptic transmission in both the in vitro and in vivo systems. FR236924 increased the rate of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated miniature excitatory postsynaptic currents, without affecting the amplitude, triggered by nicotine in CA1 pyramidal neurons of rat hippocampal slices, that is inhibited by GF109203X, a selective protein kinase C (PKC) inhibitor or alpha-bungarotoxin, an inhibitor of alpha7 acetylcholine (ACh) receptors. FR236924 stimulated glutamate release from rat hippocampal slices and in the hippocampus of freely behaving rats, and the effect was also inhibited by GF109203X or alpha-bungarotoxin. FR236924 induced a transient huge potentiation followed by a long-lasting potentiation in the slope of field excitatory postsynaptic potentials recorded from the CA1 region of rat hippocampal slices, and the latter effect was blocked by GF109203X or alpha-bungarotoxin. Likewise, the compound persistently facilitated hippocampal synaptic transmission in the CA1 region of the intact rat hippocampus. It is concluded from these results that FR236924 stimulates glutamate release by functionally targeting presynaptic alpha7 ACh receptors on the glutamatergic terminals under the influence of PKC, responsible for the facilitatory action on hippocampal synaptic transmission. This may provide evidence for a link between cis-unsaturated free fatty acids and presynaptic alpha7 ACh receptors in hippocampal synaptic plasticity.