Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/ß, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Cyclin-Dependent Kinase Inhibitor BMI-1026 Induces Apoptosis by Downregulating Mcl-1 (L) and c-FLIP (L) and Inactivating p-Akt in Human Renal Carcinoma Cells.

Previous studies have investigated the inhibitory effect of BMI-1026 on cyclin-dependent kinase 1 in vitro. However, the molecular mechanisms by which BMI-1026 treatment leads to cancer cell death remain unclear. This study was conducted to investigate the anticancer mechanisms of BMI-1026 on human renal carcinoma Caki cells. BMI-1026 induced apoptosis in association with the cleavage of poly(ADP-ribose) polymerase and pro-caspase-3 and the release of apoptosis-inducing factor and cytochrome c from mitochondria in Caki cells. BMI-1026-induced apoptosis was inhibited by the pan-caspase inhibitor z-VAD-fmk. Furthermore, BMI-1026 downregulated Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) at the transcriptional level and Mcl-1 (L) and cellular FADD-like IL-1ß-converting enzyme inhibitory protein (c-FLIP (L)) at the post-transcriptional level. Interestingly, Mcl-1 (L) and c-FLIP (L), but not Bcl-2 or XIAP, played important roles in BMI-1026-induced Caki cell apoptosis. Although the constitutively active form of Akt did not attenuate BMI-1026-induced apoptosis, blockade of the PI3K/Akt pathway using a subcytotoxic concentration of the PI3K/Akt inhibitor LY294002 enhanced Caki cell apoptosis induced by BMI-1026. Electrophysiological safety was confirmed by determining the cardiotoxicity of BMI-1026 via left ventricular pressure analysis. These results suggest that BMI-1026 is a potent multitarget anticancer agent with electrophysiological safety and should be further investigated.

KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins.

The anti-proliferative effects of a newly developed N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191, have been previously evaluated in various cancer cells. However, the detailed anti-cancer molecular mechanisms of KMU-191 remain unknown. In this study, we investigated anti-cancer mechanisms by which KMU-191 regulates apoptosis-related genes in human clear cell renal cell carcinoma Caki cells. KMU-191 induced poly ADP-ribose polymerase cleavage and caspase-dependent apoptosis. In addition, KMU-191 induced down-regulation of the long form of cellular FADD-like IL-1ß-converting enzyme inhibitory protein (c-FLIP (L)) at the transcriptional level as well as that of long form of myeloid cell leukemia (Mcl-1 (L)) and B-cell lymphoma-extra large at the post-transcriptional level. Furthermore, KMU-191-induced apoptosis was closely associated with the Mcl-1 (L) down-regulation, but also partially associated with c-FLIP (L) down-regulation. In contrast, KMU-191 up-regulated p53, which is closely related to KMU-191-induced apoptosis. Although KMU-191 showed cytotoxicity of normal cells, it unusually did not induce cardiotoxicity. Taken together, these results suggest that a multi-target small molecule, N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191 is a potential anti-cancer agent that does not induce cardiotoxicity.

Spark Plasma Sintering Behavior of Nb-Mo-Si Alloy Powders Fabricated by Hydrogenation-Dehydrogenation Method.

In this study, the sintering behaviors of Nb-6Mo-20Si-3Cr (at percentage) in situ composite powders were studied. The Nb alloy powder was fabricated by a hydrogenation-dehydrogenation method, and both the alloy ingot and powders consisted of two phases: An Nb metal phase and the α-Nb5Si3 phase. Consolidation of the alloy powders was performed at 1500, 1600, and 1700 °C using spark plasma sintering, and the microstructures and phases formed at various sintering temperatures were analyzed. Micropores were observed in the compact sintered at 1500 °C due to the lack of complete densification at that temperature. The densification was completed at 1600 °C and the microstructure was slightly coarsened at 1700 °C compared to the microstructure of the compact sintered at 1600 °C. The microstructures prepared by the powder metallurgy method were finer than the microstructure of the ingot prepared by the casting method. The phase formation behavior varied according to the sintering temperature. Specifically, the α-Nb5Si3 phase, which is a stable structure of the Nb5Si3 phase at a low temperature, was transformed to the ß-Nb5Si3 phase (which is stable at a high temperature) with an increasing sintering temperature.

Metabolome Profiling of Partial and Fully Reprogrammed Induced Pluripotent Stem Cells.

Acquisition of proper metabolomic fate is required to convert somatic cells toward fully reprogrammed pluripotent stem cells. The majority of induced pluripotent stem cells (iPSCs) are partially reprogrammed and have a transcriptome different from that of the pluripotent stem cells. The metabolomic profile and mitochondrial metabolic functions required to achieve full reprogramming of somatic cells to iPSC status have not yet been elucidated. Clarification of the metabolites underlying reprogramming mechanisms should enable further optimization to enhance the efficiency of obtaining fully reprogrammed iPSCs. In this study, we characterized the metabolites of human fully reprogrammed iPSCs, partially reprogrammed iPSCs, and embryonic stem cells (ESCs). Using capillary electrophoresis time-of-flight mass spectrometry-based metabolomics, we found that 89% of analyzed metabolites were similarly expressed in fully reprogrammed iPSCs and human ESCs (hESCs), whereas partially reprogrammed iPSCs shared only 74% similarly expressed metabolites with hESCs. Metabolomic profiling analysis suggested that converting mitochondrial respiration to glycolytic flux is critical for reprogramming of somatic cells into fully reprogrammed iPSCs. This characterization of metabolic reprogramming in iPSCs may enable the development of new reprogramming parameters for enhancing the generation of fully reprogrammed human iPSCs.

Mechanochemical Synthesis and Rapid Consolidation of Nanostructured CoTi-Al2O3 Composite by Pulsed Current Activated Sintering and Its Mechanical Properties.

Nano-powders of CoTi and Al2O3 were synthesized from CoTiO3 and 2Al powders by high energy ball milling. Nanocrystalline Al2O3 reinforced composite was consolidated by pulsed current activated sintering within one minute from mechanochemically synthesized powders of CoTi and Al2O3. The relative density of the composite was 97%. The average hardness and fracture toughness values obtained were 1180 kg/mm2 and 8.5 MPa · m1/2, respectively.

High Frequency Induction Heated Synthesis and Consolidation of Nanostructured TaSi2-WSi2 Composite.

A dense nanostructured TaSi2-WSi2 composite was simultaneously synthesized and sintered by the high frequency induction heating method within 2 minutes from mechanically activated powder of Ta, W and Si. A highly-dense TaSi2-WSi2 composite was produced under simultaneous application of a 80 MPa pressure and the induced current. The mechanical properties and microstructure were investigated.