Ascorbic acid (AsA) is an abundant component of plants and acts as a strong and active antioxidant. In order to maintain the antioxidative capacity of AsA, the rapid regeneration of AsA is regulated ...by dehydroascorbate reductase (DHAR) and monodehydroascorbate reductase (MDHAR). To understand how MDHAR functions under extreme temperature conditions, this study characterized its biochemical properties and determined the crystal structure of MDHAR from the Antarctic hairgrass Deschampsia antarctica (DaMDHAR) at 2.2 Å resolution. This allowed for a structural comparison with the mesophilic MDHAR from Oryza sativa L. japonica (OsMDHAR). In the functional analysis, yeast cells expressing DaMDHAR were tolerant to freezing and thawing cycles. It is possible that the expression of DaMDHAR in yeast enhanced the tolerance for ROS-induced abiotic stress.
Patients’ gender, which can be one of the most important determinants of traumatic brain injury (TBI) outcomes, is also likely to interact with many other outcome variables of TBI. This multicenter ...descriptive study investigated gender differences in epidemiological, clinical, treatment, mortality, and variable characteristics in adult TBI patients.
The selection criteria were defined as patients who had been diagnosed with TBI and were admitted to the hospital between January 1, 2016 and December 31, 2018. A total of 4468 adult TBI patients were enrolled at eight University Hospitals. Based on the list of enrolled patients, the medical records of the patients were reviewed and they were registered online at each hospital. The registered patients were classified into three groups according to the Glasgow coma scale (GCS) score: mild (13–15), moderate (9−12), and severe (3–8), and the differences between men and women in each group were investigated. The risk factors of moderated and severe TBI compared to mild TBI were also investigated.
The study included 3075 men and 1393 women and the proportion of total males was 68.8%. Among all the TBI patients, there were significant differences between men and women in age, past history, and GCS score. While the mild and severe TBI groups showed significant differences in age, past history, and clinical symptoms, the moderate TBI group showed significant differences in age, past history, cause of justice, and diagnosis.
To the best of our knowledge, this multicenter study is the first to focus on gender differences of adult patients with TBI in Korea. This study shows significant differences between men and women in many aspects of adult TBI. Therefore, gender differences should be strongly considered in TBI studies.
Skin color is determined by the melanin pigments that are produced in melanocytes then transferred to surrounding keratinocytes. Despite the growing number of commercial products claiming the ...pigmentation-regulatory effects, there is still a demand for the development of new materials that are safe and more efficacious. We tried to screen the pigmentation-regulatory materials using a commercially available drugs, and found that nilotinib could induce pigmentation in melanoma cells. When HM3KO melanoma cells were treated with nilotinib, melanin content was increased together with increase of tyrosinase activity. Nilotinib increased the expression of pigmentation-related genes such as MITF, tyrosinase and TRP1. Consistent with these results, the protein level for MITF, tyrosinase, and TRP1 was significantly increased by nilotinib. To delineate the action mechanism of nilotinib, we investigated the effects of nilotinib on intracellular signaling. As a result, nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB. The pretreatment of PKA inhibitor H89 markedly blocked the nilotinib-induced phosphorylation of CREB. In accordance with, pretreatment of H89 significantly inhibited the nilotinib-induced pigmentation, indicating that nilotinib induces pigmentation via the activation of PKA signaling. Together, our data suggest that nilotinib can be developed for the treatment of hypopigmentary disorder such as vitiligo.
•The nilotinib induced the pigmentation of HM3KO melanoma cells.•The nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB.•The inhibition of PKA signaling abrogated nilotinib-induced pigmentation.
Cardiorenal syndrome is now frequently recognized, and the combined dysfunction of heart and kidney increases morbidity and mortality. This study aimed to investigate possible mechanisms that ...underlie renal damage following heart dysfunction using a rat myocardial infarction model, focusing on the inflammatory pathway.
Rats were randomized into four groups: normal, volume depletion, sham operation and myocardial infarction (MI). MI was induced by the ligation of the left coronary artery and a volume depletion model was produced by low-salt diet and furosemide injection. Biochemical, histological and flow cytometric analyses were performed at 3 days and 4 and 8 weeks after MI.
On Day 3 following MI, the development of subclinical acute kidney injury was identified through significantly increased serum and urine neutrophil gelatinase-associated lipocalin level. We detected the increase of activated monocytes (CC chemokine receptor 2(+) ED-1(+)) in peripheral blood, along with the infiltration of ED-1(+) macrophages and the increment of nuclear p65 in the kidney of MI rats, suggesting the contribution of nuclear factor-kappa B-mediated inflammation in the development of Type 1 cardiorenal syndrome (CRS). The inflammatory cytokines, interleukin-6 and tumour necrosis factor-α (TNF-α) mRNA expression, as well as microvascular endothelial permeability and tubular cell apoptosis, significantly increased in the kidneys of MI rats. At 4 and 8 weeks after MI, tubular cell apoptosis, ED-1(+) macrophage infiltration and interstitial fibrosis increased in MI rats, and these chronic changes were significantly mitigated by systemic monocyte/macrophage depletion using liposome clodronate.
This study identifies the possible important role of inflammatory response as a mediator of heart-kidney crosstalk in CRS.
The Sepsis-3 criteria introduced the system that uses the Sequential Organ-Failure Assessment (SOFA) score to define sepsis. The cardiovascular SOFA (CV SOFA) scoring system needs modification due to ...the change in guideline-recommended vasopressors. In this study, we aimed to develop and to validate the modified CV SOFA score.
We developed, internally validated, and externally validated the modified CV SOFA score using the suspected infection cohort, sepsis cohort, and septic shock cohort. The primary outcome was 28-day mortality. The modified CV SOFA score system was constructed with consideration of the recently recommended use of the vasopressor norepinephrine with or without lactate level. The predictive validity of the modified SOFA score was evaluated by the discrimination for the primary outcome. Discrimination was assessed using the area under the receiver operating characteristics curve (AUC). Calibration was assessed using the calibration curve. We compared the prognostic performance of the original CV/total SOFA score and the modified CV/total SOFA score to detect mortality in patients with suspected infection, sepsis, or septic shock.
We identified 7,393 patients in the suspected cohort, 4038 patients in the sepsis cohort, and 3,107 patients in the septic shock cohort in seven Korean emergency departments (EDs). The 28-day mortality rates were 7.9%, 21.4%, and 20.5%, respectively, in the suspected infection, sepsis, and septic shock cohorts. The model performance is higher when vasopressor and lactate were used in combination than the vasopressor only used model. The modified CV/total SOFA score was well-developed and internally and externally validated in terms of discrimination and calibration. Predictive validity of the modified CV SOFA was significantly higher than that of the original CV SOFA in the development set (0.682 vs 0.624, p < 0.001), test set (0.716 vs 0.638), and all other cohorts (0.648 vs 0.557, 0.674 vs 0.589). Calibration was modest. In the suspected infection cohort, the modified model classified more patients to sepsis (66.0 vs 62.5%) and identified more patients at risk of septic mortality than the SOFA score (92.6 vs 89.5%).
Among ED patients with suspected infection, sepsis, and septic shock, the newly-developed modified CV/total SOFA score had higher predictive validity and identified more patients at risk of septic mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with International Metastatic RCC Database Consortium (IMDC) poor risk metastatic renal cell carcinoma (mRCC) rarely respond to first-line tyrosine kinase inhibitors (TKIs) including ...sunitinib, and carries a very poor prognosis. In recent years, combination therapy involving immune checkpoint inhibitors (ICIs) have demonstrated superior efficacy to sunitinib in poor risk disease.
In a retrospective study using a cancer chemotherapy registry, 206 consecutive patients with mRCC in the first-line setting were identified between Oct 2019 and Dec 2020. Sixty-one patients had a poor risk mRCC, and were treated with TKI monotherapy (n=36), nivolumab plus ipilimumab (n=16), or pembrolizumab plus axitinib (n=9). Endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), and safety.
Patients' median age was 61 years and the median number of risk factors was 3 (range, 3-5). During a median 23.0 months of follow-up, the median OS was 24.3 months with ICI-based combinations and 14.8 months with TKI monotherapy, and the median PFS periods were 9.3 months and 3.4 months, respectively. An objective response occurred in 60% of the patients receiving ICI-based combinations and in 19% of those receiving TKI monotherapy (P=0.001). In the multivariate regression model, number of IMDC risk factors and the ICI-based combination therapy were independent prognostic factors for PFS. All-causality grade 3 or 4 adverse events were 44% for ICI-based combinations and 50% for TKI monotherapy.
Among patients with poor risk mRCC, first-line ICI-based therapy showed significantly longer OS and PFS, as well as a higher RR, than TKI monotherapy.
The Kidney-Gut-Brain Axis in AKI Yang, Jihyun; Choi, Young Eun; Kim, Sungyeon ...
Journal of the American Society of Nephrology,
11/2023, Letnik:
34, Številka:
11S
Journal Article
Glioblastoma (GBM) is a disease without any definite cure. Numerous approaches have been tested in efforts to conquer this brain disease, but patients invariably experience recurrence or develop ...resistance to treatment. New surgical tools, carefully chosen samples, and experimental methods are enabling discoveries at single-cell resolution. The present article reviews the cell-of-origin of isocitrate dehydrogenase (IDH)-wildtype GBM, beginning with the historical background for focusing on cellular origin and introducing the cancer genesis patterned on firework. The authors also review mutations associated with the senescence process in cells of the subventricular zone (SVZ), and biological validation of somatic mutations in a mouse SVZ model. Understanding GBM would facilitate research on the origin of other cancers and may catalyze the development of new management approaches or treatments against IDH-wildtype GBM.
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