Alpha‐2‐Glycoprotein 1, Zinc‐binding (AZGP1, ZAG) is a secreted protein that is synthesized by adipocytes and epithelial cells; it is downregulated in several malignancies such as breast, prostate, ...liver and lung cancers. However, its function remains unclear in cholangiocarcinoma (CCA). Here, we evaluated the impact AZGP1 in CCA using Gene Expression Omnibus (GEO) and GEPIA. In addition, we analysed AZGP1 expression using quantitative reverse transcription PCR and western blotting. Expression of AZGP1 was nearly deficient in CCA patients and cell lines and was associated with poor prognosis. AZGP1 overexpression upregulated apoptosis markers. Co‐immunoprecipitation experiments showed that AZGP1 interacts with tripartite motif‐containing protein 25 (TRIM25), and tissue microarray and bioinformatic analysis showed that AZGP1 is negatively correlated with TRIM25 expression in CCA. Thereafter, TRIM25 knockdown led to AZGP1 upregulation and induced cancer cell apoptosis. TRIM25 targets AZGP1 for degradation by catalysing its ubiquitination. AZGP1 overexpression significantly suppressed tumour growth in a xenograft mouse model. This study findings suggest that AZGP1 is a potential therapeutic target or a diagnostic biomarker for treating patients with CCA.
Objective
Exposure to ultraviolet (UV) radiation from sunlight induces the production of essential vitamin D, whereas overexposure to sunlight leads to skin cancer. Sunlight exposure has been ...measured using questionnaires, dosimeters, and vitamin D levels. Several studies have measured vitamin D in the working population; however, these studies were limited to certain occupations such as farmers and construction workers. In the present study, we evaluated sunlight exposure using blood vitamin D as an exposure surrogate across industries and occupations.
Methods
The Korea National Health and Nutrition Examination Survey (KNHANES) is a nationwide study representing the Korean population. We analyzed data from KNHANES between 2008 and 2009. We examined the association between vitamin D levels and pertinent personal, seasonal, residential, and occupational factors. Furthermore, we developed a multiple regression model with factors other than occupational factors (industry and occupation) and obtained residual values. We computed the third quartile (Q3) of the residuals and then calculated the fractions exceeding the Q3 level for each combination of industry and occupation.
Results
Age, sex, body mass index, year, season, latitude, living area, living in an apartment, industry, and occupation were significantly associated with vitamin D levels. Based on the exceeding fraction, the armed forces showed the highest exceeding fraction level of 0.71.
Conclusions
Our results present the high exposure groups to sunlight across industries and occupations. Our results may provide a source for prioritizing occupational groups with a high risk of adverse health effects from sunlight exposure.
This study aimed to identify the major industries and jobs with the highest proportion of workers’ compensation (WC) claims for COVID-19, characterize COVID-19 WC claims in terms of their demographic ...properties and disease severity, and identify factors influencing the approval of COVID-19 WC claims as occupational disease. A total of 488 workers who submitted COVID-19-related claims to the Korea Workers’ Compensation and Welfare Service (KWCWS) from January 2020 to July 2021 were analyzed. A Fisher’s exact test was employed to associate the severity of COVID-19 infection with demographic properties. The highest proportion of all COVID-19 WC claims compensated as occupational disease (N=462) were submitted by healthcare workers (HCW=233, 50%), while only 9% (N=41) of the total originated from manufacturing industries. The 5% (N=26) of the COVID-19 WC claims accepted were evaluated as severe (N=15) and acute respiratory distress syndrome (N=9). A total of 71% (N=329) of the COVID-19 patients compensated (N=462) were from workplaces with infection clusters. A total of 26 WC cases were rejected for various reasons, including unclear infection routes, infection at private gatherings (including within families), no diagnosis, and more. Given our findings, we suggest an official system should be established to detect and compensate more job-associated infectious diseases like COVID-19.
Objectives Benzene is a well-known haematological toxin causing aplastic anaemia and leukaemia. Some recent studies have shown that low-level benzene exposure (<1 ppm) disturbs the haematopoietic ...system. However, other studies showed inconsistent results. The aim of the present study was to examine the relationship between low-level benzene exposure and blood cell counts in Korean workers. Methods Blood cell counts of benzene-exposed workers were extracted from a nationwide Special Health Examination Database from 2000 to 2008. If a worker did not take a blood test for benzene between 2000 and 2004, the worker was selected for analysis. In total, 8679 personal air benzene measurements were extracted from the nationwide Workplace Environment Measurement Database from 2004 to 2008. Mean benzene levels were calculated and assigned to benzene-exposed workers using various combinations of factory/industry/process codes. Mixed-effects models were used to examine dose-related associations between benzene levels and white blood cell (WBC), red blood cell (RBC), platelet, neutrophil and lymphocyte counts. Results In total, 21 140 blood samples were tested from 10 702 workers between 2005 and 2008; 40% of the workers had repeated blood tests (average, 3.4 times). RBC counts in male workers showed a significant negative association with low-level benzene exposure. WBC, platelet, neutrophil and lymphocyte counts did not show a consistent association with low-level benzene exposure. Conclusions Our findings support the potential haematotoxicity of low-level benzene exposure (<1 ppm). A longitudinal study with direct benzene measurements for exposed workers is needed to confirm the toxicity of low-level benzene exposure.
The aryl hydrocarbon receptor (AHR) is a key ligand-dependent transcription factor that mediates the toxic effects of compounds such as dioxin. Recently, natural ligands of AHR, including flavonoids, ...have been attracting physiological and toxicological attention as they have been reported to regulate major biological functions such as inflammation and anti-cancer by reducing the toxic effects of dioxin. Additionally, it is known that natural AHR ligands can accumulate in wildlife tissues, such as fish. However, studies in fish have investigated only a few ligands in experimental fish species, and the AHR response of marine fish to natural AHR ligands of various other structures has not been thoroughly investigated. To explore various natural AHR ligands in marine fish, which make up the most fish, it is necessary to develop new screening methods that consider the specificity of marine fish. In this study, we investigated the response of natural ligands by constructing in vitro and in silico experimental systems using red seabream as a model species. We attempted to develop a new predictive model to screen potential ligands that can induce transcriptional activation of red seabream AHR1 and AHR2 (rsAHR1 and rsAHR2). This was achieved through multiple analyses using in silico/ in vitro data and Tox21 big data. First, we constructed an in vitro reporter gene assay of rsAHR1 and rsAHR2 and measured the response of 10 representatives natural AHR ligands in COS-7 cells. The results showed that FICZ, Genistein, Daidzein, I3C, DIM, Quercetin and Baicalin induced the transcriptional activity of rsAHR1 and rsAHR2, while Resveratrol and Retinol did not induce the transcriptional activity of rsAHR isoforms. Comparing the EC50 values of the respective compounds in rsAHR1 and rsAHR2, FICZ, Genistein, and Daidzein exhibited similar isoform responses, but I3C, Baicalin, DIM and Quercetin show the isoform-specific responses. These results suggest that natural AHR ligands have specific profiling and transcriptional activity for each rsAHR isoform. In silico analysis, we constructed homology models of the ligand binding domains (LBDs) of rsAHR1 and rsAHR2 and calculated the docking energies (U_dock values) of natural ligands with measured in vitro transcriptional activity and dioxins reported in previous studies. The results showed a significant correlation (R2=0.74(rsAHR1), R2=0.83(rsAHR2)) between docking energy and transcriptional activity (EC50) value, suggesting that the homology model of rsAHR1 and rsAHR2 can be utilized to predict the potential transactivation of ligands. To broaden the applicability of the homology model to diverse compound structures and validate the correlation with transcriptional activity, we conducted additional analyses utilizing Tox21 big data. We calculated the docking energy values for 1860 chemicals in both rsAHR1 and rsAHR2, which were tested for transcriptional activation in Tox21 data against human AHR. By comparing the U_dock energy values between 775 active compounds and 1085 inactive compounds, a significant difference (p<0.001) was observed between the U_dock energy values in the two groups, suggesting that the U_dock value can be applied to distinguish the activation of compounds. Furthermore, we observed a significant correlation (R2=0.45) between the AC50 of Tox21 database and U_dock values of human AHR model. In conclusion, we calculated equations to translate the results of an in silico prediction model for ligand screening of rsAHR1 and rsAHR2 transactivation. This ligand screening model can be a powerful tool to quantitatively estimate AHR transactivation of major marine agents to which red seabream may be exposed. The study introduces a new screening approach for potential natural AHR ligands in marine fish, based on homology model-docking energy values of rsAHR1 and rsAHR2, with implications for future agonist development and applications bridging in silico and in vitro data.
•The study developed a screening approach for natural AHR ligands in marine fish.•In vitro experiments revealed that natural AHR ligands have specific profiling and transcriptional activity for each rsAHR isoform.•In silico analysis demonstrated a significant correlation between docking energy and transcriptional activity, suggesting the predictive utility of the rsAHR homology model.•The study's screening approach, based on homology model-docking energy values, may contribute to future agonist development and applications bridging in silico and in vitro data.
Tris(2-chloroethyl) phosphate (TCEP) is an organophosphate flame retardant that used in textiles, industrial materials, and furniture to delay the spread of fire after ignition. TCEP has been ...detected in the tissues and eggs of fish and birds. However, there are no studies regarding the effects of TCEP on avian embryos. In the present study, we investigated the developmental toxicity of TCEP exposure on chicken embryos in a shell-less incubation system, which enables in situ observation. Chicken embryos were treated with graded doses of TCEP (50, 250, and 500 nmol/g egg) on incubation day 0. The survival rate, morphological biometrics, heart rate, and length and branch number of extraembryonic blood vessels were measured on incubation days 3–9. Survival rates were reduced from incubation day 3 and were significantly decreased until day 9. Body length, head + bill length and eye diameter were significantly reduced by TCEP exposure. Regarding skeletal effects, spine length was decreased in a dose-dependent manner on day 9. Body weight on day 9 significantly reduced in all TCEP treatment groups. These results suggest that TCEP exposure to >50 nmol/g egg retards development in chicken embryos. TCEP exposure to 500 nmol/g egg significantly increased heart weight to body weight ratio in the embryos. More than 250 nmol/g egg of TCEP significantly reduced the heart rate of embryos in the early developmental stage. The formation of extraembryonic blood vessels and the number of erythrocytes were significantly reduced even with 50 nmol/g egg of TCEP. These findings suggest that TCEP exposure specifically affects the cardiovascular system in chicken embryos, which leads to developmental delay. The results of this study also demonstrate that the shell-less incubation system can be used to continuously monitor the effects of chemicals on developing avian embryos.
•We studied TCEP developmental toxicity on chicken embryos in a shell-less system.•Extraembryonic blood vessel formation was significantly reduced by 50 nmol/g egg TCEP.•Erythrocyte number was significantly reduced by 50 nmol/g egg TCEP.•TCEP of >50 nmol/g egg retarded development, possibly via cardiovascular effects.•The shell-less system enables to continuously monitor chemical effects on avian development.
This study focuses on assessing occupational risk for the health hazards encountered during maintenance works (MW) in semiconductor fabrication (FAB) facilities.
The objectives of this study include: ...1) identifying the primary health hazards during MW in semiconductor FAB facilities; 2) reviewing the methods used in evaluating the likelihood and severity of health hazards through occupational health risk assessment (OHRA); and 3) suggesting variables for the categorization of likelihood of exposures to health hazards and the severity of health effects associated with MW in FAB facilities.
A literature review was undertaken on OHRA methodology and health hazards resulting from MW in FAB facilities. Based on this review, approaches for categorizing the exposure to health hazards and the severity of health effects related to MW were recommended.
Maintenance workers in FAB facilities face exposure to hazards such as debris, machinery entanglement, and airborne particles laden with various chemical components. The level of engineering and administrative control measures is suggested to assess the likelihood of simultaneous chemical and dust exposure. Qualitative key factors for mixed exposure estimation during MW include the presence of safe operational protocols, the use of air-jet machines, the presence and effectiveness of local exhaust ventilation system, chamber post-purge and cooling, and proper respirator use. Using the risk (R) and hazard (H) codes of the Globally Harmonized System alongside carcinogenic, mutagenic, or reprotoxic classifications aid in categorizing health effect severity for OHRA.
Further research is needed to apply our proposed variables in OHRA for MW in FAB facilities and subsequently validate the findings.
Ovarian cancer is the leading cause of gynecologic cancer death. Among the most innovative anti-cancer approaches, the genetic concept of synthetic lethality is that mutations in multiple genes work ...synergistically to effect cell death. Previous studies found that although vaccinia-related kinase-1 (VRK1) associates with DNA damage repair proteins, its underlying mechanisms remain unclear. Here, we found high VRK1 expression in ovarian tumors, and that VRK1 depletion can significantly promote apoptosis and cell cycle arrest. The effect of VRK1 knockdown on apoptosis was manifested by increased DNA damage, genomic instability, and apoptosis, and also blocked non-homologous end joining (NHEJ) by destabilizing DNA-PK. Further, we verified that VRK1 depletion enhanced sensitivity to a PARP inhibitor (PARPi), olaparib, promoting apoptosis through DNA damage, especially in ovarian cancer cell lines with high VRK1 expression. Proteins implicated in DNA damage responses are suitable targets for the development of new anti-cancer therapeutic strategies, and their combination could represent an alternative form of synthetic lethality. Therefore, normal protective DNA damage responses are impaired by combining olaparib with elimination of VRK1 and could be used to reduce drug dose and its associated toxicity. In summary, VRK1 represents both a potential biomarker for PARPi sensitivity, and a new DDR-associated therapeutic target, in ovarian cancer.
•VRK1 is highly expressed in OC patients.•The downregulation of VRK1 in OC cells induces DNA damage.•VRK1 depletion disrupts DNA-PK stability in OC cells.•VRK1 reduction attenuates the resistance of OC cells to PARP inhibitor.
Background
A known metastasis suppressor gene,
NME1
(Nm23), downregulated in melanoma, breast cancer, and other cancers, suppresses migration and invasion of tumor cells. However, in pancreatic ...cancer (PC), one of the common and deadly cancers worldwide that largely eludes early diagnosis,
NME1
function remains unstudied, prompting us to investigate its role.
Objective
The aim of this study is to investigate biological function of
NME1
in pancreatic cancer growth and metastasis and explored potential mechanism mediated by MAPK/JNK signaling pathway.
Results
Western blots showed lower
NME1
expression in pancreatic tumors than in normal tissues, while its overexpression in cultured PC cells induced cell death and inhibited proliferation, growth, migration, and invasion.
NME1
was also found involved in multiple signaling pathways that confer metastatic properties.
Conclusion
This study identifies the important potential of
NME1
in pancreatic cancer cells and role of novel biomarker and/or therapeutic target.
In discovering the potential antagonist of peroxisome proliferator-activated receptor gamma (PPARγ), the structure–activity relationship (SAR) is a useful in silico method. However, it is difficult ...for conventional SAR approaches to predict the activities of antagonists owing to the large structural diversity of antagonistic compounds. This study provides evidence that multi-step SAR screening is applicable for predicting PPARγ antagonists by combining different complementary methodologies. We constructed three models: read-across-like SAR, docking-simulation-interpreting SAR, and deep-learning-based SAR. To provide user-customized prediction results, our multi-step SAR screening model combined the three SAR models in a stepwise manner, which subdivided them according to potential levels of the PPARγ antagonist. The read-across-like SAR, which considered specific antagonist scaffolds, revealed the highest positive predictive value (PPV). The docking-simulation-interpreting SAR, which considered the molecular surface features, revealed high statistics for the PPV and the true-positive rate (TPR). The deep-learning-based SAR showed the highest TPR at the last classification step. This multi-step SAR screening covered the antagonists of high reliability provided by a read-across-like SAR, as well as the antagonists of diverse scaffolds provided by docking-simulation-interpreting SAR and deep-learning-based SAR. Therefore, to predict PPARγ antagonists, multi-step SAR screening could be as a useful tool.
•The antagonists of PPARγ have recently received attention as modulators of obesity, insulin resistance, and inflammatory response.•To discover potential antagonists of PPARγ, a multi-step structure-activity relationship (SAR) approach was developed using by combining different complementary methodologies.•As far as we know, this is the first study to build an integrated SAR model that combines multiple algorithm models to obtain PPARγ antagonists.•This SAR model could be used as an effective screening tool for determining the PPARγ antagonists.
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