Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via ...molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions.
Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by memory decline and cognitive dysfunction. Although the primary causes of AD are not clear, it is widely ...accepted that the accumulation of amyloid beta (Aβ) and consecutive hyper-phosphorylation of tau, synaptic loss, oxidative stress and neuronal death might play a vital role in AD pathogenesis. Recently, it has been widely suggested that extracellular vesicles (EVs), which are released from virtually all cell types, are a mediator in regulating AD pathogenesis. Clinical evidence for the diagnostic performance of EV-associated biomarkers, particularly exosome biomarkers in the blood, is also emerging. In this review, we briefly introduce the biological function of EVs in the central nervous system and discuss the roles of EVs in AD pathogenesis. In particular, the roles of EVs associated with autophagy and lysosomal degradation systems in AD proteinopathy and in disease propagation are discussed. Next, we summarize candidates for biochemical AD biomarkers in EVs, including proteins and miRNAs. The accumulating data brings hope that the application of EVs will be helpful for early diagnostics and the identification of new therapeutic targets for AD. However, at the same time, there are several challenges in developing valid EV biomarkers. We highlight considerations for the development of AD biomarkers from circulating EVs, which includes the standardization of pre-analytical sources of variability, yield and purity of isolated EVs and quantification of EV biomarkers. The development of valid EV AD biomarkers may be facilitated by collaboration between investigators and the industry.
In patients with hypertension, left ventricular hypertrophy (LVH) represents a risk factor for cardiovascular disease and asymptomatic organ damage. Currently, electrocardiography (ECG) and ...two‐dimensional echocardiography (Echo) are the most widely used methods for LVH evaluation. This study aimed to compare the long‐term outcomes of LVH, as evaluated by ECG and Echo, in patients with hypertension. Patients diagnosed with hypertension as a primary disease between 2006 and 2011 were enrolled in the Korean Hypertension Cohort study. The study finally included 1743 patients who underwent both ECG and Echo. The primary endpoint was defined as the composite of major adverse cardiovascular events (MACEs) or death. Overall, LVH was identified in 747 patients. The patients were categorized into four groups according to the detection of LVH by ECG or Echo: No LVH (n = 996), LVH diagnosed by ECG alone (n = 181), LVH diagnosed by Echo alone (n = 415), LVH diagnosed by both ECG and Echo (n = 151). After adjusting for variables, the incidence of MACEs or death was significantly greater in patients with LVH diagnosed by ECG alone (hazards ratio HR: 1.69; 95% confidence interval CI: 1.22–2.35; P = .001), LVH diagnosed by Echo alone (HR: 1.54; 95% CI: 1.16–2.05; P = .002), and LVH diagnosed by both ECG and Echo (HR: 1.87; 95% CI: 1.18–2.94; P = .002) than in those with no LVH. Both ECG and Echo are efficient diagnostic tools for LVH and useful for long‐term risk stratification. Additional Echo evaluation for LVH is helpful for predicting long‐term outcomes only in patients without LVH diagnosis by ECG.
In this study, we examined the effect of different fractions and components of Chaga mushroom (Inonotus Obliquus) on viability and apoptosis of colon cancer cells. Among them, one component showed ...the most effective growth inhibition and was identified as ergosterol peroxide by NMR analysis. We investigated the anti-proliferative and apoptosis mechanisms of ergosterol peroxide associated with its anti-cancer activities in human colorectal cancer (CRC) cell lines and tested its anti-tumor effect on colitis-induced CRC developed by Azoxymethane (AOM)/Dextran sulfate sodium (DSS) in a mouse model.
We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, Western blot analysis, colony formation assays, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and AOM/DSS mouse models to study the molecular mechanism of metastatic activities in CRC cells.
Ergosterol peroxide inhibited cell proliferation and also suppressed clonogenic colony formation in HCT116, HT-29, SW620 and DLD-1 CRC cell lines. The growth inhibition observed in these CRC cell lines was the result of apoptosis, which was confirmed by FACS analysis and Western blotting. Ergosterol peroxide inhibited the nuclear levels of β-catenin, which ultimately resulted in reduced transcription of c-Myc, cyclin D1, and CDK-8. Ergosterol peroxide administration showed a tendency to suppress tumor growth in the colon of AOM/DSS-treated mice, and quantification of the IHC staining showed a dramatic decrease in the Ki67-positive staining and an increase in the TUNEL staining of colonic epithelial cells in AOM/DSS-treated mice by ergosterol peroxide for both prevention and therapy.
Our data suggest that ergosterol peroxide suppresses the proliferation of CRC cell lines and effectively inhibits colitis-associated colon cancer in AOM/DSS-treated mice. Ergosterol peroxide down-regulated β-catenin signaling, which exerted anti-proliferative and pro-apoptotic activities in CRC cells. These properties of ergosterol peroxide advocate its use as a supplement in colon cancer chemoprevention.
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Skin flaps are necessary in plastic and reconstructive surgery for the removal of skin cancer, wounds, and ulcers. A skin flap is a portion of skin with its own blood supply that is partially ...separated from its original position and moved from one place to another. The use of skin flaps is often accompanied by cell necrosis or apoptosis due to ischemia-reperfusion (I/R) injury. Proinflammatory cytokines, such as nuclear factor kappa B (NF-κB), inhibitor of kappa B (IκB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and oxygen free radicals are known causative agents of cell necrosis and apoptosis. To prevent I/R injury, many investigators have suggested the inhibition of proinflammatory cytokines, stem-cell therapies, and drug-based therapies. Ischemic preconditioning (IPC) is a strategy used to prevent I/R injury. IPC is an experimental technique that uses short-term repetition of occlusion and reperfusion to adapt the area to the loss of blood supply. IPC can prevent I/R injury by inhibiting proinflammatory cytokine activity. Various stem cell applications have been studied to facilitate flap survival and promote angiogenesis and vascularization in animal models. The possibility of constructing tissue engineered flaps has also been investigated. Although numerous animal studies have been published, clinical data with regard to IPC in flap reconstruction have never been reported. In this study, we present various experimental skin flap methods, IPC methods, and methods utilizing molecular factors associated with IPC.
Hypertension is a chronic disease that requires long‐term follow‐up in many patients, however, optimal visit intervals are not well‐established. This study aimed to evaluate the incidences of major ...cardiovascular events (MACEs) according to visit intervals. We analyzed data from 9894 hypertensive patients in the Korean Hypertension Cohort, which enrolled and followed up 11,043 patients for over 10 years. Participants were classified into five groups based on their median visit intervals (MVIs) during the 4‐year period and MACEs were compared among the groups. The patients were divided into clinically relevant MVIs of one (1013; 10%), two (1299; 13%), three (2732; 28%), four (2355; 24%), and six months (2515; 25%). The median follow‐up period was 5 years (range: 1745 ± 293 days). The longer visit interval groups did not have an increased cumulative incidence of MACE (12.9%, 11.8%, 6.7%, 5.9%, and 4%, respectively). In the Cox proportional hazards model, those in the longer MVI group had a smaller hazard ratio (HR) for MACEs or all‐cause death: 1.77 (95% confidence interval CI, 1.45–2.17), 1.7 (95% CI: 1.41–2.05), 0.90 (95% CI: 0.74–1.09) and 0.64 (95% CI: 0.52–0.79), respectively (Reference MVI group of 75–104 days). In conclusion, a follow‐up visits with a longer interval of 3–6 months was not associated with an increased risk of MACE or all‐cause death in hypertensive patients. Therefore, once medication adjustment is stabilized, a longer interval of 3–6 months is reasonable, reducing medical expenses without increasing the risk of cardiovascular outcomes.
Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, ...medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin
software version 8.1 (a Certara™ company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters.
In recent years, many researchers have aimed to construct robotic soft grippers that can handle fragile or unusually shaped objects without causing damage. This study proposes a smart ...textile-composite actuator and its application to a soft robotic gripper. An active fiber and an inactive fiber are combined together using knitting techniques to manufacture a textile actuator. The active fiber is a shape memory alloy (SMA) that is wire-wrapped with conventional fibers, and the inactive fiber is a knitting yarn. A knitted textile structure is flexible, with an excellent structure retention ability and high compliance, which is suitable for developing soft grippers. A driving source of the actuator is the SMA wire, which deforms under heating due to the shape memory effect. Through experiments, the course-to-wale ratio, the number of bundling SMA wires, and the driving current value needed to achieve the maximum deformation of the actuator were investigated. Three actuators were stitched together to make up each finger of the gripper, and layer placement research was completed to find the fingers' suitable bending angle for object grasping. Finally, the gripping performance was evaluated through a test of grasping various object shapes, which demonstrated that the gripper could successfully lift flat/spherical/uniquely shaped objects.
Multi‐valued logic (MVL) technology that utilizes more than two logic states has recently been reconsidered because of the demand for greater power saving in current binary logic systems. Extensive ...efforts have been invested in developing MVL devices with multiple threshold voltages by adopting negative differential transconductance and resistance. In this study, a reconfigurable, multiple negative‐differential‐resistance (m‐NDR) device with an electric‐field‐induced tunability of multiple threshold voltages is reported, which comprises a BP/ReS2 heterojunction and a ReS2/h‐BN/metal capacitor. Tunability for the m‐NDR phenomenon is achieved via the resistance modulation of the ReS2 layer by electrical pulses applied to the capacitor region. Reconfigurability is verified in terms of the function of an MVL circuit composed of a reconfigurable m‐NDR device and a load transistor, wherein staggered‐type and broken‐type double peak‐NDR device operations are adopted for ternary inverter and latch circuits, respectively.
A reconfigurable, multiple negative‐differential‐resistance device with an electric‐field‐induced tunability of multiple threshold voltages is proposed. Following the successful verification of the tunability of multiple negative‐differential‐resistance phenomenon, the reconfigurability in terms of the function of multi‐valued logic circuits, from ternary inverter to latch circuit, is demonstrated.
To investigate the impacts of depression screening, diagnosis and treatment on major adverse cardiac events (MACEs) in acute coronary syndrome (ACS).
Prospective cohort study including a nested ...24-week randomised clinical trial for treating depression was performed with 5-12 years after the index ACS. A total of 1152 patients recently hospitalised with ACS were recruited from 2006 to 2012, and were divided by depression screening and diagnosis at baseline and 24-week treatment allocation into five groups: 651 screening negative (N), 55 screening positive but no depressive disorder (S), 149 depressive disorder randomised to escitalopram (E), 151 depressive disorder randomised to placebo (P) and 146 depressive disorder receiving medical treatment only (M).
Cumulative MACE incidences over a median 8.4-year follow-up period were 29.6% in N, 43.6% in S, 40.9% in E, 53.6% in P and 59.6% in M. Compared to N, screening positive was associated with higher incidence of MACE adjusted hazards ratio 2.15 (95% confidence interval 1.63-2.83). No differences were found between screening positive with and without a formal depressive disorder diagnosis. Of those screening positive, E was associated with a lower incidence of MACE than P and M. M had the worst outcomes even compared to P, despite significantly milder depressive symptoms at baseline.
Routine depression screening in patients with recent ACS and subsequent appropriate treatment of depression could improve long-term cardiac outcomes.
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