Search

Background: The brain-gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement., Objective: This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer's dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT., Methods: Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients' fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients' genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction., Results: Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT., Conclusion: These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background and Objective: Semi-supervised learning for medical image segmentation is an important area of research for alleviating the huge cost associated with the construction of reliable large-scale annotations in the medical domain. Recent semi-supervised approaches have demonstrated promising results by employing consistency regularization, pseudo-labeling techniques, and adversarial learning. These methods primarily attempt to learn the distribution of labeled and unlabeled data by enforcing consistency in the predictions or embedding context. However, previous approaches have focused only on local discrepancy minimization or context relations across single classes., Methods: In this paper, we introduce a novel adversarial learning-based semi-supervised segmentation method that effectively embeds both local and global features from multiple hidden layers and learns context relations between multiple classes. Our voxel-wise adversarial learning method utilizes a voxel-wise feature discriminator, which considers multilayer voxel-wise features (involving both local and global features) as an input by embedding class-specific voxel-wise feature distribution. Furthermore, our previous representation learning method is improved by overcoming information loss and learning stability problems, which enables rich representations of labeled data., Result: In the experiments, we used the Left Atrial Segmentation Challenge dataset and the Abdominal Multi-Organ dataset to prove the effectiveness of our method in both single class and multiclass segmentation. The experimental results demonstrate that our method outperforms current best-performing state-of-the-art semi-supervised learning approaches. Our proposed adversarial learning-based semi-supervised segmentation method successfully leveraged unlabeled data to improve the network performance by 2% in Dice score coefficient for multi-organ dataset., Conclusion: We compare our approach to a wide range of medical datasets, and showed our method can be adapted to embed class-specific features. Furthermore, visual interpretation of the feature space demonstrates that our proposed method enables a well-distributed and separated feature space from both labeled and unlabeled data, which improves the overall prediction results., 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 © 2022 Elsevier Ltd. All rights reserved.)

Intermittent hypoxia (IH) has been an issue of considerable research in recent years and triggers a bewildering array of both detrimental and beneficial effects in several physiological systems. However, the mechanisms leading to the effect are not yet clear. Consequently, we investigated the effects of IH on allergen-induced allergic asthma via the mitogen-activated protein kinase (MAPK) signaling pathway. Forty BALB/c mice were dived into four groups. We evaluated the influence of IH on the cell signaling system of the airway during the allergen-induced challenge in an animal model, especially through the MAPK (mitogen-activated protein kinase) pathway. The protein concentrations of p-ERK/ERK, p-JNK/JNK, p-p38/p38, and pMEK/MEK were significantly reduced in the allergen-induced+IH group, compared to the allergen-induced group (p-value < 0.05 as considered statistically significant). The number of eosinophils, neutrophils, macrophages, and lymphocytes in the bronchoalveolar lavage fluid and Dp (Dermatophagoides pteronyssinus)-specific IgG2a and interleukins 4, 5, 13, and 17 were significantly reduced in the Dp+IH group, compared to the Dp group. These findings suggest that the MAPK pathway might be associated with the beneficial effect of IH on the attenuation of allergic response in an allergen-induced mouse model.

MicroRNAs (miRNAs) are small non‑coding RNAs that control patterns of gene expression by inducing the degradation of mRNAs. In addition, miRNAs are known to serve an important role in the pathogenesis of atrial fibrillation (AF). In general, AF is diagnosed using electrocardiography. However, the present study investigated whether specific miRNAs derived from microarray analysis of human urine could regulate AF through the inhibition of calcium handling protein phosphorylation in an AF model. Microarray analysis of the transcriptome in the human urine of patients with paroxysmal supraventricular tachycardia and AF revealed that 7 differentially expressed miRNAs were significantly downregulated (miR‑3613, 6763, 423, 3162, 1180, 6511, 3197) in patients with AF. In addition, quantitative PCR results demonstrated that collagen I, collagen III, fibronectin and TGF‑β, which are fibrosis‑related genes, were upregulated in patients with AF. Furthermore, fibrosis‑related genes were upregulated in angiotensin II‑induced atrial myocytes, which demonstrated that these genes may be targets of miR‑423. In the AF cell model transfected with miR‑423, the expression of calcium handling proteins, including phosphorylated calmodulin‑dependent protein kinase II, was reduced. The transfection of miR‑423 attenuated damage to cardiac cells caused by calcium handling proteins. The findings highlight the importance of calcium handling protein phosphorylation changes in fibrosis‑induced AF and support miR‑423 detection in human urine as a potential novel approach of AF diagnosis.

Background and Objectives: Ambient particulate matter (PM) in real urban air pollution (RUA) is an environmental health risk factor associated with increased cardiac events. This study investigated the threshold level to induce arrhythmia, as well as arrhythmogenic mechanism of RUA that mainly consisted of PM <2.5 μm in aerodynamic diameter close to ultrafine particles., Methods: RUA was artificially produced by a lately developed pyrolysis based RUA generator. C57BL/6 mice were divided into 4 groups: a control group (control, n=12) and three groups with exposure to RUA with the concentration of 200 μg/m³ (n=12), 400 μg/m³ (n=12), and 800 μg/m³ (n=12). Mice were exposed to RUA at each concentration for 8 hr/day and 5 day/week to mimic ordinary human activity during 3 weeks., Results: The QRS and QTc intervals, as well as intracellular Ca 2+ duration, apicobasal action potential duration (APD) gradient, fibrosis, and inflammation of left ventricle of mouse hearts were increased dose-dependently with the increase of RUA concentration, and significantly increased at RUA concentration of 400 μg/m³ compared to control (all p<0.001). In mice exposed to RUA concentration of 800 μg/m³, spontaneous ventricular arrhythmia was observed in 42%, with significant increase of inflammatory markers, phosphorylated Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), and phospholamban (PLB) compared to control., Conclusions: RUA could induce electrophysiological changes such as APD and QT prolongation, fibrosis, and inflammation dose-dependently, with significant increase of ventricular arrhythmia at the concentration of 400 μg/m³. RUA concentration of 800 μg/m³ increased phosphorylation of CaMKII and PLB., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2021. The Korean Society of Cardiology.)

As agonists of TLR7/8, single-stranded RNAs (ssRNAs) are safe and promising adjuvants that do not cause off-target effects or innate immune overactivation. However, low stability prevents them from mounting sufficient immune responses. This study evaluates the adjuvant effects of ssRNA derived from the cricket paralysis virus intergenic region internal ribosome entry site, formulated as nanoparticles with a coordinative amphiphile, containing a zinc/dipicolylamine complex moiety as a coordinative phosphate binder, as a stabilizer for RNA-based adjuvants. The nanoformulated ssRNA adjuvant was resistant to enzymatic degradation in vitro and in vivo, and that with a coordinative amphiphile bearing an oleyl group (CA-O) was approximately 100 nm, promoted effective recognition, and improved activation of antigen-presenting cells, leading to better induction of neutralizing antibodies following single immunization. Hence, CA-O may increase the efficacy of ssRNA-based adjuvants, proving useful to meet the urgent need for vaccines during pathogen outbreaks., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An ideal adjuvant should increase vaccine efficacy through balanced Th1/Th2 responses and be safe to use. Recombinant protein-based vaccines are usually formulated with aluminum (alum)-based adjuvants to ensure an adequate immune response. However, use of alum triggers a Th2-biased immune induction, and hence is not optimal. Although the adjuvanticity of RNA has been reported, a systematic and overall investigation on its efficacy is lacking. We found that single strand RNA (termed RNA adjuvant) derived from cricket paralysis virus intergenic region internal ribosome entry site induced the expression of various adjuvant-function-related genes, such as type 1 and 2 interferon (IFN) and toll-like receptor (TLR), T cell activation, and leukocyte chemotaxis in human peripheral blood mononuclear cells; furthermore, its innate and IFN transcriptome profile patterns were similar to those of a live-attenuated yellow fever vaccine. This suggests that protein-based vaccines formulated using RNA adjuvant function as live-attenuated vaccines. Application of the RNA adjuvant in mouse enhanced the efficacy of Middle East respiratory syndrome spike protein, a protein-subunit vaccine and human papillomavirus L1 protein, a virus-like particle vaccine, by activating innate immune response through TLR7 and enhancing pAPC chemotaxis, leading to a balanced Th1/Th2 responses. Moreover, the combination of alum and the RNA adjuvant synergistically induced humoral and cellular immune responses and endowed long-term immunity. Therefore, RNA adjuvants have broad applicability and can be used with all conventional vaccines to improve vaccine efficacy qualitatively and quantitively., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Exosomes serve important functions in cell‑to‑cell communication and biological functions by serving as a delivery cargo shuttle for various molecules. The application of an improved delivery method for microRNAs (miRNAs/miRs) may enhance their potential as a therapeutic tool in cardiac diseases. Thus, the present study investigated whether human peripheral blood‑derived exosomes may be used as a delivery cargo system for miRNAs, and whether the delivery of miR‑21 using a human peripheral blood derived‑exosome may influence the degree of remodeling following myocardial infarction (MI). In H9C2 and HL‑1 cells, miR‑21 expression was successfully regulated by treatment with human peripheral blood derived‑exosomes loaded with an miR‑21 mimic or inhibitor compared with untreated cells. In addition, the mRNA and protein expression levels of SMAD family member 7 (Smad7), phosphatase and tensin homolog (PTEN) and matrix metalloproteinase 2 (MMP2), which are involved in cardiac fibrosis, were associated with the uptake of miR‑21 mimic‑ or inhibitor‑loaded exosomes. Similarly, the in vivo mRNA and protein expression of Smad7, PTEN and MMP2 were altered following treatment with miR‑21 mimic‑ or inhibitor‑loaded exosomes. Furthermore, miR‑21 mimic‑loaded exosomes enhanced fibrosis, whereas miR‑21 inhibitor‑loaded exosomes reduced fibrosis in a mouse MI model. These results suggested that miRNA‑loaded human peripheral blood derived‑exosomes may be used as a therapeutic tool for cardiac diseases. [the original article was published in International Journal of Molecular Medicine 43: 2319‑2328, 2019; DOI:10.3892/ijmm.2019.4150].

Exosomes serve important functions in cell‑to‑cell communication and biological functions by serving as a delivery cargo shuttle for various molecules. The application of an improved delivery method for microRNAs (miRNAs/miRs) may enhance their potential as a therapeutic tool in cardiac diseases. Thus, the present study investigated whether human peripheral blood‑derived exosomes may be used as a delivery cargo system for miRNAs, and whether the delivery of miR‑21 using a human peripheral blood derived‑exosome may influence the degree of remodeling following myocardial infarction (MI). In H9C2 and HL‑1 cells, miR‑21 expression was successfully regulated by treatment with human peripheral blood derived‑exosomes loaded with an miR‑21 mimic or inhibitor compared with untreated cells. In addition, the mRNA and protein expression levels of SMAD family member 7 (Smad7), phosphatase and tensin homolog (PTEN) and matrix metalloproteinase 2 (MMP2), which are involved in cardiac fibrosis, were associated with the uptake of miR‑21 mimic‑ or inhibitor‑loaded exosomes. Similarly, the in vivo mRNA and protein expression of Smad7, PTEN and MMP2 were altered following treatment with miR‑21 mimic‑ or inhibitor‑loaded exosomes. Furthermore, miR‑21 mimic‑loaded exosomes enhanced fibrosis, whereas miR‑21 inhibitor‑loaded exosomes reduced fibrosis in a mouse MI model. These results suggested that miRNA‑loaded human peripheral blood derived‑exosomes may be used as a therapeutic tool for cardiac diseases.

Atrial fibrillation (AF), the most common type of cardiac arrhythmia, is thought to be regulated by changes in microRNA (miRNA) expression. However, the evidence for this is inconsistent. The high stability and expression of circulating exosomal miRNAs may allow their use as candidate biomarkers. For the discovery phase, exosomes were isolated from the serum of patients with supraventricular tachycardia (SVT) as the controls ( n = 5) and with paroxysmal AF ( n = 4) and persistent AF ( n = 5) for microarray analysis of miRNAs. Forty-five miRNAs were expressed significantly higher (>1.5-fold) in patients with persistent AF, but not in patients with paroxysmal AF, relative to the levels in patients with SVT control. Notably, expression of 5 miRNAs (miRNA-103a, -107, -320d, -486, and let-7b) was elevated by more than 4.5-fold in patients with persistent AF. For the validation phase, miRNAs were analyzed using quantitative RT-PCR analysis in exosomes from the serum of patients with SVT control ( n = 20) and patients with persistent AF ( n = 40). These miRNAs and their target genes were involved in atrial function and structure, oxidative stress, and fibrosis pathways. These findings suggest that serum exosomal miRNAs might be used as novel biomarkers to reflect the progression of AF.-Mun, D., Kim, H., Kang, J.-Y., Park, H., Park, H., Lee, S.-H., Yun, N., Joung, B. Expression of miRNAs in circulating exosomes derived from patients with persistent atrial fibrillation.

We investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer's disease dementia (ADD) using interdigitated microelectrode (IME) biosensors and determined the predictive value of Aβ in nasal secretions for ADD diagnosis. Nasal secretions were obtained from 35 patients with ADD, 18 with cognitive decline associated with other neurological disorders (OND), and 26 cognitively unimpaired (CU) participants. Capacitance changes in IMEs were measured by capturing total Aβ (ΔC tAβ ). After 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) was injected, additional capacitance changes due to the smaller molecular weight Aβ oligomers disassembled from the higher molecular weight oligomeric Aβ were determined (ΔC oAβ ). By dividing two values, the capacitance ratio (ΔC oAβ /ΔC tAβ ) was determined and then normalized to the capacitance change index (CCI). The CCI was higher in the ADD group than in the OND (p = 0.040) and CU groups (p = 0.007). The accuracy of the CCI was fair in separating into the ADD and CU groups (area under the receiver operating characteristic curve = 0.718, 95% confidence interval = 0.591-0.845). These results demonstrate that the level of Aβ in nasal secretions increases in ADD and the detection of Aβ in nasal secretions using IME biosensors may be possible in predicting ADD.

Background: Community-dwelling older adults living in rural areas are in a less favorable environment for health care compared with urban older adults. We believe that intermittent coaching through wearable devices can help optimize health care for older adults in medically limited environments., Objective: We aimed to evaluate whether a wearable device and mobile-based intermittent coaching or self-management could increase physical activity and health outcomes of small groups of older adults in rural areas., Methods: To address the above evaluation goal, we carried out the "Smart Walk" program, a health care model wherein a wearable device is used to promote self-exercise particularly among community-dwelling older adults managed by a community health center. We randomly selected older adults who had enrolled in a population-based, prospective cohort study of aging, the Aging Study of Pyeongchang Rural Area. The "Smart Walk" program was a 13-month program conducted from March 2017 to March 2018 and included 6 months of coaching, 1 month of rest, and 6 months of self-management. We evaluated differences in physical activity and health outcomes according to frailty status and conducted pre- and postanalyses of the Smart Walk program. We also performed intergroup analysis according to adherence of wearable devices., Results: We recruited 22 participants (11 robust and 11 prefrail older adults). The two groups were similar in most of the variables, except for age, frailty index, and Short Physical Performance Battery score associated with frailty criteria. After a 6-month coaching program, the prefrail group showed significant improvement in usual gait speed (mean 0.73 [SD 0.11] vs mean 0.96 [SD 0.27], P=.02), International Physical Activity Questionnaire scores in kcal (mean 2790.36 [SD 2224.62] vs mean 7589.72 [SD 4452.52], P=.01), and European Quality of Life-5 Dimensions score (mean 0.84 [SD 0.07] vs mean 0.90 [SD 0.07], P=.02), although no significant improvement was found in the robust group. The average total step count was significantly different and was approximately four times higher in the coaching period than in the self-management period (5,584,295.83 vs 1,289,084.66, P<.001). We found that participants in the "long-self" group who used the wearable device for the longest time showed increased body weight and body mass index by mean 0.65 (SD 1.317) and mean 0.097 (SD 0.513), respectively, compared with the other groups., Conclusions: Our "Smart Walk" program improved physical fitness, anthropometric measurements, and geriatric assessment categories in a small group of older adults in rural areas with limited resources for monitoring. Further validation through various rural public health centers and in a large number of rural older adults is required., (©Il-Young Jang, Hae Reong Kim, Eunju Lee, Hee-Won Jung, Hyelim Park, Seon-Hee Cheon, Young Soo Lee, Yu Rang Park. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 21.11.2018.)

Purpose: The primary aim of this study was to evaluate the effectiveness of a 6-month multicomponent intervention on physical function in socioeconomically vulnerable older adults in rural communities. As secondary aims, we evaluated the effectiveness of the intervention on frailty and other geriatric syndromes, sustained benefit at 12 months, and baseline characteristics associated with poor response., Patients and Methods: This designed-delay study was conducted in 187 adults (mean age: 77 years; 75% women) who were living alone or on a low income in three rural regions of Korea. A 24-week multicomponent program that consisted of group exercise, nutritional supplementation, depression management, deprescribing medications, and home hazard reduction was implemented with a planned 6-month interval from August 2015 through January 2017. The primary outcome was physical function, measured using the Short Physical Performance Battery (SPPB) score (range: 0-12; minimum clinically important difference ≥1) at 6 months. Secondary outcomes included frailty phenotype, sarcopenia, Mini Nutritional Assessment-Short Form score (range: 0-14), Center for Epidemiologic Studies-Depression Scale score (range: 0-60), and falls., Results: At 6 months, the SPPB score increased by 3.18 points (95% CI: 2.89, 3.48) from baseline. The program improved frailty (odds ratio: 0.06; 95% CI: 0.02, 0.16), sarcopenia (odds ratio: 0.32; 95% CI: 0.15, 0.68), Mini Nutritional Assessment-Short Form score by 1.67 points (95% CI: 1.28, 2.06), and Center for Epidemiologic Studies-Depression Scale score by -3.83 points (95% CI: -5.26, -2.39), except for fall (rate ratio: 0.99; 95% CI: 0.69, 1.43). These beneficial effects were sustained at 12 months. Body mass index ≥27 kg/m 2 and instrumental activities of daily living disability at baseline were associated with poor improvement in the SPPB score., Conclusion: This 24-week multicomponent program had sustained beneficial effects up to 1 year on physical function, frailty, sarcopenia, depressive symptoms, and nutritional status in socioeconomically vulnerable older adults in rural communities. (ClinicalTrials.gov, NCT 02554994)., Competing Interests: Disclosure Dr Dae Hyun Kim is a consultant to Alosa Health, a nonprofit educational organization with no relationship to any drug or device manufacturer. The other authors declare that there is no potential conflict of interests regarding the publication of this article.

Purpose: Bioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotective effects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effects of EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs)., Materials and Methods: EV solutions (0.4 μg/μL) derived from normoxia-preconditioned MSCs (EV(NM)) and hypoxia-preconditioned MSCs (EV(HM)) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26 staining in hearts from EV-treated rats., Results: EV(HM) significantly reduced infarct size (24±2% vs. 8±1%, p<0.001), and diminished arrhythmias by recovering electrical conduction, I(Na) current, and Cx43 expression. EV(HM) also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3β induced after IR injury. miRNA-26a was significantly increased in EV(HM), compared with EV(NM), in real-time PCR. Finally, in in vitro experiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a., Conclusion: EV(HM) reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. These findings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018.)

Naturally occurring RNA carriers such as exosomes might be an untapped source of effective delivery vehicles. However, if exosomes are to be exploited for therapeutic applications, they must target specific tissues or cell types to avoid off-target effects. This study evaluated whether genetic modification of exosomes could enhance exosome delivery to heart cells and heart tissue without toxicity. Exosomes expressing cardiac-targeting peptide (CTP)-Lamp2b on the exosomal membrane (CTP-Exo) were generated by introducing vectors encoding CTP-Lamp2b into HEK 293 cells. The expression of CTP-Lamp2b peptide on exosomes was stabilized by attaching glycosylation sequences. Exosomes expressing only Lamp2b on exosomal membranes (CTL-Exo) were generated as a control. The in vitro and in vivo uptake of CTL-Exo and CTP-Exo was evaluated in cell lines and mice. Both exosomes were delivered to HEK 293 and H9C2 cells. The delivery of the exosome was not different between CTP-Exo and CTL-Exo in HEK 293 cells, whereas the delivery of CTP-Exo was 16% greater than that of CTL-Exo in H9C2 cells (P = 0.047). Cell viability was maintained at almost 100% with different dosages of both CTL-Exo and CTP-Exo. Moreover, compared with CTL-Exo, the in vivo delivery of exosomes to the hearts of mice was increased by 15% with CTP-Exo (P = 0.035). The delivery to livers and spleens was not different between the two exosomes. Genetic modification of exosomes by expressing CTP-Lamp2b on the exosomal membrane enhanced exosome delivery to heart cells and the heart tissue. These results suggested that CTP-Exo might be used as a therapeutic tool for heart disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Left stellectomy has become an important therapeutic option for patients with potentially fatal arrhythmias. However, the antiarrhythmic mechanism of left stellectomy is not well known. The cholinergic anti-inflammatory pathway (CAIP) is a complex immune mechanism that regulates peripheral inflammatory responses., Objective: The purpose of this study was to evaluate the effect of left stellectomy on CAIP using rat experimental autoimmune myocarditis (EAM) models., Methods: EAM was produced by injecting 2 mg of porcine cardiac myosin into the footpads of rats. Left stellectomy was performed before EAM induction. We evaluated the effect of left stellectomy on arrhythmic events, survival, inflammation, and CAIP in rats without and with EAM., Results: Left stellectomy prevented arrhythmia and improved survival in EAM rats. Left stellectomy decreased the levels of tumor necrosis factor α, interleukin 6, and high mobility group box 1 (P < .05 vs EAM) in serum and heart tissues from EAM rats. In heart rate variability analysis, high-frequency peaks of the power spectrum densities, reflecting parasympathetic cardiovagal tone, were significantly decreased in EAM rats, but increased after left stellectomy. The ratios of phosphorylated STAT3/STAT3 (signal transducer and activator of transcription 3) and phosphorylated JAK2/JAK2 (Janus kinase 2) decreased in cell lysates of the spleen, liver, and heart in EAM rats. However, the same ratios significantly increased after left stellectomy. Nuclear factor κB in cell lysates of the spleen, liver, and heart increased in EAM rats, but decreased after left stellectomy., Conclusion: In EAM models, left stellectomy increased survival of the rats while showing antiarrhythmic effects with reduced inflammation via activation of the JAK2-STAT3-mediated signaling cascade. Our findings suggest an exciting opportunity to develop new and novel therapeutics to attenuate cardiac inflammation., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy., Materials and Methods: We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP)., Results: During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP., Conclusion: Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018)

IK can downregulate interferon-gamma-induced major histocompatibility complex (MHC) class II expression through the MHC class II transactivator, which suggests that IK can inhibit the interactions between immune cells. We delivered adeno-associated virus serotype 2 (AAV2) encoding the genes for truncated IK (tIK) or green fluorescent protein (GFP) to DBA1/J mice via intravenous injection. Seven weeks after injection, collagen-induced arthritis was induced in the AAV2-treated mice. AAV2-tIK injection reduced the severity of arthritis and the percentage of pathogenic Th17 cells compared with AAV2-GFP injection. These results suggest a novel gene therapy strategy for treatment of inflammatory arthritis.

Continuous monitoring of an arterial pulse using a pressure sensor attached on the epidermis is an important technology for detecting the early onset of cardiovascular disease and assessing personal health status. Conventional pulse sensors have the capability of detecting human biosignals, but have significant drawbacks of power consumption issues that limit sustainable operation of wearable medical devices. Here, a self-powered piezoelectric pulse sensor is demonstrated to enable in vivo measurement of radial/carotid pulse signals in near-surface arteries. The inorganic piezoelectric sensor on an ultrathin plastic achieves conformal contact with the complex texture of the rugged skin, which allows to respond to the tiny pulse changes arising on the surface of epidermis. Experimental studies provide characteristics of the sensor with a sensitivity (≈0.018 kPa -1 ), response time (≈60 ms), and good mechanical stability. Wireless transmission of detected arterial pressure signals to a smart phone demonstrates the possibility of self-powered and real-time pulse monitoring system., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Inhibitor K562 (IK) protein was first isolated from the culture medium of K562, a leukemia cell line. It is known to be an inhibitory regulator of interferon-γ-induced major histocompatibility complex class (MHC) II expression. Previously, we found that transgenic (Tg) mice constitutively expressing truncated IK (tIK) showed reduced numbers of pathogenic Th1 and Th17 cells, which are known to be involved in the development of rheumatoid arthritis (RA). Here, we investigated whether exogenous tIK protein has a therapeutic effect in arthritis in disease models and analyzed its mechanism. Exogenous tIK protein was produced in an insect expression system and applied to the collagen antibody-induced arthritis (CAIA) mouse disease model. Injection of tIK protein alleviated the symptoms of arthritis in the CAIA model and reduced Th1 and Th17 cell populations. In addition, treatment of cultured T cells with tIK protein induced expression of A20, a negative regulator of nuclear factor-κB (NFκB)-induced inflammation, and reduced expression of several transcription factors related to T cell activation. We conclude that exogenous tIK protein has the potential to act as a new therapeutic agent for RA patients, because it has a different mode of action to biopharmaceutical agents, such as tumor necrosis factor antagonists, that are currently used to treat RA., Competing Interests: The authors declared no conflicts of interest.

The level of antibody production induced by a vaccine involves a variety of host factors. One of these, insulin-like growth factor-1 (IGF-1), plays an important role in lymphocyte maturation and antibody expression. Here, we investigated the role of macrophage-derived IGF-1 in the induction of influenza vaccine-specific antibodies using macrophage-derived IGF-1 gene knockout (MIKO) mice. The titers of vaccine-specific total immunoglobulin G (IgG) and IgG1 after immunization were about two- to fourfold lower in MIKO mice than in WT mice. Moreover, MIKO mice showed a relatively weak booster effect of repeated immunization. In contrast, antigen-nonspecific total IgG was about threefold higher in MIKO mice than in WT mice. After viral challenge, the viral titer and the pathological damage in lungs of MIKO mice were higher than those in WT mice despite vaccination. Interestingly, the proportions of proinflammatory immune cells including M1 macrophages, Th1 and Th17 cells was higher in unvaccinated MIKO mice than in unvaccinated WT mice. This suggests that nonspecific activation of immune cells may paradoxically impair the response to the vaccine. In addition, although the proportions of T follicular helper (Tfh) cells and GL-7 + germinal center (GC) B cells were higher in MIKO mice than in WT mice, the population of CD138 + B220 + antibody-secreting plasmablasts was lower in MIKO mice, which may be a cause of the low influenza-specific antibody titer in MIKO mice. Taken together, these results suggest that macrophage-derived IGF-1 might play an important role in the vaccine-triggered immune response by regulating immune cell homeostasis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Adverse health effects of ambient particulate matter (PM) have been demonstrated in humans, mostly in terms of respiratory and cardiovascular events. However, whether ambient particle could affect the eyes had not been fully revealed., Objective: This study investigated the effect of acute respiratory exposure to PM on eyes., Methods: Diesel exhaust product (DEP) of 200 mg/l was given endotracheally in Sprague-Dawley rats for 1 h (n = 12) and compared to normal control (n = 4). We enucleated eyes and histologically evaluated. Immunohistochemical stains for CD34 (Dako, Glostrup, Denmark, 1:50) and Ki-67 (DakoCytomation, Glostrup, Denmark, 1:150) were performed to evaluate new vessel formation and proliferation activity., Results: After endotracheal DEP exposure, the thickness of retina was significantly increased to 258 ± 96 μm in DEP group, while that of control was 113 ± 9 μm (p = 0.025). Among the retinal structure, inner plexiform, inner and outer nuclear and rod/cone cell layers were significantly thickened (p = 0.00, 0.017, 0.004, 0.001, respectively). The outer plexiform layer of DEP group showed a tendency of thickening, but statistically insignificant. The afferent fiber and ganglion cell layer showed no thickness difference between two groups, but prominent capillaries with congestion were noted in DEP group. Neither neovascularization nor increased proliferation was demonstrated on CD34 and Ki-67 immunohistochemical staining in DEP group., Conclusion: This study shows that the acute respiratory exposure of ambient PM increased retinal thickness, especially inner plexiform, inner and outer nuclear and rod/cone cell layers. We thought that increase of retinal thickness in DEP group resulted in hypoxia-induced edema.

Expression of receptor for advanced glycation end-products (RAGE) is suggested to play a crucial role in mediating cardiac ischemia/reperfusion (IR) injury, and the blockade of RAGE signaling has been considered as a potential therapeutic strategy for the treatment of IR-induced cardiac damage. In this study, we primarily investigated the effects of RAGE suppression particularly on IR-induced ventricular arrhythmia. To inhibit the IR-induced upregulation of RAGE, siRNA targeting RAGE (siRAGE) was delivered to myocardium by using deoxycholic acid-modified polyethylenimine (PEI-DA) as a non-viral gene carrier. The resultant PEI-DA/siRAGE nanocomplexes successfully silenced the expression of RAGE and attenuated the inflammation and apoptosis in the ischemic-reperfused myocardium. According to our results, the electrophysiological properties (e.g., action potential propagation, action potential duration, and conduction velocity), disrupted by IR injury, were restored to normal level and the induction of ventricular tachycardia was abolished by RAGE silencing. We further found that RAGE suppression led to the activation of Wnt signaling, followed by the expression of gap junction protein, connexin43. Thus it could be concluded that successful siRAGE delivery is protective against IR-induced ventricular arrhythmia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia., Methods and Results: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a(-/-)) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a(-/-)mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a(-/-)mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a(-/-)LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a(-/-)mice., Conclusions: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.

A flexible single-crystalline PMN-PT piezoelectric energy harvester is demonstrated to achieve a self-powered artificial cardiac pacemaker. The energy-harvesting device generates a short-circuit current of 0.223 mA and an open-circuit voltage of 8.2 V, which are enough not only to meet the standard for charging commercial batteries but also for stimulating the heart without an external power source., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Because fatal arrhythmia is an important cause of death in patients with myocarditis, we investigated the proarrhythmic mechanisms of experimental autoimmune myocarditis. METHODS AND RESULTS: Myocarditis was induced by injection of 2 mg porcine cardiac myosin into the footpads of adult Lewis rats on days 1 and 8 (Myo, n=15) and the results compared with Control rats (Control, n=15). In an additional 15 rats, 6 mg/kg prednisolone was injected into the gluteus muscle before the injection of porcine cardiac myosin on days 1 and 8 (MyoS, n=15). Hearts with myocarditis had longer action potential duration (APD), slower conduction velocity (CV; P<0.01 vs. Control), higher CV heterogeneity, greater fibrosis, higher levels of immunoblotting of high-mobility group protein B1, interleukin 6 and tumor necrosis factor-α proteins. Steroid treatment partially reversed the translations for myocarditis, CV heterogeneity, reduced APD at 90% recovery to baseline, increased CV (P<0.01), and reversed fibrosis (P<0.05). Programmed stimulation triggered sustained ventricular tachycardia in Myo rats (n=4/5), but not in controls (n=0/5) or Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor (KN93) treated Myo rats (n=0/5, P=0.01). CaMKII autophosphorylation at Thr287 (201%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 126%) and Ser2814 (CaMKII site, 21%) were increased in rats with myocarditis and reversed by steroid., Conclusions: The myocarditis group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca(2+)handling proteins. These changes were partially reversed by an antiinflammatory treatment and CaMKII inhibition.

Background: The cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO)., Methods and Results: 9 week old Apo E KO mice were infused subcutaneously with AngII (1 µg/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 µg, 1 µg, to 2 µg/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 µg, 1 µg, and 2 µg of sRAGE in AngII group resulted in the dose-dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells., Conclusion: The results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII-induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by particulate matter (PM) isolated from ambient air and linked to prolonged repolarization and cardiac arrhythmia. We evaluated whether alpha B-crystallin (CryAB), a heat shock protein, could prevent the arrhythmogenic effects of PM by preventing CaMKII activation. CryAB was delivered into cardiac cells using a TAT-protein transduction domain (TAT-CryAB). ECGs were measured before and after tracheal exposure of diesel exhaust particles (DEP) and each intervention in adult Sprague-Dawley rats. After endotracheal exposure of DEP (200 μg/mL for 30 minutes, n=11), QT intervals were prolonged from 115±14 ms to 144±20 ms (p=0.03), and premature ventricular contractions were observed more frequently (0% vs. 44%) than control (n=5) and TAT-Cry (n=5). However, DEP-induced arrhythmia was not observed in TAT-CryAB (1 mg/kg) pretreated rats (n=5). In optical mapping of Langendorff-perfused rat heats, compared with baseline, DEP infusion of 12.5 μg/mL (n=12) increased apicobasal action potential duration (APD) differences from 2±6 ms to 36±15 ms (p<0.001), APD restitution slope from 0.26±0.07 to 1.19±0.11 (p<0.001) and ventricular tachycardia (VT) from 0% to 75% (p<0.001). DEP infusion easily induced spatially discordant alternans. However, the effects of DEP were prevented by TAT-CryAB (1mg/kg, n=9). In rat myocytes, while DEP increased reactive oxygen species (ROS) generation and phosphated CaMKII, TAT-CryAB prevented these effects. In conclusion, CryAB, a small heat shock protein, might prevent the arrhythmogenic effects of PM by attenuating ROS generation and CaMKII activation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ambient particulate matter (PM) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of PM is poorly understood. This study investigated the arrhythmogenic mechanism of PM. In Sprague-Dawley rats, QT interval was increased from 115.0±14.0 to 142.1±18.4ms (p=0.02) after endotracheal exposure of DEP (200μg/ml for 30min, n=5). Ventricular premature contractions were more frequently observed after DEP exposure (100%) than baseline (20%, p=0.04). These effects were prevented by pretreatment of N-acetylcysteine (NAC, 5mmol/L, n=3). In 12 Langendorff-perfused rat hearts, DEP infusion of 12.5μg/ml for 20min prolonged action potential duration (APD) at only left ventricular base increasing apicobasal repolarization gradients. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any hearts before DEP infusion. DEP-induced APD prolongation, EAD and VT were successfully prevented with NAC (5mmol/L, n=5), nifedipine (10μmol/L, n=5), and active Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1μmol/L, n=5), but not by thapsigargin (200nmol/L) plus ryanodine (10μmol/L, n=5) and inactive CaMKII blockade, KN 92 (1μmol/L, n=5). In neonatal rat cardiomyocytes, DEP provoked ROS generation in dose dependant manner. DEP (12.5μg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Thus, this study shows that in vivo and vitro exposure of PM induced APD prolongation, EAD and ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation., (Copyright © 2012 Elsevier Inc. All rights reserved.)