BACKGROUNDTraumatic brain injury (TBI) is a significant global health concern and is characterized by brain dysfunction resulting from external physical forces, leading to brain pathology and neuropsychiatric disorders such as anxiety. This study investigates the effects of TC-DAPK6 on tau hyper-phosphorylation, gene expression, anxiety, and behavior impairment in the TBI mice model.METHODS AND RESULTSA weight drop model induced the TBI and the anxiety levels were evaluated using an elevated plus maze (EPM) test. TC-DAPK6 was intraperitoneally administered one-month post-TBI and continued for two months. The total cis-p-tau ratio in the brain was assessed using western blot and immunofluorescence staining. Molecular analysis was conducted on Aff2, Zkscan16, Kcna1, Pcdhac2, and Pcdhga8 to investigate the function and pathogenic role of TC-DAPK6 in neurological diseases in the cerebral cortex tissues of TBI-model mice, and the results were compared with TC-DAPK6 TBI-treatment group. The anxiety level and phosphorylation of tau protein in the TBI group were significantly increased compared to the sham groups and decreased substantially in the TBI-treatment group after TC-DAPK6 administration; the TBI group mostly spent their time with open arms. TC-DAPK6 decreased the expression level of genes as much as the sham group. Meanwhile, KCNA1 showed the highest fold of changes in the TBI and TBI-treatment groups.CONCLUSIONSThe study demonstrates a clear association between cis-p-tau and neuro-related gene expression levels in TBI-induced mice. Targeting these pathways with DAPK1 inhibitors, shows promise for therapeutic interventions in TBI and related neurodegenerative disorders.

01 Jul 2011·Anti-Cancer DrugsQ4 · MEDICINE

An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies

Q4 · MEDICINE

Article

Author: Spaniol, Kristina ; Boos, Joachim ; Lanvers-Kaminsky, Claudia

Polo-like kinase 1 (PLK1) is a regulator of mitosis and its upregulation in tumours is often associated with poor prognosis. Although PLK1 inhibitors have already entered phase 1 clinical trials, little is known about their impact on the treatment of paediatric malignancies. Thus, we evaluated the concept of PKL1 inhibition by testing the effects of the PLK1 inhibitor GW843682X alone and in combination with the topoisomerase 1 inhibitor, camptothecin, against a panel of 18 paediatric tumour cell lines. Cytotoxicity was evaluated by MTT test and by caspase 3/7 activation. Expression of target was confirmed by western blot analysis. Expression of ATP binding cassette transporters was analysed by quantitative real-time reverse transcription PCR. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 μmol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status. Neither synergistic nor antagonistic effects were observed for the combination of GW843682X and camptothecin in 14 cell lines. GW843682X showed considerable toxicity against a panel of paediatric tumour cell lines suggesting that PLK1 inhibitors under clinical development should be evaluated against paediatric malignancies too.

Circulation

Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease

Article

Author: Hesse, Julia ; Al-Kassis, Gabrielle ; Borst, Oliver ; Wollnitzke, Philipp ; Wildeis, Laura ; Zeus, Tobias ; Dannenberg, Lisa ; Deister-Jonas, Jennifer ; Akhyari, Payam ; Zako, Saif ; Benkhoff, Marcel ; Seel, Jasmin ; Petzold, Tobias ; Semleit, Nina ; Mourikis, Philipp ; Helten, Carolin ; Cramer, Mareike ; Metzen, Daniel ; Huckenbeck, Tim ; Dahlmanns, Jana ; Coman, Cristina ; Gerdes, Norbert ; Levkau, Bodo ; Polzin, Amin ; Quast, Christine ; Barcik, Maike ; Hu, Hao ; Hering, Moritz ; Ahrends, Robert ; Lichtenberg, Artur ; Weber, Jessica ; Barth, Mareike ; Kahmann, Paulina ; Kelm, Malte ; Hoppe, Julia

BACKGROUND:Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.METHODS:AVD progression and its consequences for cardiac function were examined in a murine wire injury–induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS.RESULTS:Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.CONCLUSIONS:Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

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disorder of aging	Preclinical	KR	Amorepacific Corp.	01 Dec 2022

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