天然蛋白質の機能化のための新規化学修飾法の開発

京都大学0048新制・課程博士博士(工学)甲第15759号工博第3348号新制||工||1506(附属図書館)28320京都大学大学院工学研究科合成・生物化学専攻(主査)教授 濵地 格, 教授 森 泰生, 教授 白川 昌宏学位規則第4条第1項該当Doctor of Philosophy (Engineering)Kyoto UniversityDA

Effects of ultrasound-guided erector spinae plane block with dexmedetomidine combined with ropivacaine of the same dose and different concentrations on analgesic effect and rehabilitation quality of patients undergoing thoracoscopic wedge resection of the lung: a prospective, randomized, controlled trial

Abstract Objective To investigate the analgesic effect and rehabilitation quality of patients undergoing thoracoscopic wedge resection of the lung under erector spinae plane (ESP) block with dexmedetomidine combined with the same dose and different concentrations of ropivacaine. Methods Seventy patients undergoing thoracoscopic wedge resection were randomly divided into groups A (n = 35) and B (n = 35). To perform ESP block, the groups were administered dexmedetomidine (0.5 μg/kg) combined with 30 mL of 0.33% ropivacaine or 20 mL of 0.5% ropivacaine, respectively, half an hour before general anesthesia induction. We compared the onset time of anesthesia, the block level, and the duration of the block between the two groups. The number of compressions of the analgesic pump within 24 h and 48 h postoperatively and the time of the first compression were noted. The visual analog scale (VAS) scores of static and cough at 0.5 h, 6 h, 12 h, 24 h, and 48 h postoperatively were noted. Furthermore, the 40-item quality of recovery questionnaire (QoR-40) score was recorded at 24 h postoperatively. In addition, we noted the time taken to get out of the bed for the first time, the length of hospital stay, analgesia satisfaction, and the occurrence of related adverse reactions and complications within 48 h postoperatively. Results The range of ESP block was wider in Group A than in Group B (P < 0.05). Group B had a significantly shorter onset time (P < 0.05) and lower static and cough VAS scores at 6 h and 12 h postoperatively (P < 0.05); this was associated with significantly fewer compressions of the analgesic pump within 24 h and 48 h postoperatively and significantly more time until the first compression of the analgesic pump was required (P < 0.05). Group B was associated with significantly superior QoR-40 scores 24 h postoperatively and significantly shorter time to get out of the bed for the first time than Group A (P < 0.05). Conclusion Dexmedetomidine combined with 0.5% ropivacaine for ESP block is better than 0.33% ropivacaine for overall analgesia and postoperative rehabilitation of patients undergoing thoracoscopic wedge resection. Trial registration ChiCTR2200058114 , Date of registration: 30/03/2022

Oral liposomal delivery of an activatable budesonide prodrug reduces colitis in experimental mice

AbstractInflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic

Ultrasmall organosilica nanoparticles with strong solid-state fluorescence for multifunctional applications

Introduction: Organosilica nanoparticles (ONs), which are a new type of photoluminescent nanomaterial (PM) with excellent biocompatibility, have caught more attention in recent years. However, their applications are significantly impeded by the complicated preparation process, poor photostability, and especially aggregation-induced quenching. Objectives: The present study was aimed to design and prepare solid-state fluorescent ONs to avoid aggregation-induced quenching effect. In addition, the uses of ONs for fingerprint detection, white light-emitting diodes (WLEDs) and lysosome-targetable cellular imaging were demonstrated. Methods: Here, for the first time, we designed and prepared novel solid-state fluorescent ultrasmall ONs with orange-emitting photoluminescence via a one-step hydrothermal method. Results: The prepared solid-state fluorescent ONs could be successfully employed in fingerprint detection, WLEDs fabrication and cellular imaging. Intriguingly, the ultrasmall ONs specifically localized to lysosomes rather than other subcellular organelles across distinct cell lines, including cancer cells and noncancerous cells. Conclusion: Collectively, these data showed that the new ONs presented in this study could be ideal candidates for PMs in biological and photoelectric applications

<i>N</i>‑Heterocyclic Carbene-Stabilized Palladium Complexes as Organometallic Catalysts for Bioorthogonal Cross-Coupling Reactions

A small library of water-soluble <i>N</i>-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd–NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki–Miyaura coupling of various unnatural amino acids and proteins bearing <i>p</i>-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC-stabilized metal complexes have potential utility in cellular systems

Renal clearable polyfluorophore nanosensors for early diagnosis of cancer and allograft rejection

Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.Ministry of Education (MOE)K.P. thanks the Ministry of Education Singapore, Academic Research Fund Tier 1 (2019-T1-002-045 RG125/19 and RT05/20) and Academic Research Fund Tier 2 (MOE2018-T2-2-042 and MOE-T2EP30220-0010) for financial support. H.W. thanks the Zhejiang Provincial Natural Science Foundation of China (LR19H160002) and the National Natural Science Foundation of China (82073296 and 81773193) for financial support

A renally clearable activatable polymeric nanoprobe for early detection of hepatic ischemia-reperfusion injury

Although hepatic ischemia-reperfusion injury (IRI) represents a major complication in many clinical settings, it remains a diagnostic dilemma due to its reliance on insensitive assays or invasive biopsy. The development of an activatable polymeric nanoprobe (APNSO ) for real-time in vivo near-infrared fluorescence (NIRF) imaging and urinalysis of hepatic IRI is reported here. APNSO has a backbone comprising renally clearable fluorophore fragments and self-immolative structural units. In the presence of an oxidative stress biomarker (superoxide anion, O2 •- ) during hepatic IRI, APNSO can be fluorescently activated for in vivo NIRF imaging and depolymerized to release renally clearable fluorophores for urinalysis. By virtue of its high hepatic accumulation, sensitive response toward O2 •- , and effective release of renally clearable fluorophores, APNSO -based imaging and urinalysis detect hepatic IRI at least 7 h earlier than typical clinical assays in a mouse model. This study not only provides new opportunities for noninvasive diagnosis of hepatic IRI, but also reveals guidelines for the development of optical nanosensors for early urinalysis.Ministry of Education (MOE)K.P. thanks Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19), Academic Research Fund Tier 2 (MOE2018-T2-2-042 and MOE-T2EP30220-0010) for the financial support. J.H. acknowledges the support from the start-up funding of Sun Yat-Sen University. H.W. thanks Zhejiang Provincial Natural Science Foundation of China (LR19H160002), National Natural Science Foundation of China (82073296 and 81773193), Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022010B) for the financial support

Rhodium-Catalyzed Transannulation of <i>N</i>‑Sulfonyl-1,2,3-triazoles and Epoxides: Regioselective Synthesis of Substituted 3,4-Dihydro‑2<i>H</i>‑1,4-oxazines

Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2<i>H</i>-1,4-oxazines are obtained in moderate yields probably involving generation of α-imino rhodium­(II) carbene species