Therapeutic effect of novel drug candidate, PRG-N-01, on NF2 syndrome-related tumor.

Background: NF2-related schwannomatosis (NF2-SWN) is associated with multiple benign tumors in the nervous system. NF2-SWN, caused by mutations in the NF2 gene, has developed into intracranial and spinal schwannomas. Because of the high surgical risk and frequent recurrence of multiple tumors, targeted therapy is necessary.

The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression.

Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated.

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders).

Asymmetric gradient orbital interaction of hetero-diatomic active sites for promoting C - C coupling.

Diatomic-site catalysts (DACs) garner tremendous attention for selective CO photoreduction, especially in the thermodynamical and kinetical mechanism of CO to C products. Herein, we first engineer a novel Zn-porphyrin/RuCu-pincer complex DAC (ZnPor-RuCuDAC). The heteronuclear ZnPor-RuCuDAC exhibits the best acetate selectivity (95.

Progerinin, an Inhibitor of Progerin, Alleviates Cardiac Abnormalities in a Model Mouse of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare human premature aging disorder that precipitates death because of cardiac disease. Almost all cases of HGPS are caused by aberrant splicing of the gene that results in the production of a mutant Lamin A protein termed progerin. In our previous study, treatment with Progerinin has been shown to reduce progerin expression and improve aging phenotypes in vitro and in vivo HGPS models.

Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation.

Eukaryotic Cu, Zn-superoxide dismutase (SOD1) is primarily responsible for cytotoxic filament formation in amyotrophic lateral sclerosis (ALS) neurons. Two cysteine residues in SOD1 form an intramolecular disulfide bond. This study aims to explore the molecular mechanism of SOD1 filament formation by cysteine overoxidation in sporadic ALS (sALS).

Splicing Variants, Protein-Protein Interactions, and Drug Targeting in Hutchinson-Gilford Progeria Syndrome and Small Cell Lung Cancer.

Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or properties. This process provides one of the major sources of use for understanding the proteomic diversity of multicellular organisms. In combination with post-translational modifications, it contributes to generating a variety of protein-protein interactions (PPIs) that are essential to cellular homeostasis or proteostasis.

Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu, Zn-superoxide dismutase (SOD1) causing the gain of its toxic property are the major culprit of familial ALS (fALS). The abnormal SOD1 aggregation in the motor neurons has been suggested as the major pathological hallmark of ALS patients.

RKIP Induction Promotes Tumor Differentiation via SOX2 Degradation in NF2-Deficient Conditions.

Unlabelled: Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGFβ receptor 2 (TβR2) expression and reduction or loss of NF2 activated non-canonical TGFβ signaling, which reduced Raf kinase inhibitor protein (RKIP) expression via TβR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions.

Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome.

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011).

Adsorption and Oxidative Desorption of Acetaldehyde over Mesoporous Fe O H /AlO.

Fe O H nanostructures were incorporated into commercially available and highly porous alumina using the temperature-regulated chemical vapor deposition method with ferrocene as an Fe precursor and subsequent annealing. All processes were conducted under ambient pressure conditions without using any high-vacuum equipment. The entire internal micro- and mesopores of the AlO substrate with a bead diameter of ∼2 mm were evenly decorated with Fe O H nanoparticles.

Binding thiourea derivatives with dimethyl methylphosphonate for sensing nerve agents.

In an effort to develop efficient substrates to sense organophosphonate nerve agents, we used the density-functional theory calculations to determine binding energies and geometries of 1 : 1 complexes formed between dimethyl methylphosphonate (DMMP) and 13 thiourea derivatives (TUn), including four newly-synthesized ones (n = 10-13). The four new thiourea derivatives have a 3,5-bis-(trifluoromethyl)phenyl group as one -substituent and an alkylphenyl group with zero to three methylene linkages as the other -substituent. The calculated geometries show that intermolecular double H-bonding is the most important factor influencing the formation of stable complexes at the molecular level.

p53 induces senescence through Lamin A/C stabilization-mediated nuclear deformation.

p53-mediated cellular senescence has been intensively investigated, because it is important for tumor suppressive function. In addition, p16/INK4A is well known to be critical for cellular senescence. However, detailed molecular mechanism or relevance between p53 and p16-mediated senescence has not been demonstrated yet.

Loss of NF2 Induces TGFβ Receptor 1-mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome.

Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease, and there has been no proper treatment for it until now. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGFβ receptor 2 (TβR2) expression, and an overwhelming expression of TGFβ receptor 1 (TβR1) is activated by physical stimuli such as pressure or heavy materials.

Therapeutic Effect of Quinacrine, an Antiprotozoan Drug, by Selective Suppression of p-CHK1/2 in p53-Negative Malignant Cancers.

Quinacrine (QNC), antiprotozoan drug commonly used against and , has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-κB and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions.

Anti-cancer effect of novel PAK1 inhibitor via induction of PUMA-mediated cell death and p21-mediated cell cycle arrest.

Hyper-activation of PAK1 (p21-activated kinase 1) is frequently observed in human cancer and speculated as a target of novel anti-tumor drug. In previous, we also showed that PAK1 is highly activated in the Smad4-deficient condition and suppresses PUMA (p53 upregulated modulator of apoptosis) through direct binding and phosphorylation. On the basis of this result, we have tried to find novel PAK1-PUMA binding inhibitors.

Interruption of progerin-lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations.

Prevention effect of rare ginsenosides against stress-hormone induced MTOC amplification.

Stress has been suggested as one of important cause of human cancer without molecular biological evidence. Thus, we test the effect of stress-related hormones on cell viability and mitotic fidelity. Similarly to estrogen, stress hormone cortisol and its relative cortisone increase microtubule organizing center (MTOC) number through elevated expression of γ-tubulin and provide the Taxol resistance to human cancer cell lines.

Extracellular p53 fragment re-enters K-Ras mutated cells through the caveolin-1 dependent early endosomal system.

K-Ras mutation is detected in over 30% of human malignancies. In particular, 90% of human pancreatic cancers are initiated by K-Ras mutation. Thus, selective elimination of K-Ras mutated cells would be a plausible strategy to prevent or cure the malignancies.