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Da-Sol Kim,1,2,* Nam-Gyu Jo,3,* Dong-Won Lee,4,5 Myoung-Hwan Ko,1,2 Jeong-Hwan Seo,1,2 Gi-Wook Kim1,2,4 1Department of Physical Medicine & Rehabilitation, Jeonbuk National University Medical School, Jeonju, Republic of Korea; 2Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea; 3Department of Physical Medicine and Rehabilitation, Hansol Convalescence Rehabilitation Hospital, Jeonju, Republic of Korea; 4Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju, Republic of Korea; 5Department of Polymer Nano Science and Technology, Jeonbuk National University, Jeonju, Republic of Korea*These authors contributed equally to this workCorrespondence: Gi-Wook Kim, Department of Physical Medicine & Rehabilitation, Jeonbuk National University Medical School, Geonjiro 20, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea, Tel +82-63-259-3144, Fax +82-10-254-4145, Email k26@jbnu.ac.krPurpose: Peripheral nerve damage lacks an appropriate diagnosis consistent with the patient’s symptoms, despite expensive magnetic resonance imaging or electrodiagnostic assessments, which cause discomfort. Ultrasonography is valuable for diagnosing and treating nerve lesions; however, it is unsuitable for detecting small lesions. Poly(vanillin-oxalate) (PVO) nanoparticles are prepared from vanillin, a phytochemical with antioxidant and anti-inflammatory properties. Previously, PVO nanoparticles were cleaved by H2O2 to release vanillin, exert therapeutic efficacy, and generate CO2 to increase ultrasound contrast. However, the role of PVO nanoparticles in peripheral nerve lesion models is still unknown. Herein, we aimed to determine whether PVO nanoparticles can function as contrast and therapeutic agents for nerve lesions.Methods: To induce sciatic neuritis, rats were administered a perineural injection of carrageenan using a nerve stimulator under ultrasonographic guidance, and PVO nanoparticles were injected perineurally to evaluate ultrasonographic contrast and therapeutic effects. Reverse transcription-quantitative PCR was performed to detect mRNA levels of pro-inflammatory cytokines, ie, tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2.Results: In the rat model of sciatic neuritis, PVO nanoparticles generated CO2 bubbles to increase ultrasonographic contrast, and a single perineural injection of PVO nanoparticles suppressed the expression of tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2, reduced the expression of F4/80, and increased the expression of GAP43.Conclusion: The results of the current study suggest that PVO nanoparticles could be developed as ultrasonographic contrast agents and therapeutic agents for nerve lesions.Keywords: neuroinflammation, ultrasonography, contrast media, polymer nanoparticles, hydrogen peroxide

Jun Soo Park,1 Min Seop Kim,1 Min Yeong Joung,1 Hyun Jin Park,1 Myoung-Jin Ho,1 Jun Hyuk Choi,1 Jae Hee Seo,1 Woo Heon Song,1 Young Wook Choi,2 Sangkil Lee,3 Yong Seok Choi,1 Myung Joo Kang1 1College of Pharmacy, Dankook University, Cheonan, Republic of Korea; 2College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 3College of Pharmacy, Keimyung University, Daegu, Republic of KoreaCorrespondence: Myung Joo Kang, College of Pharmacy, Dankook University, Dongnam-gu, Cheonan, 31116, Republic of Korea, Tel +82 41 550 1446, Fax +82 41 550 7899, Email kangmj@dankook.ac.krBackground: Montelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer’s disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency.Purpose: This study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration.Methods: To decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats.Results: Microscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 μm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 μm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks.Conclusion: The MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer’s disease with extended dose intervals.Graphical Abstract: Keywords: montelukast, parenteral prolonged release delivery, crystallinity, nanocrystalline suspension, bead-milling, pharmacokinetics, local tolerability

Eun A Kim, Jun Soo Park, Min Seop Kim, Min Young Jeong, Hyun Jin Park, Jun Hyuk Choi, Jae Hee Seo, Yong Seok Choi, Myung Joo Kang College of Pharmacy, Dankook University, Cheonan, Chungnam, 330-714, KoreaCorrespondence: Myung Joo KangCollege of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan, 330-714, KoreaTel +82 41 550 1446Fax +82 41 550 7899. Email kangmj@dankook.ac.krBackground: The titrated extract of Centella asiatica (CA) has received much attention as a cosmeceutical ingredient owing to its anti-wrinkle effect. However, due to the low solubility and high molecular weight of pharmacologically active constituents, including asiatic acid (AA), madecassic acid (MA), and asiaticoside (AS), it is challenging to fabricate high-payload topical preparations of CA with satisfactory skin absorption profiles.Purpose: This study aimed to design a high-payload topical preparation of CA using nanocrystallization technique and to evaluate its skin absorption profile and local tolerability.Methods: High-payload nanocrystal suspensions (NSs) were prepared using lab-scale bead-milling technology, by adjusting the type and amount of suspending agent, CA content, type of vehicle, and milling speed. CA-loaded NSs were characterized in terms of morphology, particle size, crystallinity, and in vitro dissolution pattern. Skin absorption of CA nanocrystals was evaluated using a vertical Franz diffusion cell mounted with porcine skin. In vivo skin irritation following topical application of high-payload NS was assessed in normal rats.Results: The optimized NS system, composed of 10% (w/v) CA, 0.5% polyvinylpyrrolidone (PVP) K30 as steric stabilizer, and 89.5% of distilled water, was characterized as follows: spherical or elliptical in shape, 200 nm in size, with low crystallinity. The in vitro dissolution of AA or MA from NSs was markedly faster compared to raw material, under sink condition. Penetration of AA, MA, and AS in the porcine skin was markedly elevated using the high-payload NS formula, providing 5-, 4-, and 4.5-fold higher accumulation in skin layer, compared to that of the marketed cream formula (CA 1%, Madeca cream). Moreover, topical application of high-payload NS was tolerable, showing neither erythema nor oedema in normal rats.Conclusion: The novel NS system is expected to be a virtuous approach for offering a better skin absorption of CA, without using an excess quantity of solubilizers.Keywords: Centella asiatica, asiatic acid, madecassic acid, asiaticoside, nanocrystal suspension, bead-milling, dissolution, skin absorption, skin irritation

Dong-Kyo Seo,1 Ho-Seong Lee,2 Joon Pio Hong,3 Jeong-Ho Seo,4 Jin Woo Shin5 1Department of Orthopedic Surgery, GangNeung Asan Hospital, College of Medicine, University of Ulsan, GangNeung-si, South Korea; 2Department of Orthopedic Surgery, 3Department of Plastic Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea; 4Department of Orthopedic Surgery, Cheil Orthopedic Hospital, Gangnam-gu, Seoul, South Korea; 5Department of Anesthesia, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea Abstract: Complex regional pain syndrome is a chronic progressive illness with sensory, autonomic, trophic, and motor abnormalities. Treatment is difficult and controversial. We report the results of free-flap and vein wrapping of the superficial peroneal nerve surgery to treat complex regional pain syndrome. Keywords: foot, ankle, superficial peroneal nerve, vein wrapping

Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs) is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol, desipramine, imipramine, dextromethorphan, and tolterodine following single and multiple sarpogrelate hydrochloride oral doses were within the range of ≥1.25, but

Keun Sang Oh,1,* Kyungim Kim,1,* Byeong Deok Yoon,1 Hye Jin Lee,1 Dal Yong Park,1 Eun-yeong Kim,1 Kiho Lee,1 Jae Hong Seo,2 Soon Hong Yuk1,2 1College of Pharmacy, Korea University, Sejong, 2Biomedical Research Center, Korea University Guro Hospital, Guro-gu, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: A mixture of docetaxel (DTX) and Solutol® HS 15 (Solutol) transiently formed nanodroplets when it was suspended in an aqueous medium. However, nanodroplets that comprised DTX and Solutol showed a rapid precipitation of DTX because of their unstable characteristics in the aqueous medium. The incorporation of nanodroplets that comprised DTX and Solutol through vesicle fusion and subsequent stabilization was designed to prepare multilayer nanoparticles (NPs) with a DTX-loaded Solutol nanodroplet (as template NPs) core for an efficient delivery of DTX as a chemotherapeutic drug. As a result, the DTX-loaded Solutol nanodroplets (~11.7 nm) were observed to have an increased average diameter (from 11.7 nm to 156.1 nm) and a good stability of the hydrated NPs without precipitation of DTX by vesicle fusion and multilayered structure, respectively. Also, a long circulation of the multilayer NPs was observed, and this was due to the presence of Pluronic F-68 on the surface of the multilayer NPs. This led to an improved antitumor efficacy based on the enhanced permeation and retention effect. Therefore, this study indicated that the multilayer NPs have a considerable potential as a drug delivery system with an enhanced therapeutic efficacy by blood circulation and with low side effects. Keywords: multilayer nanoparticles, Solutol, Pluronic F-68, docetaxel, cancer therapy

Jae Hong Seo, Jung Bae Park, Woong-Kee Choi, Sunhwa Park, Yun Jin Sung, Euichaul Oh, Soo Kyung Bae College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea Objective: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.Methods: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.Results: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2–6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in Cmax and AUCt of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.Conclusion: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet. Keywords: BCS class II, cilostazol, besylate, mesylate, acid addition reaction, dissolution

Keun Sang Oh,1 Ji Young Yhee,2 Dong-Eun Lee,3 Kwangmeyung Kim,2 Ick Chan Kwon,2 Jae Hong Seo,4 Sang Yoon Kim,5 Soon Hong Yuk1,4 1College of Pharmacy, Korea University, Sejong, 2Biomedical Research Center, Korea Institute of Science and Technology, Seoul, 3Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeonbuk, 4Biomedical Research Center, Korea University Guro Hospital, Seoul, 5Department of Otolaryngology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea Abstract: Primary tumor and tumor-associated metastatic lymphatics have emerged as new targets for anticancer therapy, given that these are difficult to treat using traditional chemotherapy. In this study, docetaxel-loaded Pluronic nanoparticles with Flamma™ (FPR-675, fluorescence molecular imaging dye; DTX/FPR-675 Pluronic NPs) were prepared using a temperature-induced phase transition for accurate detection of metastatic lymphatics. Significant accumulation was seen at the primary tumor and in metastatic lymph nodes within a short time. Particle size, maximum drug loading capacity, and drug encapsulation efficiency of the docetaxel-loaded Pluronic NPs were approximately 10.34±4.28 nm, 3.84 wt%, and 94±2.67 wt%, respectively. Lymphatic tracking after local and systemic delivery showed that DTX/FPR-675 Pluronic NPs were more potent in tumor-bearing mice than in normal mice, and excised mouse lymphatics showed stronger near-infrared fluorescence intensity on the tumor-bearing side than on the non-tumor-bearing side at 60 minutes post-injection. In vivo cytotoxicity and efficacy data for the NPs demonstrated that the systemically administered NPs caused little tissue damage and had minimal side effects in terms of slow renal excretion and prolonged circulation in tumor-bearing mice, and rapid renal excretion in non-tumor-bearing mice using an in vivo real-time near-infrared fluorescence imaging system. These results clearly indicate that docetaxel-loaded Pluronic NPs could provide a strategy to achieve effective cancer therapy by simultaneous delivery to primary tumors, tumor lymphatics, and tumor-associated metastatic lymphatics. Keywords: metastatic lymphatics, primary tumor targeting, lymphatic tracking, temperature-induced phase transition, Pluronic nanoparticles

Jae-Yoon Shin,1,* Yoosoo Yang,1,* Paul Heo,1 Ji-Chun Lee,1 ByoungJae Kong,1 Jae Youl Cho,1 Keejung Yoon,1 Cheol-Su Shin,2 Jin-Ho Seo,3 Sung-Gun Kim,4 Dae-Hyuk Kweon11Department of Genetic Engineering, College of Biotechnology and Bioengineering, and Center for Human Interface Nano Technology, Sungkyunkwan University, 2APTech Research Center, Suwon, 3Department of Agricultural Biotechnology, Seoul National University, Seoul, 4Department of Biomedical Science, Youngdong University, Chungbuk, South Korea*These authors contributed equally to this workBackground: Nanoparticles undergoing physicochemical changes to release enclosed drugs at acidic pH conditions are promising vehicles for antitumor drug delivery. Among the various drug carriers, high-density lipoprotein (HDL)-like nanoparticles have been shown to be beneficial for cancer chemotherapy, but have not yet been designed to be pH-responsive.Methods and results: In this study, we developed a pH-responsive HDL-like nanoparticle that selectively releases paclitaxel, a model antitumor drug, at acidic pH. While the well known HDL-like nanoparticle containing phospholipids, phosphatidylcholine, and apolipoprotein A-I, as well as paclitaxel (PTX-PL-NP) was structurally robust at a wide range of pH values (3.8–10.0), the paclitaxel nanoparticle that only contained paclitaxel and apoA-I selectively released paclitaxel into the medium at low pH. The paclitaxel nanoparticle was stable at physiological and basic pH values, and over a wide range of temperatures, which is a required feature for efficient cancer chemotherapy. The homogeneous assembly enabled high paclitaxel loading per nanoparticle, which was 62.2% (w/w). The molar ratio of apolipoprotein A-I and paclitaxel was 1:55, suggesting that a single nanoparticle contained approximately 110 paclitaxel particles in a spherical structure with a 9.2 nm diameter. Among the several reconstitution methods applied, simple dilution following sonication enhanced the reconstitution yield of soluble paclitaxel nanoparticles, which was 0.66. As a result of the pH responsiveness, the anticancer effect of paclitaxel nanoparticles was much more potent than free paclitaxel or PTX-PL-NP.Conclusion: The anticancer efficacy of both paclitaxel nanoparticles and PTX-PL-NP was dependent on the expression of scavenger receptor class B type I, while the killing efficacy of free paclitaxel was independent of this receptor. We speculate that the pH responsiveness of paclitaxel nanoparticles enabled efficient endosomal escape of paclitaxel before lysosomal break down. This is the first report on pH-responsive nanoparticles that do not contain any synthetic polymer.Keywords: pH responsiveness, nanoparticle, apolipoprotein A-I, paclitaxel

© The Korean Institute of Metals and Materials. Anode materials of the Na-Sn battery experience a series of phase transitions during charging and discharging. These phase transitions in many cases are accompanied by a large volume change in the electrode materials, which leads to pulverization, a major source of reducing the battery capacity. In contrast to the rich literature on the phase transition behaviors of the Li-Si battery, those of the Na-Sn battery are much less understood due to experimental difficulties in determining the chemical composition of the phases. In this study, we demonstrate a simple method of analyzing the composition of the reaction compounds of the Na-Sn battery electrodes using energy dispersive X-ray spectroscopy.

Background: Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A(225)) acetylates HIF-1alpha, triggering its degradation, and thus may play a role in decreased expression of VEGFA.Methods: We generated Apc(Min/+)/mARD1A(225) transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A(225) were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A(225) acetylation of Lys532 in HIF-1alpha, we injected B16F10-mARD1A(225) cell lines stably expressing mutant HIF-1alpha/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.Results: Apc(Min/+)/mARD1A(225) transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc(Min/+) mice (n = 21) (number of intestinal polyps per mouse: Apc(Min/+) mice vs Apc(Min/+)/mARD1A(225) transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A(225)-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A(225) decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and Apc(Min/+) intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1alpha in B16F10-mARD1A(225) cells prevented HIF-1alpha degradation and inhibited the antimetastatic effect of mARD1A(225) (P < .001).Conclusion: mARD1A(225) may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis. [ABSTRACT FROM AUTHOR]

Polyrotaxane (PR) is a mechanically interlocked polymer (MIP) utilized as an electrolyte because of its distinctive property of dynamic molecular mobility. While numerous studies have concentrated on modifying external properties to decrease high crystallinity, few have explored the control of intrinsic properties. This study examines the crystalline properties and molecular mobility of PR-based electrolytes, along with their effects on ionic conductivity, by manipulating intrinsic properties. By systematically varying the inclusion ratio, we demonstrate that lower inclusion ratios lead to reduced crystallinity, enhancing molecular mobility. Consequently, 100PRE exhibits decreased crystallinity due to lower aggregation probabilities of α-cyclodextrins (α-CDs), longer T 2 relaxation times (0.215 s), and higher ionic conductivity (3.4 × 10 -3 S cm -1 at 25 °C).

Background: Immunoglobulin G4-related disease (IgG4-RD) is a complex immune-mediated condition that causes fibrotic inflammation in several organs. A significant clinical feature of IgG4-RD is hypertrophic pachymeningitis, which manifests as inflammation of the dura mater in intracranial or spinal regions. Although IgG4-RD can affect multiple areas, the spine is a relatively rare site compared to the more frequent involvement of intracranial structures., Case Summary: A 70-year-old male presented to our hospital with a two-day history of fever, altered mental status, and generalized weakness. The initial brain magnetic resonance imaging (MRI) revealed multiple small infarcts across various cerebral regions. On the second day after admission, a physical examination revealed motor weakness in both lower extremities and diminished sensation in the right lower extremity. Electromyographic evaluation revealed findings consistent with acute motor sensory neuropathy. Despite initial management with intravenous immunoglobulin for presumed Guillain-Barré syndrome, the patient exhibited progressive worsening of motor deficits. On the 45 th day of hospitalization, an enhanced MRI of the entire spine, focusing specifically on the thoracic 9 to lumbar 1 vertebral level, raised the suspicion of IgG4-related spinal pachymeningitis. Subsequently, the patient was administered oral prednisolone and participated in a comprehensive rehabilitation program that included gait training and lower extremity strengthening exercises., Conclusion: IgG4-related spinal pachymeningitis, diagnosed on MRI, was treated with corticosteroids and a structured rehabilitation regimen, leading to significant improvement., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Over the past five years, maleimide scaffolds have gained considerable attention in organic synthesis for their role in forming cyclized molecules through annulation and C-H activation. As versatile and reactive coupling agents, maleimides have enabled the efficient synthesis of various cyclized products, including annulation, benzannulation, cycloaddition, and spirocyclization, with applications in medicinal chemistry, drug discovery, and materials science. Despite the extensive study of maleimide chemistry, certain reactions-such as cycloaddition-based annulation, photoannulation, and electrochemical transformations-remain underexplored despite their promising potential in the pharmaceutical and chemical industries. Recent advancements, such as photocatalysis and electrochemical methods, have expanded the utility of maleimides, providing more sustainable and selective approaches for synthesizing complex molecules. This review compiles research published between 2019 and 2024, highlighting the substrate scope, reaction diversity, and industrial relevance of maleimide-based annulation strategies. Additionally, we discuss emerging trends and future directions in maleimide chemistry, exploring opportunities for novel reaction pathways and broader applications in synthetic biology and materials science.

Background: Chronic obstructive pulmonary disease (COPD) is a significant respiratory disorder in humans characterized by persistent airway constriction or obstruction due to chronic bronchitis and pulmonary emphysema. Various methods of inducing COPD in mouse models are frequently used in COPD research; however, these cannot completely reproduce histopathologic lesions. This study aimed to establish a new COPD mouse model that reproduces histopathological lesions closely resembling clinical COPD within a shorter induction time., Methods: The new strategy involved the co-administration of porcine pancreatic elastase (PPE) and lipopolysaccharide (LPS), with PPE intended to induce pulmonary emphysema and LPS intended to induce chronic bronchitis. Male C57BL/6J mice were administered PPE (8 U/kg) on days 0 and 3 and LPS (400 µg/kg) on days 6, 9, 12, and 15. Each administration was performed using a noninvasive intubation-mediated intratracheal instillation method with a laryngoscope., Results: Postmortem examination on day 22 revealed that pulmonary emphysema and chronic bronchitis were simultaneously induced in 90.91% of the lung lobes. Molecular studies revealed higher messenger ribonucleic acid (mRNA) expression levels of interleukin-6(IL-6) and matrix metalloproteinase-12(MMP-12) associated with the pathogenesis of COPD., Conclusion: A new method was developed to establish a COPD mouse model that displays a more severe representation of the histopathological findings of clinical COPD than previous COPD models. It also reduces the time required for model induction. This newly developed COPD mouse model is expected to be a valuable tool for the pathogenesis and therapeutic research on human COPD., Competing Interests: Declarations Ethics approval and consent to participate This study was conducted following the ARRIVE guidelines. This study obtained approval from the Institutional Animal Care and Use Committee at Konkuk University, Seoul, Republic of Korea, for all experimental animal usage and procedures, with approval number KU23078. All animal experiments were performed under anesthesia to minimize suffering to the mice. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Renal replacement therapy (RRT) is an important treatment option for sepsis-associated acute kidney injury (AKI); however, the optimal timing for its initiation remains controversial. Herein, we investigated the clinical outcomes of early continuous kidney replacement therapy (CKRT), defined as CKRT initiation within 6 hours of sepsis-associated AKI onset, which was earlier than the initiation time defined in previous studies., Methods: We used clinical data sourced from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. This study included patients aged ≥ 18 years who met the sepsis diagnostic criteria and received CKRT because of stage 2 or 3 AKI. Early and late CKRTs were defined as CKRT initiation within 6 hours and after 6 hours of the development of sepsis-associated AKI, respectively., Results: Of the 33,236 patients diagnosed with sepsis, 553 underwent CKRT for sepsis-associated AKI. After excluding cases of early mortality and patients with a dialysis history, 45 and 334 patients were included in the early and late CKRT groups, respectively. After propensity score matching, the 28-day mortality rate was significantly lower in the early CKRT group than in the late CKRT group (26.7% vs. 43.9%, P = 0.035). The early CKRT group also had a significantly greater number of days free of mechanical ventilation (median, 19; interquartile range [IQR], 3-25) and vasopressor administration (median, 21; IQR, 5-26) than the late CKRT group did (median, 10.5; IQR, 0-23; P = 0.037 and median, 13.5; IQR, 0-25; P = 0.028, respectively). The Kaplan-Meier curve also showed that early CKRT initiation was associated with an improved 28-day mortality rate (log-rank test, P = 0.040). In contrast, there was no significant difference in the 28-day mortality between patients who started CKRT within 12 hours and those who did not (log-rank test, P = 0.237)., Conclusion: Early CKRT initiation improved the survival of patients with sepsis-associated AKI. Initiation of CKRT should be considered as early as possible after sepsis-associated AKI onset, preferably within 6 hours., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Androgen receptor (AR)-mediated transcription plays a critical role in development and prostate cancer growth. AR drives gene expression by binding to thousands of cis-regulatory elements (CRE) that loop to hundreds of target promoters. With multiple CREs interacting with a single promoter, it remains unclear how individual AR bound CREs contribute to gene expression. To characterize the involvement of these CREs, we investigate the AR-driven epigenetic and chromosomal chromatin looping changes by generating a kinetic multi-omic dataset comprised of steady-state mRNA, chromatin accessibility, transcription factor binding, histone modifications, chromatin looping, and nascent RNA. Using an integrated regulatory network, we find that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we show that binding of AR does not result in a substantial rewiring of chromatin loops, but instead increases the contact frequency of pre-existing loops to target promoters. Our results show that gene expression strongly correlates to the changes in contact frequency. We then propose and experimentally validate an unbalanced multi-enhancer model where the impact on gene expression of AR-bound enhancers is heterogeneous, and is proportional to their contact frequency with target gene promoters. Overall, these findings provide insights into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations., (© 2024. The Author(s).)

Purpose: Single-sided deafness (SSD) presents significant challenges for patients, including compromised sound localization, reduced speech recognition, and often, tinnitus. These issues are typically addressed using interventions such as cochlear implantation (CI) and bone conduction implant (BCI). However, evidence regarding the efficacy of BCI in reducing tinnitus in SSD patients remains limited. This study explored the ability of a novel active transcutaneous BCI (Bonebridge BCI602) to alleviate tinnitus in SSD patients., Study Design: Prospective cohort multicenter study., Setting: Tertiary referral hospitals., Methods: A prospective multicenter study of 30 SSD patients was conducted. The patients were divided into two groups: those with (n = 19) and without (n = 11) tinnitus. Audiometric assessments, subjective questionnaires including the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Bern Benefit in Single-Sided Deafness (BBSS), and tinnitus evaluations with the Tinnitus Handicap Inventory (THI) and tinnitogram were conducted before and after BCI surgery., Results: THI scores after surgery were significantly reduced in SSD patients with tinnitus. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups; however, the former group exhibited a significantly greater improvement in the APHAB questionnaire score. According to tinnitograms, the loudness of tinnitus decreased, particularly in patients with ipsilateral tinnitus. Patients with residual hearing had greater reductions in their THI scores. However, three patients without residual hearing had a relative worsening of tinnitus after surgery., Conclusion: The Bonebridge BCI602 effectively reduced tinnitus in SSD patients, particularly in those with residual hearing. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups. These findings demonstrate the therapeutic potential of BCI for managing SSD and associated tinnitus., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Unhealthy diet-related behaviors and poor diet quality during childhood and adolescence are the main factors contributing to noncommunicable diseases such as obesity, dyslipidemia, diabetes, hypertension, and cardiometabolic syndrome. Unhealthy diet-related behaviors can become lifelong habits associated with mental health problems, including depression, anxiety, attention deficit hyperactivity disorder, and substance abuse issues such as smoking, drinking, and other chemical compounds. Children and adolescents are in the developmental stages of brain structure, function, and neurotransmission systems, which can make them more susceptible to substance abuse (tobacco, alcohol, and drugs). Thus, mental health problems and substance use in children and adolescents may originate from unhealthy diet-related behaviors and poor diet quality. Here we reviewed the impact of diet-related behaviors and diet quality on children's and adolescents' physical and mental health and substance use by scrutinizing the 2021 Korean Youth Risk Behavior Survey (54,848 participants) and other relevant studies.

Objectives: This study compared the ischemic cardiovascular events (iCVEs) effectiveness and safety of initiating empagliflozin or dapagliflozin with those of dipeptidyl peptidase-4 inhibitors (DPP-4is), as well as the comparative effects between empagliflozin and dapagliflozin., Methods: Using data from the National Health Insurance Service in Korea, patients with type 2 diabetes mellitus (T2DM) who were newly prescribed empagliflozin, dapagliflozin, or DPP-4is from 2016 to 2019 and who did not have a recent CVE history were included. A Cox proportional hazards regression model was used to estimate the adjusted hazard ratio (aHR) with 95% confidence intervals (CIs) for iCVEs and safety events., Results: Empagliflozin and dapagliflozin significantly reduced the risks of ischemic stroke (aHR 0.568, 95% CI 0.408-0.791; aHR 0.612, 95% CI 0.476-0.786, respectively) and all-cause mortality (aHR 0.590, 95% CI 0.442-0.788; aHR 0.730, 95% CI 0.603-0.884, respectively) compared with DPP-4is. Initiating dapagliflozin or empagliflozin was associated with significantly lower incidence of severe hypoglycemia, bone fracture, urinary tract infection, and acute kidney injury than that of DPP-4is. No significant differences were observed between empagliflozin and dapagliflozin in iCVEs and most safety outcomes., Conclusion: Empagliflozin and dapagliflozin showed significant preventive effects on ischemic stroke and all-cause mortality compared with DPP-4is in patients with T2DM, and their protective effects were similar. Both empagliflozin and dapagliflozin were not related to the harmful effects on most safety events. These results suggest that it may be beneficial to initiate empagliflozin or dapagliflozin for ischemic stroke prevention in patients with T2DM. However, further validation studies, such as randomized controlled trials, are needed to generalize these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Seo, Nam, Lim, Choi and Kim.)

We present a novel in situ liquid-cell transmission electron microscopy (TEM) approach to study the behavior of metal nanoparticles under high-energy electron irradiation. By utilizing a radically-inert liquid environment, we aim to minimize radiolysis effects and explore the influence of charge-induced transformations. We observed complex dynamics in nanoparticle behavior, including morphological changes and transitions between amorphous and crystalline states. These transformations are attributed to the delicate interplay between charge accumulation on the nanoparticles and enhanced radiolysis, suggesting a significant role for charge-assisted processes in nanoparticle evolution. Our findings provide valuable insights into the fundamental mechanisms driving nanoparticle behavior at the nanoscale and demonstrate the potential of liquid-cell TEM for studying complex physicochemical processes in controlled environments.

Bulking agents have gained attention as new, minimally invasive treatments for fecal incontinence. Various materials and surface treatment techniques have been extensively studied to ensure good biocompatibility and long-term stability. Despite significant improvements in biocompatibility, the nonuniform particle size of existing materials has led to other challenges, such as the induction of phagocytosis or reduction of injectability during in vivo tests. This study aimed to conduct a preclinical test of the midterm stability of bulking agents with newly formulated particles with uniform size. To this end, the particles were fabricated using microfluidics, resulting in a narrow size dispersity of less than 5% as the coefficient of variation, which is essentially distinct from conventional bulking agents. The microfluidic fabrication resulted in uniformly sized particles larger than the in vivo migratory limit of 80 μm and in a reduction in maximum injection pressure. Histological staining and microscopic observations confirmed proper positioning of the filler materials in vivo and a negligible immune response for up to 6 months, indicating successful midterm stability., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Mitochondrial regulation plays a crucial role in cancer immunity in the tumor microenvironment (TME). Infiltrating immune cells, including T cells, natural killer (NK) cells, and macrophages, undergo mitochondrial metabolic reprogramming to survive the harsh conditions of the TME and enhance their antitumor activity. On the other hand, immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), mast cells, and tumor-associated macrophages (TAMs) rely on mitochondrial regulation to maintain their function as well. Additionally, mitochondrial regulation of cancer cells facilitates immune evasion and even hijacks mitochondria from immune cells to enhance their function. Recent studies suggest that targeting mitochondria can synergistically reduce cancer progression, especially when combined with traditional cancer therapies and immune checkpoint inhibitors. Many mitochondrial-targeting drugs are currently in clinical trials and have the potential to enhance the efficacy of immunotherapy. This mini review highlights the critical role of mitochondrial regulation in cancer immunity and provides lists of mitochondrial targeting drugs that have potential to enhance the efficacy of cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ahn, Ali and Seo.)

Corneal endothelial cells (CECs) are essential for maintaining corneal transparency and hydration through their barrier and pump functions. The COL8A2 gene encodes a component of the extracellular matrix of the cornea, which is crucial for the normal functioning of these cells. Mutations in COL8A2 are linked to corneal dystrophies, emphasizing the gene's importance in corneal health. The purpose of this research is to explore the effects of COL8A2 activation within CECs, to understand its contribution to cellular behavior and health. COL8A2 CRISPR/dCas9 activation system (aCOL8A2) was used to activate the COL8A2. In rats, wound healing and mitochondrial function were assessed after COL8A2 activation. As a result, aCOL8A2 promoted wound healing of rat corneal endothelium by increasing mitochondrial membrane potential. In cultured human CECs, proteomic analysis was performed to screen and identify the differential protein profiles between control and aCOL8A2 cells. Western blot was used to validate the differential proteins from both cells. Mitochondrial function and intracellular distribution were assessed by measuring ATP production and mitochondrial membrane potential. In cultured human CECs, aCOL8A2 increased COL8A2 and phospho-YAP levels. Transendothelial electrical resistance (TEER) was increased and actin cytoskeleton was attenuated by aCOL8A2. Gene ontology analysis revealed that the proteins were mainly involved in the regulation of folate biosynthesis, ECM-receptor interaction, cell differentiation, NADP activity and cytoskeleton. ATP production was increased, mitochondrial membrane potential was polarized and mitochondrial distribution was widespread in the aCOL8A2 group. In conclusion, aCOL8A2 induces a regulatory cascade affecting mitochondrial positioning and efficiency, mediated by alterations in the cytoskeletal architecture and the YAP signaling pathway. This sequence of events serves to bolster the functional capacities of corneal endothelial cells, including their pump and barrier functions, essential for corneal health and transparency., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Cyclodextrin (CD) derivatives have gained significant attention in biomedical applications due to their remarkable biocompatibility, unique inclusion capabilities, and potential for functionalization. This review focuses on recent advancements in CD-based assemblies, specifically their role in improving drug delivery, emphasizing remdesivir (RMD). The review introduces CD materials and their versatile applications in self-assembly and supramolecular assembly. CD materials offer immense potential for designing drug delivery systems with enhanced activity. Their inherent inclusion capabilities enable the encapsulation of diverse therapeutic agents, including RMD, resulting in improved solubility, stability, and bioavailability. The recent advances in CD-based assemblies, focusing on their integration with RMD have been concentrated here. Various strategies for constructing these assemblies are discussed, including physical encapsulation, covalent conjugation, and surface functionalization techniques. Furthermore, exploring future directions in these fields has also been provided. Ongoing research efforts are directed toward developing novel CD derivatives with enhanced properties, such as increased encapsulation efficiency and improved release kinetics. Moreover, the integration of CD-based assemblies with advanced technologies such as nanomedicine and gene therapy holds tremendous promise for personalized medicine and precision therapeutics.

A series of indazole analogs, derived from the B,C-ring-truncated scaffold of deguelin, were designed to function as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antitumor agents against HER2-positive breast cancer. Among the synthesized compounds, compound 12d exhibited substantial inhibitory effects in trastuzumab-sensitive (BT474) and trastuzumab-resistant (JIMT-1) breast cancer cells, with IC 50 values of 6.86 and 4.42 μM, respectively. Notably, compound 12d exhibited no cytotoxicity in normal cells. Compound 12d markedly downregulated the expression of the major HSP90 client proteins in both cell types, attributing its cytotoxicity to the destabilization and inactivation of HSP90 client proteins. Molecular docking studies using the homology model of an HSP90 homodimer demonstrated that inhibitor 12d fit nicely into the C-terminal domain, boasting a higher electrostatic complementary score than ATP. In vivo pharmacokinetic study indicated the high oral bioavailability of compound 12 d at F = 66.9 %, while toxicological studies indicated its negligible impact on hERG channels and CYP isozymes. Genotoxicity tests further confirmed its safety profile. The findings collectively position compound 12d as a promising candidate for further development as an antitumor agent against HER2-positive breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)