Protein disulfide isomerase (PDI) participates in the pathogenesis of numerous diseases. Increasing evidence indicates that intravascular cell-derived PDI plays an important role in the initiation ...and progression of cardiovascular diseases, including thrombosis and vascular inflammation. Recent studies with PDI conditional knockout mice have advanced our understanding of the function of cell-specific PDI in disease processes. Furthermore, the identification and development of novel small-molecule PDI inhibitors has led into a new era of PDI research that transitioned from the bench to bedside. In this review, we will discuss recent findings on the regulatory role of PDI in cardiovascular disease.
Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their ...sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very longchain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.
Human pluripotent stem cell (hPSC)-derived intestinal organoids (hIOs) form 3D structures organized into crypt and villus domains, making them an excellent in vitro model system for studying human ...intestinal development and disease. However, hPSC-derived hIOs still require in vivo maturation to fully recapitulate adult intestine, with the mechanism of maturation remaining elusive. Here, we show that the co-culture with human T lymphocytes induce the in vitro maturation of hIOs, and identify STAT3-activating interleukin-2 (IL-2) as the major factor inducing maturation. hIOs exposed to IL-2 closely mimic the adult intestinal epithelium and have comparable expression levels of mature intestinal markers, as well as increased intestine-specific functional activities. Even after in vivo engraftment, in vitro-matured hIOs retain their maturation status. The results of our study demonstrate that STAT3 signaling can induce the maturation of hIOs in vitro, thereby circumventing the need for animal models and in vivo maturation.
Due to the rapid development of mobile phone technology, we are continuously exposed to 1.7 GHz LTE radio frequency electromagnetic fields (RF-EMFs), but their biological effects have not been ...clarified. Here, we investigated the non-thermal cellular effects of these RF-EMFs on human cells, including human adipose tissue-derived stem cells (ASCs), Huh7 and Hep3B liver cancer stem cells (CSCs), HeLa and SH-SY5Y cancer cells, and normal fibroblast IMR-90 cells. When continuously exposed to 1.7 GHz LTE RF-EMF for 72 h at 1 and 2 SAR, cell proliferation was consistently decreased in all the human cells. The anti-proliferative effect was higher at 2 SAR than 1 SAR and was less severe in ASCs. The exposure to RF-EMF for 72 h at 1 and 2 SAR did not induce DNA double strand breaks or apoptotic cell death, but did trigger a slight delay in the G1 to S cell cycle transition. Cell senescence was also clearly observed in ASC and Huh7 cells exposed to RF-EMF at 2 SAR for 72 h. Intracellular ROS increased in these cells and the treatment with an ROS scavenger recapitulated the anti-proliferative effect of RF-EMF. These observations strongly suggest that 1.7 GHz LTE RF-EMF decrease proliferation and increase senescence by increasing intracellular ROS in human cells.
Predictive models for the benthic macroinvertebrate community based on environmental variables facilitate the identification of the organisms expected to inhabit an area according to the target ...environmental conditions when restoring rivers. In this investigation, a biotic community predictive model was developed using benthic macroinvertebrate and environmental variable data collected from 1,210 sites in the Republic of Korea from 2010 to 2020. The sites were classified into six groups according to Two Way Indicator Species Analysis (TWINSPAN) and based on their individual abundance/m
2
of benthic macroinvertebrates. The TWINSPAN groups were related to 14 variables by stepwise multi-discriminant analysis. The relative importance of the environmental variables that classified each TWINSPAN group was in the order of mean diameter of particle size, catchment area, altitude, velocity, total phosphorus, latitude, pH, longitude, conductivity, water depth, suspended solids, biochemical oxygen demand, stream order, and total nitrogen. Discriminant functions 1-4 showed statistically significant and a predictive model was developed using functions 1 and 2 based on Wilks' lambda values. The fit of the derived model was confirmed using Sørensen similarity (number of taxa) and Bray-Curtis dissimilarity (individual abundance/m
2
) analyses between the predicted organisms and those observed at the sites. The distributions of similarity and dissimilarity that were confirmed by stream type ranged from 0.60 to 0.72 and 0.46-0.56, respectively, based on the mean. Based on the predicted and observed values, the ratio of shredders and scrapers to collectors showed similar results overall for each stream type. The predictive model derived using nationally managed available data is expected to be applicable to stream and river restorations in the future, as it provides a statistical assessment of the biotic communities that are expected to inhabit a given environment.
A biotic community predictive model is presented. The model was developed using benthic macroinvertebrate and environmental variable data collected from 1,210 sites across the Republic of Korea from 2010 to 2020.
The purpose of the model is to identify communities that should be present in river environments after restoration under modified environmental conditions.
The model can function on a larger scale to address the increasing need for river restoration from a broader perspective.
Model usage will provide successful and sustainable results and meet the needs of policy makers to restore riverine environments.
The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also ...contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood-retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.
Background Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. ...Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC. Methods In total, 395 patients with histologically confirmed T1N0-2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors. Results The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio OR, 8.16; 95% confidence interval CI, 1.80-36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91-11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21-7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and greater than or equal to 3, respectively. Conclusions For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis. Keywords: Colorectal neoplasm, Histopathology, Lymph nodes metastasis, Tumor budding
Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease characterized by structural deterioration of the aorta caused by inflammation and oxidative stress, leading to aortic dilatation ...and rupture. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, has been reported as a potential negative regulator of inflammatory vascular diseases, and it has been identified as a protein that is increased in patients with ruptured AAA compared to patients with nonruptured AAA. In this study, we demonstrated that PRDX2 was a pivotal factor involved in the inhibition of AAA progression. PRDX2 levels were increased in AAA compared with those in normal aortas in both humans and mice. Ultrasound imaging revealed that the loss of PRDX2 accelerated the development of AAA in the early stages and increased AAA incidence in mice infused with angiotensin II (Ang II). Prdx2
mice infused with Ang II exhibited increased aortic dilatation and maximal aortic diameter without a change in blood pressure. Structural deterioration of the aortas from Prdx2
mice infused with Ang II was associated with increases in the degradation of elastin, oxidative stress, and intramural thrombi caused by microhemorrhages, immature neovessels, and the activation of matrix metalloproteinases compared to that observed in controls. Moreover, an increase in inflammatory responses, including the production of cell adhesion molecules and the accumulation of inflammatory cells and proinflammatory cytokines due to PRDX2 deficiency, accelerated Ang II-induced AAA progression. Our data confirm that PRDX2 plays a role as a negative regulator of the pathological process of AAA and suggest that increasing PRDX2 activity may be a novel strategy for the prevention and treatment of AAA.
Surface oxygen vacancies in anatase-type Fe@TiO2 nanoparticles for superior photocatalytic activities can be readily controlled by simple pH treatment. A comprehensive analysis at the atomic to ...mesoscopic scale clearly reveals that the point defects are maximized and predominantly formed on the surface of the anatase NPs in basic pH condition, thereby resulting in electronically different core-shell nanostructures.
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•Surface oxygen vacancies in the nanoparticles are controlled via the pH treatment.•The surface defect population can be maximized by use of basic pH condition.•pH treatment affects catalytic properties of Fe-doped anatase TiO2 nanoparticles.•The nanoparticles treated at basic pH condition show the best catalytic properties.•Atomic analysis reveals that the anatase structure was kept in the whole pH range.
Introduction of defect structures into Fe-doped TiO2 nanoparticles (Fe@TiO2 NPs) has been shown to endow NPs with improved photocatalytic properties. However, current strategies for the preparation of defect-containing NPs require high temperature or complicated treatments, which can induce unwanted phase transition. In this paper, we report a facile method to introduce surface oxygen vacancies into anatase-type Fe@TiO2 NPs without altering the crystalline phase via simple pH treatments at moderate temperatures. Furthermore, we present the effects of pH on the formation of surface oxygen vacancies. The optimized treatment under basic conditions is revealed to promote the formation of oxygen vacancies on the surface of anatase Fe@TiO2 NPs and effectively reduces the particle size by more than 25%, thereby causing a significant enhancement in the photocatalytic activities of the NPs (e.g. ~3.5 times better in photocatalytic degradation rate of 4-CP as compared to acid-treated Fe@TiO2). Comprehensive structural and chemical characterizations reveal that the point defects are predominantly formed on the surface of anatase NPs, and their population can be maximized by use of basic pH conditions. Our results pave a way toward the facile and efficient engineering of surface defect structures on catalytic metal oxide NPs for the design of high-performance photocatalysts.
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