Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury

Ischemic strokes (IS) and spinal cord injuries (SCI) are major causes of disability. RhoA is a small GTPase protein that activates a downstream effector, ROCK. The up-regulation of the RhoA/ROCK pathway contributes to neuronal apoptosis, neuroinflammation, blood-brain barrier dysfunction, astrogliosis, and axon growth inhibition in IS and SCI. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), were previously considered to be non-functional. However, they have attracted much attention because they play an essential role in regulating gene expression in physiological and pathological conditions. There is growing evidence that ROCK inhibitors, such as fasudil and VX-210, can reduce injury in IS and SCI in animal models and clinical trials. Recently, it has been reported that miRNAs are decreased in IS and SCI, while lncRNAs are increased. Inhibiting the Rho/ROCK pathway with miRNAs alleviates apoptosis, neuroinflammation, oxidative stress, and axon growth inhibition in IS and SCI. Further studies are required to explore the significance of ncRNAs in IS and SCI and to establish new strategies for preventing and treating these devastating diseases.     

Carbon Nitride Loaded with an Ultrafine,Monodisperse, Metallic Platinum-Cluster Cocatalyst for the Photocatalytic Hydrogen-Evolution Reaction

For the realization of a next-generation energy society, further improvement in the activity of water-splitting photocatalysts is essential. Platinum (Pt) is predicted to be the most effective cocatalyst for hydrogen evolution from water. However, when the number of active sites is increased by decreasing the particle size, the Pt cocatalyst is easily oxidized and thereby loses its activity. In this study, a method to load ultrafine, monodisperse, metallic Pt nanoclusters (NCs) on graphitic carbon nitride is developed, which is a promising visible-light-driven photocatalyst. In this photocatalyst, a part of the surface of the Pt NCs is protected by sulfur atoms, preventing oxidation. Consequently, the hydrogen-evolution activity per loading weight of Pt cocatalyst is significantly improved, 53 times, compared with that of a Pt-cocatalyst loaded photocatalyst by the conventional method. The developed method is also effective to enhance the overall water-splitting activity of other advanced photocatalysts such as SrTiO₃ and BaLa₄Ti₄O₁₅.     

Platinum on Carbon‐Catalyzed Precise Reduction Control of Trichloromethyl to Geminal‐Dichloromethyl Groups

Geminal‐dichloromethyl derivatives could be efficiently synthesized by the highly chemoselective platinum on carbon‐catalyzed mono‐dechlorination of trichloromethyl substrates in dimethylacetamide (DMA) as a specific solvent at 25 °C under a hydrogen atmosphere.     

Functional Graphene for Peritumoral Brain Microenvironment Modulation Therapy in Glioblastoma

Peritumoral brain invasion is the main target to cure glioblastoma. Chemoradiotherapy and targeted therapies fail to combat peritumoral relapse. Brain inaccessibility and tumor heterogeneity explain this failure, combined with overlooking the peritumor microenvironment. Reduce graphene oxide (rGO) provides a unique opportunity to modulate the local brain microenvironment. Multimodal graphene impacts are reported on glioblastoma cells in vitro but fail when translated in vivo because of low diffusion. This issue is solved by developing a new rGO formulation involving ultramixing during the functionalization with polyethyleneimine (PEI) leading to the formation of highly water-stable rGO-PEI. Wide mice brain diffusion and biocompatibility are demonstrated. Using an invasive GL261 model, an anti-invasive effect is observed. A major unexpected modification of the peritumoral area is also observed with the neutralization of gliosis. In vitro, mechanistic investigations are performed using primary astrocytes and cytokine array. The result suggests that direct contact of rGO-PEI_UT neutralizes astrogliosis, decreasing several proinflammatory cytokines that would explain a bystander tumor anti-invasive effect. rGO also significantly downregulates several proinvasive/protumoral cytokines at the tumor cell level. The results open the way to a new microenvironment anti-invasive nanotherapy using a new graphene nanomaterial that is optimized for in vivo brain delivery.     

Toward Engineered Biosynthesis of Drugs in Human Cells

Biosynthetic genes are not only responsible for the formation of bioactive substances but also suited for other applications including gene therapy. To test the feasibility of human cells producing antibiotics in situ when provided with a heterologous biosynthetic gene, we focused on cytochrome P450, the class of enzymes important in conferring bioactivity to natural product precursors. We selected Fma-P450 that plays a central role in the fumagillin antimicrobial biosynthesis in Aspergillus fumigatus to examine fungal metabolite production by HeLa cells that express fma-P450 heterologously. Here we show that HeLa cells harboring fma-P450 can biosynthesize 5-hydroxyl-β-trans-bergamoten and cytotoxic 5-epi-demethoxyfumagillol when supplemented with the nontoxic precursor β-trans-bergamotene. While the production level was insufficient to effect cell death, we demonstrate that programming human cells to autogenerate antibiotics by introducing a heterologous biosynthetic gene is feasible.     

Near-Infrared-Triggered On-Demand Controlled Release of Adeno-Associated Virus from Alginate Hydrogel Microbeads with Heat Transducer for Gene Therapy

Gene therapy using adeno-associated virus (AAV) has potential as a radical treatment modality for genetic diseases such as sensorineural deafness. To establish clinical applications, it is necessary to avoid immune response to AAV by controlled release system of AAV. Here, a near-infrared (NIR)-triggered on-demand AAV release system using alginate hydrogel microbeads with a heat transducer is proposed. By using a centrifuge-based microdroplet shooting device, the microbeads encapsulating AAV with Fe₃O₄ microparticles (Fe₃O₄-MPs) as a heat transducer are fabricated. Fe₃O₄-MPs generated heat by NIR enhanced the diffusion speed of the AAV, resulting in the AAV being released from the microbeads. By irradiating the microbeads encapsulating fluorescent polystyrene nanoparticles (FP-NPs) (viral model) with NIR, the fluorescence intensity decreased only for FP-NPs with a diameter of 20 nm and not for 100 or 200 nm, confirming that this system can release virus with a diameter of several tens of nanometers. By irradiating NIR to the AAV-encapsulating microbeads with Fe₃O₄-MPs, the AAV is released on demand, and gene transfection to cells by AAV is confirmed without loss of viral activity. The NIR-triggered AAV release system proposed in this study increases the number of alternatives for the method of drug release in gene therapy.     

Formation of Al2O3–GdAlO3 eutectic ceramics with a fine anisotropic structure in a flash event

An Al₂O₃–GdAlO₃ (GAP) composite with a fine eutectic microstructure was obtained through local melting and rapid solidification during a flash event. An AC field of 1 kV/cm at a frequency of 1 kHz was applied to a calcined Al₂O₃–GAP body at a furnace temperature of 1400°C to induce the flash event. The Al₂O₃–GAP body exhibited local melting through the current path. Solidification proceeded with the maximum cooling rate of about 140°C/s just after the power supply was turned off. Using this flash treatment, a refined eutectic structure with rodlike GAP phases in the Al₂O₃ matrix was obtained within 1 min. The interphase spacing of the obtained structure was approximately 170 nm, comparable with the finest Al₂O₃–GAP eutectic material obtained in previous studies. A flash event and subsequent rapid cooling can contribute to forming fine eutectic ceramics with a relatively low furnace temperature and short processing time.     

Challenges Based on Antiplasmodial and Antiviral Activities of 7-Chloro-4-aminoquinoline Derivatives

We report the structural functionalization of the terminal amino group of N¹-(7-chloroquinolin-4-yl) butane-1,4-diamine, leading to a series of 7-chloro-4-aminoquinoline derivatives, and their evaluation as potent anti-malarial and anti-viral agents. Some compounds exhibited promising anti-malarial effects against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains. In addition, these compounds were assayed in vitro against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compound 5 h , bearing an N-mesityl thiourea group, displayed pronounced anti-infectious effects against malaria, IAV, and SARS-CoV-2. These results provide new insights into drug discovery for the prevention or treatment of malaria and virus co-infection.