Dystrophin 71 deficiency causes impaired aquaporin-4 polarization contributing to glymphatic dysfunction and brain edema in cerebral ischemia.

OBJECTIVE: The glymphatic system serves as a perivascular pathway that aids in clearing liquid and solute waste from the brain, thereby enhancing neurological function. Disorders in glymphatic drainage contribute to the development of vasogenic edema following cerebral ischemia, although the molecular mechanisms involved remain poorly understood. This study aims to determine whether a deficiency in dystrophin 71 (DP71) leads to aquaporin-4 (AQP4) depolarization, contributing to glymphatic dysfunction in cerebral ischemia and resulting in brain edema. METHODS: A mice model of middle cerebral artery occlusion and reperfusion was used. A fluorescence tracer was injected into the cortex and evaluated glymphatic clearance. To investigate the role of DP71 in maintaining AQP4 polarization, an adeno-associated virus with the astrocyte promoter was used to overexpress Dp71. The expression and distribution of DP71 and AQP4 were analyzed using immunoblotting, immunofluorescence, and co-immunoprecipitation techniques. The behavior ability of mice was evaluated by open field test. Open-access transcriptome sequencing data were used to analyze the functional changes of astrocytes after cerebral ischemia. MG132 was used to inhibit the ubiquitin-proteasome system. The ubiquitination of DP71 was detected by immunoblotting and co-immunoprecipitation. RESULTS: During the vasogenic edema stage following cerebral ischemia, a decline in the efflux of interstitial fluid tracer was observed. DP71 and AQP4 were co-localized and interacted with each other in the perivascular astrocyte endfeet. After cerebral ischemia, there was a notable reduction in DP71 protein expression, accompanied by AQP4 depolarization and proliferation of reactive astrocytes. Increased DP71 expression restored glymphatic drainage and reduced brain edema. AQP4 depolarization, reactive astrocyte proliferation, and the behavior of mice were improved. After cerebral ischemia, DP71 was degraded by ubiquitination, and MG132 inhibited the decrease of DP71 protein level. CONCLUSION: AQP4 depolarization after cerebral ischemia leads to glymphatic clearance disorder and aggravates cerebral edema. DP71 plays a pivotal role in regulating AQP4 polarization and consequently influences glymphatic function. Changes in DP71 expression are associated with the ubiquitin-proteasome system. This study offers a novel perspective on the pathogenesis of brain edema following cerebral ischemia.

Azulene-Containing Bis(squaraine) Dyes: Design, Synthesis and Aggregation Behaviors.

The relationship among chemical structure, physicochemical property and aggregation behavior of organic functional material is an important research topic. Here, we designed and synthesized three bis(squaraine) dyes BSQ1, BSQ2 and BSQ3 through the combination of two kinds of unsymmetrical azulenyl squaraine monomers. Their physicochemical properties were investigated in both molecular and aggregate states. Generally, BSQ1 displayed different assembly behaviors from BSQ2 and BSQ3. Upon fabrication into nanoparticles, BSQ1 tend to form J-aggregates while BSQ2 and BSQ3 tend to form H-aggregates in aqueous medium. When in the form of thin films, three bis(squaraine) dyes all adopted J-aggregation packing modes while only BSQ1 presented the most significant rearrangement of aggregate structures as well as the improvement in the carrier mobilities upon thermal annealing. Our research highlights the discrepancy of aggregation behaviors originating from the molecular structure and surrounding circumstances, providing guidance for the molecular design and functional applications of squaraines.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Dysregulation of LINC00324 promotes poor prognosis in patients with glioma.

BACKGROUND: LINC00324 is a long-stranded non-coding RNA, which is aberrantly expressed in various cancers and is associated with poor prognosis and clinical features. It involves multiple oncogenic molecular pathways affecting cell proliferation, migration, invasion, and apoptosis. However, the expression, function, and mechanism of LINC00324 in glioma have not been reported. MATERIAL AND METHODS: We assessed the expression of LINC00324 of LINC00324 in glioma patients based on data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to identify pathways involved in LINC00324-related glioma pathogenesis. RESULTS: Based on our findings, we observed differential expression of LINC00324 between tumor and normal tissues in glioma patients. Our analysis of overall survival (OS) and disease-specific survival (DSS) indicated that glioma patients with high LINC00324 expression had a poorer prognosis compared to those with low LINC00324 expression. By integrating clinical data and genetic signatures from TCGA patients, we developed a nomogram to predict OS and DSS in glioma patients. Gene set enrichment analysis (GSEA) revealed that several pathways, including JAK/STAT3 signaling, epithelial-mesenchymal transition, STAT5 signaling, NF-κB activation, and apoptosis, were differentially enriched in glioma samples with high LINC00324 expression. Furthermore, we observed significant correlations between LINC00324 expression, immune infiltration levels, and expression of immune checkpoint-related genes (HAVCR2: r = 0.627, P = 1.54e-77; CD40: r = 0.604, P = 1.36e-70; ITGB2: r = 0.612, P = 6.33e-7; CX3CL1: r = -0.307, P = 9.24e-17). These findings highlight the potential significance of LINC00324 in glioma progression and suggest avenues for further research and potential therapeutic targets. CONCLUSION: Indeed, our results confirm that the LINC00324 signature holds promise as a prognostic predictor in glioma patients. This finding opens up new possibilities for understanding the disease and may offer valuable insights for the development of targeted therapies.

Spent Mushroom Substrate and Electric Arc Furnace Dust Recycling by Carbothermic Reduction Method.

With recent increases in environmental awareness, the circular economy concept, which involves turning waste into usable products, has gradually become widely accepted. Spent mushroom substrate (SMS) is an agricultural waste that lacks recycling channels in Taiwan. This study explored the feasibility of simultaneously recycling two completely different types of waste: spent mushroom substrate (SMS), an agricultural waste, and electric-arc furnace dust (EAFD), an industrial waste. Specifically, SMS was used to replace metallurgical coke as a reducing agent for EAFD, which underwent carbothermic reduction to recycle valuable metallic Zn. The results showed that if SMS and EAFD were mixed at a C/O ratio of 0.8, the degree of Zn removal achieved 95% at 1100 °C, which is 150 °C lower than the reduction temperature of the EAFD-coke mixture (due to volatile matter (VM) in SMS). For the reduction of ZnO in EAFD, with the assistance of VM in SMS, the C/O ratio can be decreased from 0.8 to 0.16 at 1300 °C, achieving a high degree of Zn removal over 95%. In addition, the torrefaction of SMS increased the fixed carbon content and improved the Zn productivity at the same C/O ratio, reaching almost the same productivity as the coke sample (SMS torrefaction = 500 °C, C/O = 0.8, reduction = 1200 °C, Zn removal~99%). Finally, CO2 emission reductions from the use of SMS were also estimated.

Theoretical study for evaluating and discovering organic hydride compounds as novel trifluoromethylation reagents.

Trifluoromethylation reaction is one of the significant and practical organic chemical reactions, and the design and discovery of novel trifluoromethylation reagents have been attracting more and more attention. Trifluoromethyl-substituted organic hydride compounds (XH) have the potential to be novel trifluoromethylation reagents in organic synthesis due to the favorable tendency of XH˙+ releasing ˙CF3 to form stable aromatic structures in terms of thermodynamics. The key elementary step of the trifluoromethylation is the radical cation (XH˙+) generation by catalysis or single-electron activation releasing ˙CF3 to form a stable aromatic structure, which also provides the thermodynamic driving force of the chemical process. In this work, 47 new trifluoromethylation reagent candidates of XHs were designed and calculated for the Gibbs free energy and activation free energy [ΔG‡RD(XH˙+)] of XH˙+ releasing ˙CF3 using the density functional theory (DFT) method, in order to quantitatively measure the reactivity of XHs as trifluoromethylation reagents, and to establish the molecular library as well as reactivity database of novel trifluoromethylation reagents for synthetic chemists. According to the and ΔG‡RD(XH˙+) values, all the XHs can be reasonably divided into 3 classes, including class 1 (excellent trifluoromethylation reagents), class 2 (potential trifluoromethylation reagents) and class 3 (not trifluoromethylation reagents). To our delight, 15 XHs with a 1,4-dihydropyridine structure and 3 XHs with a 3,4-dihydropyrimidin-2-one structure are identified to be novel excellent and potential trifluoromethylation reagents, respectively, according to their reactivity data. The relationship between the structural features, including methylation, heteroatom, substituents, conjugated structure and so on, and the reactivity of XHs as trifluoromethylation reagents are also discussed in this work. The computation results indicate that trifluoromethyl-substituted 1,4-dihydropyridine compounds and 3,4-dihydropyrimidin-2-one analogues could be possible trifluoromethylation reagents in organic synthesis. This work may provide the theoretical basis and references for discovering organic hydride compounds as novel reagents for trifluoromethylation or other alkylation reactions.

Theoretical investigation on the nature of 4-substituted Hantzsch esters as alkylation agents.

Recently, a variety of 4-substituted Hantzsch esters (XRH) with different structures have been widely researched as alkylation reagents in chemical reactions, and the key step of the chemical process is the elementary step of XRH˙+ releasing R˙. The purpose of this work is to investigate the essential factors which determine whether or not an XRH is a great alkylation reagent using density functional theory (DFT). This study shows that the ability of an XRH acting as an alkylation reagent can be reasonably estimated by its ΔG ≠ RD(XRH˙+) value, which can be conveniently obtained through DFT computations. Moreover, the data also show that ΔG ≠ RD(XRH˙+) has no simple correlation with the structural features of XRH, including the electronegativity of the R substituent group and the magnitude of steric resistance; therefore, it is difficult to judge whether an XRH can provide R˙ solely by experience. Thus, these results are helpful for chemists to design 4-substituted Hantzsch esters (XRH) with novel structures and to guide the application of XRH as a free radical precursor in organic synthesis.