Pulmonary delivery of cell membrane-derived nanovesicles carrying anti-miRNA155 oligonucleotides ameliorates LPS-induced acute lung injury.

Acute lung injury (ALI) is a devastating inflammatory disease. MicroRNA155 (miR155) in alveolar macrophages and lung epithelial cells enhances inflammatory reactions by inhibiting the suppressor of cytokine signaling 1 (SOCS1) in ALI. Anti-miR155 oligonucleotide (AMO155) have been suggested as a potential therapeutic reagent for ALI. However, a safe and efficient carrier is required for delivery of AMO155 into the lungs for ALI therapy. In this study, cell membrane-derived nanovesicles (CMNVs) were produced from cell membranes of LA4 mouse lung epithelial cells and evaluated as a carrier of AMO155 into the lungs. For preparation of CMNVs, cell membranes were isolated from LA4 cells and CMNVs were produced by extrusion. Cholesterol-conjugated AMO155 (AMO155c) was loaded into CMNVs and extracellular vesicles (EVs) by sonication. The physical characterization indicated that CMNVs with AMO155c (AMO155c/CMNV) were membrane-structured vesicles with a size of ∼120 nm. The delivery efficiency and therapeutic efficacy of CMNVs were compared with those of EVs or polyethylenimine (25 kDa, PEI25k). The delivery efficiency of AMO155c by CMNVs was similar to that by EVs. As a result, the miR155 levels were reduced by AMO155c/CMNV and AMO155c/EV. AMO155c/CMNV were administered intratracheally into the ALI models. The SOCS1 levels were increased more efficiently by AMO155c/CMNV than by the others, suggesting that miR155 effectively was inhibited by AMO155c/CMNV. In addition, the inflammatory cytokines were reduced more effectively by AMO155c/CMNV than they were by AMO155c/EV and AMO155c/PEI25k, reducing inflammation reactions. The results suggest that CMNVs are a useful carrier of AMO155c in the treatment of ALI.

NLRP3 inhibition attenuates the allergic rhinitis symptoms in a mouse model.

BACKGROUND: Recent human and animal studies have demonstrated that Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is closely involved in the development of allergic diseases. OBJECTIVE: To identify the mechanism underlying the activation of NLRP3 inflammasome signaling pathway in an ovalbumin (OVA)-induced allergic rhinitis (AR) mice model and to validate the effect of a specific inhibitor of the NLRP3, MCC950. METHODS: Mice were divided into three groups and each group consisted of ten mice (saline group, the negative control group; OVA group, the OVA-induced AR model group; and OVA+MCC group, treated with 10 mg/kg MCC950). MCC950 was administered intraperitoneally every second day. Multiple parameters of AR, including NLRP3, caspase-1, interleukin (IL)-1ß, and IL-18 were evaluated by using ELISA, RT-qPCR, histopathology, and immunohistochemistry. RESULTS: The mRNA and protein levels of NLRP3, caspase-1, IL-1ß and IL-18 were upregulated in the OVA group compared with those of the saline group. MCC950 significantly inhibited the mRNA and protein levels of NLRP3, caspase-1, IL-1ß and IL-18 in nasal tissue. Further, AR symptoms and eosinophil count were normalized after MCC950 treatment. However, OVA-specific IgE was not restored in the OVA+MCC group. CONCLUSION: NLRP3 inflammasome signaling pathway may be an alternative pathway to induce AR symptoms in OVA-induced AR model. MCC950 is a specific inhibitor of NLRP3 cascade, which attenuates AR symptoms regardless of IgE.

Safety & efficacy of a robotic hip exoskeleton on outpatient stroke rehabilitation.

OBJECTIVE: The objective of this study was to analyze the safety and efficacy of using a robotic hip exoskeleton designed by Samsung Electronics Co., Ltd., Korea, called the Gait Enhancing and Motivating System-Hip (GEMS-H), in assistance mode only with the poststroke population in an outpatient-rehabilitation setting. METHODS: Forty-one participants with an average age of 60 and average stroke latency of 6.5 years completed this prospective, single arm, interventional, longitudinal study during the COVID-19 pandemic. Significant modifications to the traditional outpatient clinical environment were made to adhere to organizational physical distancing policies as well as guidelines from the Centers for Disease Control. All participants received gait training with the GEMS-H in assistance mode for 18 training sessions over the course of 6-8 weeks. Performance-based and self-reported clinical outcomes were assessed at four time points: baseline, midpoint (after 9 training sessions), post (after 18 training sessions), and 1-month follow up. Daily step count was also collected throughout the duration of the study using an ankle-worn actigraphy device. Additionally, corticomotor excitability was measured at baseline and post for 4 bilateral lower limb muscles using transcranial magnetic stimulation. RESULTS: By the end of the training program, the primary outcome, walking speed, improved by 0.13 m/s (p < 0.001). Secondary outcomes of walking endurance, balance, and functional gait also improved as measured by the 6-Minute Walk Test (47 m, p < 0.001), Berg Balance Scale (2.93 points, p < 0.001), and Functional Gait Assessment (1.80 points, p < 0.001). Daily step count significantly improved with and average increase of 1,750 steps per day (p < 0.001). There was a 35% increase in detectable lower limb motor evoked potentials and a significant decrease in the active motor threshold in the medial gastrocnemius (-5.7, p < 0.05) after training with the device. CONCLUSIONS: Gait training with the GEMS-H exoskeleton showed significant improvements in walking speed, walking endurance, and balance in persons with chronic stroke. Day-to-day activity also improved as evidenced by increased daily step count. Additionally, corticomotor excitability changes suggest that training with this device may help correct interhemispheric imbalance typically seen after stroke. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT04285060).

Normative electromyography data and influencing factors in intraoperative neuromonitoring using adhesive skin electrodes during thyroid surgery.

Background: Skin electrodes have been reported to be a useful alternative recording method for intraoperative neuromonitoring (IONM) and show typical electromyography (EMG) waveforms while overcoming the shortcomings of the EMG endotracheal tube. However, the skin electrodes showed relatively lower evoked amplitudes than other recording methods. In this study, we analyzed normative EMG data using skin electrodes and factors that affect the evoked amplitude of thyroid IONM. Methods: In total, 167 patients [242 nerves at risk (NAR)] who underwent thyroidectomy under IONM with adhesive skin electrodes were analyzed. A pair of skin electrodes was attached to the lateral border of the lamina of the thyroid cartilage. Evoked EMG data, including mean amplitude and latency, obtained after stimulation of the recurrent laryngeal nerve (RLN) and vagus nerve (VN), were collected and analyzed. Results: The mean amplitudes of RLN and VN recorded via skin electrodes were 255.48±96.53 and 236.15±69.72 µV, respectively. The mean latency of the right and left RLN was 3.22±0.03 and 3.49±0.08 mS, respectively. The mean latency of the right and left VN was 5.37±0.80 and 7.57±0.10 mS, respectively. The mean amplitude was significantly lower in the obesity, male, and total thyroidectomy (TT) groups. As body mass index (BMI) and age increased, the amplitude of EMG tended to decrease significantly. Conclusions: The evoked amplitude recorded with the skin electrodes was relatively low. A larger surgical extent, obesity, male sex, and age >55 years showed significantly lower evoked amplitudes.

Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia.

Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a Fas-blocking peptide (FBP) coupled with a positively charged nona-arginine peptide (9R) to form a complex with negatively charged siRNA targeting Bax (FBP9R/siBax). This complex is specifically designed to deliver siRNA to Fas-expressing ischemic brain cells. This complex enables the targeted inhibition of Fas-mediating extrinsic apoptosis pathways and cytochrome c-mediating intrinsic apoptosis pathways. Specifically, the FBP targets the Fas/Fas ligand signaling, while siBax targets Bax involved in mitochondria disruption in the intrinsic pathway. The FBP9R carrier system enables the delivery of functional siRNA to hypoxic cells expressing the Fas receptor on their surface-a finding validated through qPCR and confocal microscopy analyses. Through intranasal (IN) administration of FBP9R/siCy5 to middle cerebral artery occlusion (MCAO) ischemic rat models, brain imaging revealed the complex specifically localized to the Fas-expressing infarcted region but did not localize in the non-infarcted region of the brain. A single IN administration of FBP9R/siBax demonstrated a significant reduction in neuronal cell death by effectively inhibiting Fas signaling and preventing the release of cytochrome c. The targeted delivery of FBP9R/siBax represents a promising alternative strategy for the treatment of brain ischemia.

Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia.

Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood-brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.

Top-Emitting Quantum Dot Light-Emitting Diodes: Theory, Optimization, and Application.

The superior optical properties of colloidal quantum dots (QDs) have garnered significant broad interest from academia and industry owing to their successful application in self-emitting QD-based light-emitting diodes (QLEDs). In particular, active research is being conducted on QLEDs with top-emission device architectures (TQLEDs) owing to their advantages such as easy integration with conventional backplanes, high color purity, and excellent light extraction. However, due to the complicated optical phenomena and their highly sensitive optoelectrical properties to experimental variations, TQLEDs cannot be optimized easily for practical use. This review summarizes previous studies that have investigated top-emitting device structures and discusses ways to advance the performance of TQLEDs. First, theories relevant to the optoelectrical properties of TQLEDs are introduced. Second, advancements in device optimization are presented, where the underlying theories for each are considered. Finally, multilateral strategies for TQLEDs to enable their wider application to advanced industries are discussed. This work believes that this review can provide valuable insights for realizing commercial TQLEDs applicable to a broad range of applications.

A Cable-Driven Portable Fitness Chair with Programmable Resistance for Effective Muscle Training.

The COVID-19 pandemic has changed the lifestyle of society and the interest in health and fitness has greatly increased, accordingly. Recently, motorized devices that allow fine and automatic adjustment of resistance without physically changing the applied weight have been released to the market. In fact, these devices have eased the resistance-changing process. However, such devices are still not portable as they must be mounted on the wall and their resistance control needs to be improved to increase the efficiency of strength training. This study introduces a portable chair-shaped fitness device that allows inducing various resistance profiles. A compact, light, and robust cable-driven actuation module design was achieved by implementing a derailing prevention mechanism. The actuator covers resistance up to 120 N for each left and right arm separately. Exercise can be conducted by pulling the elastic handle connected to cable. The controller of the proposed device allows variation of resistance according to the joint range-of-motion (ROM) to make the workout more challenging but still safe through the full ROM. Viscous resistance, ascending resistance, and descending resistance profile can be provided. The experimental results shows that various muscle activation patterns can be provided by changing the resistance profile, which is important for effective training. The device can be used anywhere, at home or office, to perform various upper and lower body exercises or for physical self-care.

Discovering Potential Anti-Oral Squamous Cell Carcinoma Mechanisms from Kochiae Fructus Using Network-Based Pharmacology Analysis and Experimental Validation.

The natural product Kochiae Fructus (KF) is the ripe fruit of Kochia scoparia (L.) Schrad and is renowned for its anti-inflammatory, anticancer, anti-fungal, and anti-pruritic effects. This study examined the anticancer effect of components of KF to assess its potential as an adjuvant for cancer treatment. Network-based pharmacological and docking analyses of KF found associations with oral squamous cell carcinoma. The molecular docking of oleanolic acid (OA) with LC3 and SQSTM1 had high binding scores, and hydrogen binding with amino acids of the receptors suggests that OA is involved in autophagy, rather than the apoptosis pathway. For experimental validation, we exposed SCC-15 squamous carcinoma cells derived from a human tongue lesion to KF extract (KFE), OA, and cisplatin. The KFE caused SCC-15 cell death, and induced an accumulation of the autophagy marker proteins LC3 and p62/SQSTM1. The novelty of this study lies in the discovery that the change in autophagy protein levels can be related to the regulatory death of SCC-15 cells. These findings suggest that KF is a promising candidate for future studies to provide insight into the role of autophagy in cancer cells and advance our understanding of cancer prevention and treatment.

Delivery systems of therapeutic nucleic acids for the treatment of acute lung injury/acute respiratory distress syndrome.

Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disease with a high mortality rate. ALI/ARDS is induced by various causes, including sepsis, infections, thoracic trauma, and inhalation of toxic reagents. Corona virus infection disease-19 (COVID-19) is also a major cause of ALI/ARDS. ALI/ARDS is characterized by inflammatory injury and increased vascular permeability, resulting in lung edema and hypoxemia. Currently available treatments for ALI/ARDS are limited, but do include mechanical ventilation for gas exchange and treatments supportive of reduction of severe symptoms. Anti-inflammatory drugs such as corticosteroids have been suggested, but their clinical effects are controversial with possible side-effects. Therefore, novel treatment modalities have been developed for ALI/ARDS, including therapeutic nucleic acids. Two classes of therapeutic nucleic acids are in use. The first constitutes knock-in genes for encoding therapeutic proteins such as heme oxygenase-1 (HO-1) and adiponectin (APN) at the site of disease. The other is oligonucleotides such as small interfering RNAs and antisense oligonucleotides for knock-down expression of target genes. Carriers have been developed for efficient delivery for therapeutic nucleic acids into the lungs based on the characteristics of the nucleic acids, administration routes, and targeting cells. In this review, ALI/ARDS gene therapy is discussed mainly in terms of delivery systems. The pathophysiology of ALI/ARDS, therapeutic genes, and their delivery strategies are presented for development of ALI/ARDS gene therapy. The current progress suggests that selected and appropriate delivery systems of therapeutic nucleic acids into the lungs may be useful for the treatment of ALI/ARDS.

Continuous cuffless blood pressure monitoring using photoplethysmography-based PPG2BP-net for high intrasubject blood pressure variations.

Continuous, comfortable, convenient (C3), and accurate blood pressure (BP) measurement and monitoring are needed for early diagnosis of various cardiovascular diseases. To supplement the limited C3 BP measurement of existing cuff-based BP technologies, though they may achieve reliable accuracy, cuffless BP measurement technologies, such as pulse transit/arrival time, pulse wave analysis, and image processing, have been studied to obtain C3 BP measurement. One of the recent cuffless BP measurement technologies, innovative machine-learning and artificial intelligence-based technologies that can estimate BP by extracting BP-related features from photoplethysmography (PPG)-based waveforms have attracted interdisciplinary attention of the medical and computer scientists owing to their handiness and effectiveness for both C3 and accurate, i.e., C3A, BP measurement. However, C3A BP measurement remains still unattainable because the accuracy of the existing PPG-based BP methods was not sufficiently justified for subject-independent and highly varying BP, which is a typical case in practice. To circumvent this issue, a novel convolutional neural network(CNN)- and calibration-based model (PPG2BP-Net) was designed by using a comparative paired one-dimensional CNN structure to estimate highly varying intrasubject BP. To this end, approximately [Formula: see text], [Formula: see text], and [Formula: see text] of 4185 cleaned, independent subjects from 25,779 surgical cases were used for training, validating, and testing the proposed PPG2BP-Net, respectively and exclusively (i.e., subject-independent modelling). For quantifying the intrasubject BP variation from an initial calibration BP, a novel 'standard deviation of subject-calibration centring (SDS)' metric is proposed wherein high SDS represents high intrasubject BP variation from the calibration BP and vice versa. PPG2BP-Net achieved accurately estimated systolic and diastolic BP values despite high intrasubject variability. In 629-subject data acquired after 20 minutes following the A-line (arterial line) insertion, low error mean and standard deviation of [Formula: see text] and [Formula: see text] for highly varying A-line systolic and diastolic BP values, respectively, where their SDSs are 15.375 and 8.745. This study moves one step forward in developing the C3A cuffless BP estimation devices that enable the push and agile pull services.

Effect of deferoxamine and ferrostatin-1 on salivary gland dysfunction in ovariectomized rats.

The mechanism underlying xerostomia after menopause has not yet been fully elucidated. This study aimed to investigate the mechanism of xerostomia and the effect of the ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (FER) on salivary gland dysfunction in a postmenopausal animal model. Twenty-four female Sprague-Dawley rats were randomly divided into four groups: a SHAM group (n = 6, sham-operated rats), an OVX group (n = 6, ovariectomized rats), an FER group (n = 6, ovariectomized rats injected intraperitoneally with FER), and a DFO group (n = 6, ovariectomized rats injected intraperitoneally with DFO). GPX4 activity, iron accumulation, lipid peroxidation, inflammation, fibrosis, and salivary gland function were analyzed. Recovery of GPX4 activity and a decrease in iron accumulation and cytosolic MDA + HAE were observed in the DFO group. In addition, collagen I, collagen III, TGF-ß, IL-6, TNF-α, and TGF-ß levels were decreased in the DFO group compared to the OVX group. Recovery of GPX4 activity and the morphology of mitochondria, and reduction of cytosolic MDA + HAE were also observed in the FER group. In addition, decreased expression of inflammatory cytokines and fibrosis markers and increased expression of AQP5 were observed in both the DFO and FER groups. Postmenopausal salivary gland dysfunction is associated with ferroptosis, and DFO and FER may reverse the postmenopausal salivary gland dysfunction after menopause. DFO and FER are hence considered promising treatments for postmenopausal xerostomia.

Brain-targeted exosome-mimetic cell membrane nanovesicles with therapeutic oligonucleotides elicit anti-tumor effects in glioblastoma animal models.

The brain-targeted delivery of therapeutic oligonucleotides has been investigated as a new treatment modality for various brain diseases, such as brain tumors. However, delivery efficiency into the brain has been limited due to the blood-brain barrier. In this research, brain-targeted exosome-mimetic cell membrane nanovesicles (CMNVs) were designed to enhance the delivery of therapeutic oligonucleotides into the brain. First, CMNVs were produced by extrusion with isolated C6 cell membrane fragments. Then, CMNVs were decorated with cholesterol-linked T7 peptides as a targeting ligand by hydrophobic interaction, producing T7-CMNV. T7-CMNV was in aqueous solution maintained its nanoparticle size for over 21 days. The targeting and delivery effects of T7-CMNVs were evaluated in an orthotopic glioblastoma animal model. 2'-O-metyl and cholesterol-TEG modified anti-microRNA-21 oligonucleotides (AMO21c) were loaded into T7-CMNVs, and biodistribution experiments indicated that T7-CMNVs delivered AMO21c more efficiently into the brain than CMNVs, scrambled T7-CMNVs, lipofectamine, and naked AMO21c after systemic administration. In addition, AMO21c down-regulated miRNA-21 (miR-21) levels in glioblastoma tissue most efficiently in the T7-CMNVs group. This enhanced suppression of miR-21 resulted in the up-regulation of PDCD4 and PTEN. Eventually, brain tumor size was reduced in the T7-CMNVs group more efficiently than in the other control groups. With stability, low toxicity, and targeting efficiency, T7-CMNVs may be useful to the development of oligonucleotide therapy for brain tumors.

Hybrid nanoparticles with cell membrane and dexamethasone-conjugated polymer for gene delivery into the lungs as therapy for acute lung injury.

Gene therapy has been suggested as a new treatment for acute lung injury (ALI), which is a severe inflammatory disease. Previously, amphiphilic polymeric carriers such as dexamethasone-conjugated polyethylenimine (PEI) (DP) have been used to transport plasmid DNA (pDNA) into the lungs. In the current study, hybrid nanoparticles comprising DP and cell membrane (CM) from LA-4 lung epithelial cells were developed for enhanced delivery of pDNA into the lungs. The CM components of the hybrid nanoparticles may interact with plasma membranes of target cells and facilitate intracellular uptake of pDNA. DP/CM/pDNA nanoparticles had the highest transfection efficiency into LA-4 cells at a weight ratio of 8 : 3 : 1. In vitro transfection assays showed that DP/CM/pDNA nanoparticles improved the cellular uptake and transfection efficiency of pDNA compared with PEI (25 kDa, PEI25k)/pDNA and DP/pDNA nanoparticles. The DP/CM/pDNA nanoparticles were approximately 80 nm in diameter with a zeta potential of +25 mV. To evaluate the therapeutic effects, heme oxygenase-1 pDNA (pHO-1) was administered to ALI animal models by intratracheal instillation. DP/CM/pHO-1 nanoparticles improved gene delivery efficiency compared with PEI25k/pHO-1 and DP/pHO-1 nanoparticles. As a result, inflammation in the lungs was alleviated by DP/CM/pHO-1 nanoparticles more effectively than by other nanoparticles. The results suggest that DP/CM/pDNA hybrid nanoparticles may be useful gene carriers for the treatment of ALI.

Recanalization Rate and Clinical Outcomes of Intravenous Tissue Plasminogen Activator Administration for Large Vessel Occlusion Stroke Patients.

OBJECTIVE: Stroke caused from large vessel occlusion (LVO) has emerged as the most common stroke subtype worldwide. Intravenous tissue plasminogen activator administration (IV-tPA) and additional intraarterial thrombectomy (IA-Tx) is regarded as standard treatment. In this study, the authors try to find the early recanalization rate of IV-tPA in LVO stroke patients. METHODS: Total 300 patients undertook IA-Tx with confirmed anterior circulation LVO, were analyzed retrospectively. Brain computed tomography angiography (CTA) was the initial imaging study and acute stroke magnetic resonance angiography (MRA) followed after finished IV-tPA. Early recanalization rate was evaluated by acute stroke MRA within 2 hours after the IV-tPA. In 167 patients undertook IV-tPA only and 133 non-recanalized patients by IV-tPA, additional IA-Tx tried (IV-tPA + IA-Tx group). And 131 patients, non-recanalized by IV-tPA (IV-tPA group) additional IA-Tx recommend and tried according to the patient condition and compliance. RESULTS: Early recanalization rate of LVO after IV-tPA was 12.0% (36/300). In recanalized patients, favorable outcome (modified Rankin Scale, 0-2) was 69.4% (25/36) while it was 32.1% (42/131, p<0.001) in non-recanalized patients. Among 133 patients, nonrecanalized after intravenous recombinant tissue plasminogen activator and undertook additional IA-Tx, the clinical outcome was better than not undertaken additional IA-Tx (favorable outcome was 42.9% vs. 32.1%, p=0.046). Analysis according to the perfusion/diffusion (P/D)-mismatching or not, in patient with IV-tPA with IA-Tx (133 patients), favorable outcome was higher in P/ D-mismatching patient (52/104; 50.0%) than P/D-matching patients (5/29; 17.2%; p=0.001). Which treatment tired, P/D-mismatching was favored in clinical outcome (iv-tPA only, p=0.008 and IV-tPA with IA-Tx, p=0.001). CONCLUSION: The P/D-mismatching influences on the recanalization and clinical outcomes of IV-tPA and IA-Tx. The authors would like to propose that we had better prepare IA-Tx when LVO is diagnosed on initial diagnostic imaging. Furthermore, if the patient shows P/D-mismatching on MRA after IV-tPA, additional IA-Tx improves treatment results and lessen the futile recanalization.

Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models.

INTRODUCTION: miRNA-21 (miR-21) is highly expressed in glioblastoma, facilitating tumor growth by blocking the expression of apoptosis-related genes. Therefore, an antisense microRNA oligonucleotide (AMO) against miR-21 was suggested as a therapeutic nucleic acid for glioblastoma. OBJECTIVES: AMO21 co-micelles were developed with tumor-targeting T7 peptides as an AMO21 delivery system by intranasal administration. METHODS: Cholesterol-conjugated AMO21 (AMO21c) was mixed with cholesterol-conjugated T7 peptides (T7c) to produce tumor-targeted co-micelles. Physical characterization was performed by dynamic light scattering, gel retardation assay, scanning electron microscope and heparin competition assay. In vitro transfection efficiency to C6 glioblastoma cells was measured by flow cytometry. The AMO21c/T7c co-micelles were administered by intranasal instillation into the brain of intracranial glioblastoma rat models. Scrambled T7 (scrT7) and scrambled AMO21c (scrAMO21c) were used as a negative control. The therapeutic effects of the AMO21c/T7c co-micelles were evaluated by real time RT-PCR, immunohistochemistry, TUNEL assay, and Nissl staining. RESULTS: The formation of the AMO21c/T7c co-micelles was confirmed in gel retardation and heparin competition assays. The highest delivery efficiency in vitro was achieved at a 1:10 wt ratio of AMO21c/T7c. The AMO21c/T7c co-micelles had higher delivery efficiency into C6 glioblastoma cells than naked AMO21c or AMO21c/lipofectamine complexes. After intranasal administration into the intracranial glioblastoma models, the delivery efficiency of the co-micelles into the brain was also higher than those of naked AMO21c and AMO21c/scrambled T7c. Thanks to their enhanced delivery efficiency, the AMO21c/T7c co-micelles downregulated miR-21, inducing the production of the pro-apoptotic phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) proteins in the tumor tissues. The tumor size was reduced by the AMO21c/T7c co-micelles more effectively than naked AMO21c, AMO21c/lipofectamine, or scrAMO21c/T7c treatment. CONCLUSION: The results suggest that the co-micelles of AMO21c and T7c may be an efficient delivery system into a brain tumor through intranasal administration.

Primary astrocytic mitochondrial transplantation ameliorates ischemic stroke.

Mitochondria are important organelles that regulate adenosine triphosphate production, intracellular calcium buffering, cell survival, and apoptosis. They play therapeutic roles in injured cells via transcellular transfer through extracellular vesicles, gap junctions, and tunneling nanotubes. Astrocytes can secrete numerous factors known to promote neuronal survival, synaptic formation, and plasticity. Recent studies have demonstrated that astrocytes can transfer mitochondria to damaged neurons to enhance their viability and recovery. In this study, we observed that treatment with mitochondria isolated from rat primary astrocytes enhanced cell viability and ameliorated hydrogen peroxide-damaged neurons. Interestingly, isolated astrocytic mitochondria increased the number of cells under damaged neuronal conditions, but not under normal conditions, although the mitochondrial transfer efficiency did not differ between the two conditions. This effect was also observed after transplanting astrocytic mitochondria in a rat middle cerebral artery occlusion model. These findings suggest that mitochondria transfer therapy can be used to treat acute ischemic stroke and other diseases. [BMB Reports 2023; 56(2): 90-95].

Modular hip exoskeleton improves walking function and reduces sedentary time in community-dwelling older adults.

BACKGROUND: Despite the benefits of physical activity for healthy physical and cognitive aging, 35% of adults over the age of 75 in the United States are inactive. Robotic exoskeleton-based exercise studies have shown benefits in improving walking function, but most are conducted in clinical settings with a neurologically impaired population. Emerging technology is starting to enable easy-to-use, lightweight, wearable robots, but their impact in the otherwise healthy older adult population remains mostly unknown. For the first time, this study investigates the feasibility and efficacy of using a lightweight, modular hip exoskeleton for in-community gait training in the older adult population to improve walking function. METHODS: Twelve adults over the age of 65 were enrolled in a gait training intervention involving twelve 30-min sessions using the Gait Enhancing and Motivating System for Hip in their own senior living community. RESULTS: Performance-based outcome measures suggest clinically significant improvements in balance, gait speed, and endurance following the exoskeleton training, and the device was safe and well tolerated. Gait speed below 1.0 m/s is an indicator of fall risk, and two out of the four participants below this threshold increased their self-selected gait speed over 1.0 m/s after intervention. Time spent in sedentary behavior also decreased significantly. CONCLUSIONS: This intervention resulted in greater improvements in speed and endurance than traditional exercise programs, in significantly less time. Together, our results demonstrated that exoskeleton-based gait training is an effective intervention and novel approach to encouraging older adults to exercise and reduce sedentary time, while improving walking function. Future work will focus on whether the device can be used independently long-term by older adults as an everyday exercise and community-use personal mobility device. Trial registration This study was retrospectively registered with ClinicalTrials.gov (ID: NCT05197127).

Survey of Korean head and neck surgeons and endocrinologists for the surgical extent of 1.5 and 2.5 cm papillary thyroid carcinoma.

Background: The surgical extent of 1-4 cm papillary thyroid carcinoma (PTC) is controversial. We aimed to determine the current trend in the extent of thyroidectomy and prophylactic central neck dissection (pCND) for 1.5 and 2.5 cm PTC, which are the most clinically controversial sizes. Methods: The questionnaire was sent to 342 Korean Society of Head and Neck Surgery and 160 one branch of Korean Endocrine Society members from June to July 2021 by e-mail. A questionnaire included extent of thyroidectomy [hemithyroidectomy (Hemi) vs. total thyroidectomy (TT)] and pCND according to the tumor location and degree of extrathyroidal extension (ETE) at 1.5 or 2.5 cm PTC. We compared the proportion of respondents' preference for each scenario. Results: Fifty-seven of 342 surgeons and twenty-seven of 160 endocrinologists responded to the questionnaire. At 1.5 and 2.5 cm PTC without ETE, both groups preferred Hemi, and there was no difference between the groups. When 1.5 or 2.5 cm PTC with anterior minimal ETE was suspected, the preference for Hemi by endocrinologists was significantly lower than that by surgeons (P<0.05). When anterior and posterior gross ETE were suspected, TT was preferred in both groups. When anterior gross ETE was suspected, the preference for Hemi by endocrinologists was significantly lower than that by surgeons (P<0.05). There was no difference between the groups in the posterior gross ETE. Surgeons preferred Hemi and endocrinologists preferred TT for a 1.5 cm PTC located in the isthmus. The pCND showed a similar pattern in both groups according to the size and location of the tumor and the degree of ETE. The proportion of Hemi did not differ between high-experience and low-experience endocrinologists. Also, there was no significant difference in preference for surgical extent between low-volume and high-volume surgeons. Conclusions: TT was frequently preferred in tumors with a large size or gross ETE, and pCND was frequently preferred in cases of suspected gross ETE. This study shows as the extent of thyroid surgery may differ between endocrinologists and surgeons and this could be confusing to patient and affect the patient outcomes. Therefore, multidisciplinary approach considering the extent of surgery for thyroid cancer is recommended.

Progress in the Development of Active-Matrix Quantum-Dot Light-Emitting Diodes Driven by Non-Si Thin-Film Transistors.

This paper aims to discuss the key accomplishments and further prospects of active-matrix (AM) quantum-dot (QD) light-emitting diodes (QLEDs) display. We present an overview and state-of-the-art of QLEDs as a frontplane and non-Si-based thin-film transistors (TFTs) as a backplane to meet the requirements for the next-generation displays, such as flexibility, transparency, low power consumption, fast response, high efficiency, and operational reliability. After a brief introduction, we first review the research on non-Si-based TFTs using metal oxides, transition metal dichalcogenides, and semiconducting carbon nanotubes as the driving unit of display devices. Next, QLED technologies are analyzed in terms of the device structure, device engineering, and QD patterning technique to realize high-performance, full-color AM-QLEDs. Lastly, recent research on the monolithic integration of TFT-QLED is examined, which proposes a new perspective on the integrated device. We anticipate that this review will help the readership understand the fundamentals, current state, and issues on TFTs and QLEDs for future AM-QLED displays.