ABSTRACT
The seeds of Cassia tora (C. tora) species mainly contain anthraquinone, anthraquinone glycoside, and naphthalene derivatives. We investigated the anti-apoptotic effects of C. tora seed extract and its isolated compounds on blue-light-induced lipofuscin (A2E)-loaded human retinal pigment epithelial (RPE) cells. For analysis of the C. tora extract, high-performance liquid chromatography method was used. A2E-loaded human retinal pigment epithelial cells and blue light were used to create excessive photo-oxidation to induce cell death. Lactate dehydrogenase (LDH) assay was used to measure cell cytotoxicity, and the mRNA expression of genes involved in apoptosis was examined to evaluate the mechanism of cell death. C. tora extract, n-hexane fraction, and chrysophanol were found to inhibit apoptotic cell death. Additionally, C. tora extract, n-hexane fraction, and chrysophanol reduced the mRNA expression of genes involved in the apoptosis pathway. C. tora and chrysophanol were considered to inhibit apoptosis and oxidative stress response. The major component of C. tora has a protective effect against apoptosis. The ingredients of C. tora can be used as therapeutic substances or to prevent diseases caused by the excessive oxidation of A2E substances in the retina, such as in age-related macular degeneration.
Subject(s)
Cassia , Humans , Cassia/genetics , Anthraquinones/pharmacology , Anthraquinones/metabolism , Light , Plant Extracts/chemistry , Retinal Pigments/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Epithelial Cells/metabolism , Seeds/metabolism , Retinal Pigment Epithelium/metabolism , Retinoids/pharmacologyABSTRACT
Astigmatism is a prevalent optical problem in which two or more focal points blur the retinal image at a particular meridian. Although many features of astigmatic vision, including orientation perception, are impaired at the retinal image level, the visual system appears to partly restore perceptual impairment after an extended period of astigmatism. However, the mechanism of orientation perception restoration in chronic astigmatism has not yet been clarified. We investigated the notable reduction of perceptual error in chronic astigmatism by comparing the orientation perception of a chronic astigmatism group with the perception of a normal-vision group, in which astigmatism was transiently induced. We found that orientation perception in the chronic group was more accurate than in the normal vision group. Interestingly, the reduction of perceptual errors was automatic; it remained even after the optical refractive errors were fully corrected, and the orientation perception was much more stable across different orientations, despite the uneven noise levels of the retinal images across meridians. We provide here a mechanistic explanation for how the compensation of astigmatic orientation perception occurred, using neural adaptation to the biased distribution of orientations.
Subject(s)
Astigmatism , Refractive Errors , Adaptation, Physiological , Humans , PerceptionABSTRACT
Chronic exposure to bile acid in the liver due to impaired bile flow induces cholestatic liver disease, resulting in hepatotoxicity and liver fibrosis. Sestrin2, a highly conserved, stress-inducible protein, has been implicated in cellular responses to multiple stress conditions and the maintenance of cellular homeostasis. However, its role in cholestatic liver injury is not fully understood. In this study, we investigated the role of hepatic Sestrin2 in cholestatic liver injury and its underlying mechanisms using in vivo and in vitro approaches. Hepatic Sestrin2 expression was upregulated by activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-ß (C/EBP-ß) after treatment with bile acids and correlated with endoplasmic reticulum (ER) stress responses. Bile-duct ligation (BDL)-induced hepatocellular apoptosis and liver fibrosis were exacerbated in Sestrin2-knockout (Sesn2-/-) mice. Moreover, Sestrin2 deficiency enhanced cholestasis-induced hepatic ER stress, whereas Sestrin2 overexpression ameliorated bile acid-induced ER stress. Notably, the mammalian target of rapamycin (mTOR) inhibitor rapamycin and the AMP-activated protein kinase (AMPK) activator AICAR reversed bile acid-induced ER stress in Sestrin2-deficient cells. Furthermore, Sestrin2 deficiency promoted cholestasis-induced hepatic pyroptosis by activating NLRP3 inflammasomes. Thus, our study provides evidence for the biological significance of Sestrin2 and its relationship with cholestatic liver injury, suggesting the potential role of Sestrin2 in regulating ER stress and inflammasome activation during cholestatic liver injury.
Subject(s)
Cholestasis , Inflammasomes , Peroxidases , Animals , Cholestasis/metabolism , Endoplasmic Reticulum Stress , Inflammasomes/metabolism , Liver/metabolism , Mammals/metabolism , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Peroxidases/genetics , Pyroptosis , Signal TransductionABSTRACT
A small physical change in the eye influences the entire neural information process along the visual pathway, causing perceptual errors and behavioral changes. Astigmatism, a refractive error in which visual images do not evenly focus on the retina, modulates visual perception, and the accompanying neural processes in the brain. However, studies on the neural representation of visual stimuli in astigmatism are scarce. We investigated the relationship between retinal input distortions and neural bias in astigmatism and how modulated neural information causes a perceptual error. We induced astigmatism by placing a cylindrical lens on the dominant eye of human participants, while they reported the orientations of the presented Gabor patches. The simultaneously recorded electroencephalogram activity revealed that stimulus orientation information estimated from the multivariate electroencephalogram activity was biased away from the neural representation of the astigmatic axis and predictive of behavioral bias. The representational neural dynamics underlying the perceptual error revealed the temporal state transition; it was transiently dynamic and unstable (approximately 350 ms from stimulus onset) that soon stabilized. The biased stimulus orientation information represented by the spatially distributed electroencephalogram activity mediated the distorted retinal images and biased orientation perception in induced astigmatism.
Subject(s)
Astigmatism/physiopathology , Cerebral Cortex/physiology , Pattern Recognition, Visual/physiology , Space Perception/physiology , Adult , Electroencephalography , Female , Humans , Male , Young AdultABSTRACT
BACKGROUND: In-hospital mortality and short-term mortality are indicators that are commonly used to evaluate the outcome of emergency department (ED) treatment. Although several scoring systems and machine learning-based approaches have been suggested to grade the severity of the condition of ED patients, methods for comparing severity-adjusted mortality in general ED patients between different systems have yet to be developed. The aim of the present study was to develop a scoring system to predict mortality in ED patients using data collected at the initial evaluation and to validate the usefulness of the scoring system for comparing severity-adjusted mortality between institutions with different severity distributions. METHODS: The study was based on the registry of the National Emergency Department Information System, which is maintained by the National Emergency Medical Center of the Republic of Korea. Data from 2016 were used to construct the prediction model, and data from 2017 were used for validation. Logistic regression was used to build the mortality prediction model. Receiver operating characteristic curves were used to evaluate the performance of the prediction model. We calculated the standardized W statistic and its 95% confidence intervals using the newly developed mortality prediction model. RESULTS: The area under the receiver operating characteristic curve of the developed scoring system for the prediction of mortality was 0.883 (95% confidence interval [CI]: 0.882-0.884). The Ws score calculated from the 2016 dataset was 0.000 (95% CI: - 0.021 - 0.021). The Ws score calculated from the 2017 dataset was 0.049 (95% CI: 0.030-0.069). CONCLUSIONS: The scoring system developed in the present study utilizing the parameters gathered in initial ED evaluations has acceptable performance for the prediction of in-hospital mortality. Standardized W statistics based on this scoring system can be used to compare the performance of an ED with the reference data or with the performance of other institutions.
Subject(s)
Emergency Service, Hospital , Hospital Mortality , Humans , Logistic Models , ROC Curve , Republic of KoreaABSTRACT
Oncogenic activation of the mammalian target of rapamycin complex 1 (mTORC1) leads to endometrial cancer cell growth and proliferation. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial-mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer.
ABSTRACT
Achillea millefolium L. (AM) is an aromatic herb with a variety of pharmacological properties, such as anti-inflammatory and anti-allergic activities. However, AM's effects on atopic dermatitis (AD) have not been investigated. This study evaluates the anti-AD activity of 50% ethanol-extracted AM in murine macrophage Raw 264.7 cells, in tumor necrosis factor-alpha/interferon-gamma (TNF-[Formula: see text]/IFN-[Formula: see text])-stimulated human immortal keratinocyte HaCaT cells in vitro, and in Biostir-AD-treated NC/Nga mice in vivo. The results showed that AM significantly downregulated expression of pro-inflammatory cytokines, such as INOS, COX-2, and interleukin (IL)-6 in lipopolysaccharide (LPS)-treated Raw 264.7 cells. The mRNA expressions of INOS, COX-2, and IL-6 decreased by 76.1%, 69.3%, and 31.8%, respectively. Overexpression of chemokines, such as activation-regulated chemokine and macrophage-derived chemokine, regulated on activation of normal T-cell expressed and secreted, and IL-8 was inhibited by 70.01%, 52.91%, 73.53%, and 18.93%, respectively, in TNF-[Formula: see text]/IFN-[Formula: see text]-stimulated HaCaT cells by downregulating the mitogen-activated protein kinase, I[Formula: see text]B[Formula: see text], and the signal transducer and activator of transcription 1 signaling pathways. AD-like symptoms, such as elevated serum immunoglobin E levels, epidermal thickening, high dermatitis severity score, transepidermal water loss, and reduced skin hydration, were relieved by the dietary administration of AM in Biostir-AD-treated NC/Nga mice. In addition, filaggrin expression increased significantly in AM-treated groups. These results suggest that AM could be a useful candidate for AD treatment.
Subject(s)
Achillea/chemistry , Anti-Inflammatory Agents , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Animals , Cytokines/metabolism , Dermatitis, Atopic/drug therapy , Down-Regulation/drug effects , Filaggrin Proteins , Humans , Inflammation Mediators/metabolism , Interferon-gamma/metabolism , Male , Mice , Mice, Inbred Strains , Mitogen-Activated Protein Kinases/metabolism , RAW 264.7 Cells , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Bowel ischemia is a life-threatening surgical emergency. We report a case of rapidly progressive bowel necrosis in a previously healthy child without proven mechanical small bowel obstruction. The definite diagnosis was established at the time of an exploratory operation. Of note, imaging studies and even a laparotomy did not reveal any evidence of acute appendicitis or mechanical obstruction such as intussusception or Meckel's diverticulum. During hospitalization, since we could not rule out surgical abdomen after inconclusive image findings, we closely followed the patient and repeated physical examinations carefully. Eventually surgical exploration was performed based on changes in clinical condition, which proved to be the right decision for the patient. We propose that in children with suspected strangulation of small bowel obstruction, especially when imaging findings do not provide a conclusive diagnosis, the timely exploratory surgical approach ought to be chosen based on carefully observed clinical findings and other evaluations.
ABSTRACT
Obesity and overweight, the most serious health problems, are associated with chronic metabolic complications such as type 2 diabetes, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). However, current pharmacological therapies for obesity are challenged by potential side effects, low effectiveness, and low aqueous solubility, which limit their clinical application. Here, we develop nifedipine-loaded nanoparticles (NFD-NPs) that alleviate obesity-related metabolic dysfunction to be used as instruments for translational medicine. Nanoparticles (NPs) composed of poly (lactic-co-glycolic acid) (PLGA) not only enhance water solubility of hydrophobic nifedipine (NFD), a calcium channel blocker, without modifying the chemical structure of NFD for intravenous administration, but also allow prolonged release of NFD in vivo. NFD-NPs do not show cytotoxicity and reduce palmitate-induced protein inclusions and endoplasmic reticulum stress in human hepatoma HepG2 cells. Importantly, tail-vein injection of NFD-NPs into diet-induced obese mice results in sustained retention of NFD-NPs in the liver and suppression of metabolic derangements associated with NAFLD by enhancing autophagic clearance through Ca2+/calmodulin-dependent kinase II (CaMKII) phosphorylation, consequently decreasing diet-induced insulin resistance and improving glucose tolerance. Our findings offer new clinical tools for NP-mediated pharmaceutical strategies to treat NAFLD and its related metabolic dysfunction.
Subject(s)
Autophagy/drug effects , Calcium Channel Blockers/therapeutic use , Nifedipine/therapeutic use , Non-alcoholic Fatty Liver Disease/drug therapy , Administration, Intravenous , Animals , Calcium Channel Blockers/administration & dosage , Delayed-Action Preparations/chemistry , Endoplasmic Reticulum Stress/drug effects , Hep G2 Cells , Humans , Insulin Resistance , Male , Mice, Inbred C57BL , Nifedipine/administration & dosage , Non-alcoholic Fatty Liver Disease/metabolism , Obesity/drug therapy , Obesity/metabolism , Polylactic Acid-Polyglycolic Acid Copolymer/chemistryABSTRACT
We demonstrate the synthesis of poly(methyl methacrylate) (PMMA) and poly(styrene-b-methyl methacrylate) (P(S-b-MMA)) brushes on crosslinked random copolymer thin films, compositionally varied poly(styrene-r-glycidyl methacrylate) (P(S-r-GMA)), which can be further functionalized with a molecule featuring an initiator group upon crosslinking to form highly stable thin films. With careful optimizations, PMMA brushes were successfully grown from the surfaces of initiator functionalized P(S-r-GMA) via surface-initiated atom transfer radical polymerization. The grafting densities of the PMMA and P(S-b-MMA) brushes were effectively controlled to be in different density regimes by controlling the composition of P(S-r-GMA) and post-crosslinking functionalization methods. Synthesized BCP brushes were stable upon repetitive washing and thermal annealing processes even at high grafting density, highlighting that the outstanding stability of crosslinked P(S-r-GMA) thin films enables close examination of the morphology of thermally annealed P(S-b-MMA) brushes in different grafting density regimes.
Subject(s)
Dexamethasone/adverse effects , Foreign-Body Migration/surgery , Anterior Chamber , Delayed-Action Preparations , Dexamethasone/administration & dosage , Drug Implants , Female , Foreign-Body Migration/diagnosis , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Humans , Macular Edema/drug therapy , Middle Aged , ReoperationABSTRACT
BACKGROUND: Troponin elevation with electrocardiography changes is not uncommon in patients with acute ischemic stroke; however, it is still unclear whether the mechanism of these changes is due to cardiac problems or neurally mediated myocytic damage. Thus, we investigated cardiac and neurological predictors of troponin elevation in those patients. METHODS AND RESULTS: We retrospectively analyzed medical data of the prospectively registered ischemic stroke patients on stroke registry who were admitted and underwent a serum cardiac troponin I and 12-lead electrocardiography within 24 hours of symptom onset. However, patients with well-known troponin-elevating comorbidities were excluded from the analysis. Among 1404 ischemic stroke patients, 121 (8.7%) had elevated troponin, which was defined as more than 0.04 mg/mL. Multivariable analysis identified electrocardiography abnormalities such as QTc-prolongation (odds ratio [OR]: 1.52, 95% CI: 1.02-2.28), left ventricular hypertrophy (OR: 2.14, 95% CI 1.43-3.19), Q-wave (OR: 2.53, 95% CI: 1.48-4.32), and ST elevation (OR: 2.74, 95% CI: 1.12-6.72) as cardiac variables associated with troponin elevation, and higher National Institutes of Health Stroke Scale score (OR: 1.04, 95% CI: 1.01-1.07) and insular cortical lesions (OR: 2.78, 95% CI: 1.85-4.19) as neurological variables associated with troponin elevation. Incidence of troponin elevation as well as QTc-prolongation was increased further in combination with cardiac and neurological factors. CONCLUSIONS: Certain cardiac and neurological conditions in acute ischemic stroke may contribute to troponin elevation. The proposed concept of cardiac vulnerability to cerebrogenic stress can be a practical interpretation of troponin elevation and electrocardiography abnormalities in stroke patients.
Subject(s)
Arrhythmias, Cardiac/blood , Brain Ischemia/blood , Cerebral Cortex/blood supply , Hypertrophy, Left Ventricular/blood , Stroke/blood , Troponin I/blood , Adult , Aged , Aged, 80 and over , Arrhythmias, Cardiac/physiopathology , Brain Ischemia/physiopathology , Electrocardiography , Female , Humans , Hypertrophy, Left Ventricular/physiopathology , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Retrospective Studies , Stroke/physiopathology , Young AdultABSTRACT
BACKGROUND: There are conflicting evidences on endothelial function in lacunar infarction. This may be attributed to the effects of risk factors on the vascular smooth muscle. To test endothelial function only in patients with lacunar infarction, we evaluated the endothelium-dependent and -independent vasodilatation of the brachial artery. METHODS: We enrolled consecutive patients with lacunar infarction defined by clinical characteristics and MRI findings. The control group included age- and sex-matched patients with hypertension who do not have any history of clinical stroke, coronary artery disease or peripheral vascular disease. Endothelial function was evaluated using flow-mediated dilatation (FMD) and nitrogen-mediated dilatation (NMD) of the brachial artery. FMD and NMD were examined by an experienced vascular sonographer using a high-resolution ultrasound. Intracranial stenosis was defined as flow gap or >50% reduction in vessel diameter on MRA. RESULTS: FMD was 6.6 +/- 4.5% in the lacunar infarction group and 12.2 +/- 4.6% in the control group (p = 0.000). NMD was 14.3 +/- 4.9% in the lacunar infarction group and 13.8 +/- 4.9% in the control group (p = 0.37). FMD in patients with lacunar infarction and intracranial arterial stenosis was 6.4 +/- 3.9%, and FMD in patients with lacunar infarction was only 6.9 +/- 5.5%. In the control group, it was 12.2 +/- 4.6%. CONCLUSION: FMD was low in patients with lacunar infarction. NMD was similar between the lacunar infarction group and the control group. These results are suggestive of pure endothelial dysfunction in lacunar infarction. Endothelial dysfunction was as severe in lacunar infarction as in intracranial arterial stenosis.