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Ecotoxicology and Environmental Safety Jun 2024Gastric cancer is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Triphenyl phosphate (TPP) is a prevalent flame...
BACKGROUND
Gastric cancer is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Triphenyl phosphate (TPP) is a prevalent flame retardant, but its health implications remain to be thoroughly understood.
OBJECTIVE
To explore the link between TPP exposure and gastric cancer by examining gene expression patterns and developing a predictive model.
METHODS
Gene expression data were sourced from The Cancer Genome Atlas (TCGA) and the Comparative Toxicogenomics Database (CTD). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were employed for analysis. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to obtain phosphate flame retardant-related scores. A predictive model was constructed through differential analysis, univariate COX regression, and LASSO regression. Molecular docking was performed to assess protein interactions with TPP.
RESULTS
ssGSEA identified scores related to phosphate flame retardants in gastric cancer, which had a strong association with immune-related traits. Several genes associated with TPP were identified and used to develop a prognostic model that has clinical significance. Molecular docking showed a high binding affinity of TPP with MTTP, a gene related to lipid metabolism. Pathway analysis indicated that TPP exposure contributes to gastric cancer through lipid metabolic processes.
CONCLUSION
The study establishes a potential correlation between TPP exposure and gastric cancer onset, pinpointing key genes and pathways involved. This underscores the significance of environmental factors in gastric cancer research and presents a potential diagnostic tool for clinical application.
PubMed: 38944011
DOI: 10.1016/j.ecoenv.2024.116618 -
Behaviour Research and Therapy Jun 2024Relevant implicit markers of suicidal thoughts and behaviors (STBs) have only been studied in isolation with mixed evidence. This is the first study that investigated a...
Implicit measures of suicide vulnerability: Investigating suicide-related information-processing biases and a deficit in behavioral impulse control in a high-risk sample and healthy controls.
OBJECTIVE
Relevant implicit markers of suicidal thoughts and behaviors (STBs) have only been studied in isolation with mixed evidence. This is the first study that investigated a suicide attentional bias, a death-identity bias and a deficit in behavioral impulsivity in a high-risk sample and healthy controls.
METHOD
We administered the Death Implicit Association Test, the Modified Suicide Stroop Task, and a Go/No-Go Task to inpatient suicide ideators (n = 42), suicide attempters (n = 40), and community controls (n = 61).
RESULTS
Suicide ideators and attempters showed a suicide attentional bias and a death-identity bias compared to healthy controls. Ideators and attempters did not differ in these implicit information-processing biases. Notably, only attempters were more behaviorally impulsive compared to controls; however, ideators and attempters did not significantly differ in behavioral impulsivity. Moreover, implicit scores were positively intercorrelated in the total sample.
CONCLUSION
In line with the Cognitive Model of Suicide, ideators and attempters display suicide-related information processing biases, which can be considered as implicit cognitive markers of suicide vulnerability. Furthermore, attempters have elevated levels of behavioral impulsiveness. These results are highly relevant in the context of crisis intervention strategies and warrant further research.
PubMed: 38943987
DOI: 10.1016/j.brat.2024.104601 -
International Immunopharmacology Jun 2024As the resident immune cells in the central nervous system, microglia exhibit a 'sensitized' or 'primed' phenotype with dystrophic morphology and dysregulated functions...
As the resident immune cells in the central nervous system, microglia exhibit a 'sensitized' or 'primed' phenotype with dystrophic morphology and dysregulated functions in aged brains. Although studies have demonstrated the inflammatory profile of aged microglia in several neurological diseases, this issue is largely uncertain in stroke. Consequently, this study investigated the effects of primed and repopulated microglia on post-ischemic brain injury in aged mice. We replaced primed microglia with newly repopulated microglia through pharmacological administration and withdrawal of the colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397. Further, we performed a series of behavioral tests and flow cytometry in mouse models of middle cerebral artery occlusion (MCAO) to study the effects of microglial replacement on ischemic injury in the aged brain. With depletion and subsequent repopulation of microglia in MCAO mice, microglial replacement in aged mice improved neurological function and decreased brain infarction. This protective effect was accompanied by the reduction of peripheral immune cells infiltrating into brains. We showed that the repopulated microglia expressed elevated neuroprotective factors (including Cluster of Differentiation 206, transforming growth factor-β, and interleukin-10) and diminished expression of inflammatory markers (including Cluster of Differentiation 86, interleukin-6, and tumor necrosis factor α). Moreover, microglial replacement protected the blood-brain barrier and relieved neuronal death in aged mice subjected to 60 min of MCAO. These results imply that the replacement of microglia in the aged brain may alleviate brain damage and neuroinflammation, and therefore, ischemic brain damage. Thus, targeting microglia could be a promising therapeutic strategy for ischemic stroke.
PubMed: 38943977
DOI: 10.1016/j.intimp.2024.112473 -
International Immunopharmacology Jun 2024The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of...
The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of comorbidities and is linked to a high mortality rate. Cholinergic anti-inflammatory pathway (CAP), an anti-inflammatory pathway mediated by the vagus nerve, acetylcholine, and α7 nicotinic acetylcholine receptors (α7nAChRs), offers new perspectives for the treatment of S-AKI. In this study, we investigated the role of CAP and α7nAChR in kidney injury by employing an LPS-induced septic kidney injury mouse model and GTS-21 intervention. C57BL/6 mice were injected with LPS, with or without GTS-21, in different subgroups. Kidney function was assessed by plasma creatinine, histology, and markers of kidney injury 24 h after intervention. The results demonstrated that GTS-21 could inhibit the systemic inflammatory response and directly protect the tubular cell injury from LPS. To explore the novel gene involved in this response, RNA sequencing of the renal proximal tubular epithelial cell (HK-2), pretreated with LPS and GTS-21, was conducted. The results indicate that GTS-21 administration reduces LPS-induced cytokines and chemokines secretion by HK-2, including CCL20, a potent chemokine attracting monocytes/macrophages. Furthermore, a macrophage transmigration assay revealed that GTS-21 inhibits macrophage transmigration by downregulating the expression of CCL20 in HK-2 cells. In conclusion, GTS-21, as an α7nAChR agonist, emerges as a noteworthy and versatile treatment for S-AKI. Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications.
PubMed: 38943973
DOI: 10.1016/j.intimp.2024.112555 -
Journal of Inorganic Biochemistry Jun 2024Recent breakthroughs in cancer immunology have propelled immunotherapy to the forefront of cancer research as a promising treatment approach that harnesses the body's...
Recent breakthroughs in cancer immunology have propelled immunotherapy to the forefront of cancer research as a promising treatment approach that harnesses the body's immune system to effectively identify and eliminate cancer cells. In this study, three novel cyclometalated Ir(III) complexes, Ir1, Ir2, and Ir3, were designed, synthesized, and assessed in vitro for cytotoxic activity against several tumor-derived cell lines. Among these, Ir1 exhibited the highest cytotoxic activity, with an IC value of 0.4 ± 0.1 μM showcasing its significant anticancer potential. Detailed mechanistic analysis revealed that co-incubation of Ir1 with 143B cells led to Ir1 accumulation within mitochondria and the endoplasmic reticulum (ER). Furthermore, Ir1 induced G0/G1 phase cell cycle arrest, while also diminishing mitochondrial membrane potential, disrupting mitochondrial function, and triggering ER stress. Intriguingly, in mice the Ir1-induced ER stress response disrupted calcium homeostasis to thereby trigger immunogenic cell death (ICD), which subsequently activated the host antitumor immune response while concurrently dampening the in vivo tumor-induced inflammatory response.
PubMed: 38943844
DOI: 10.1016/j.jinorgbio.2024.112655 -
Journal of Trace Elements in Medicine... Jun 2024Chronic kidney disease (CKD) is a global public health problem, resulting in end-stage kidney disease, cardiovascular disease, and premature death.
BACKGROUND
Chronic kidney disease (CKD) is a global public health problem, resulting in end-stage kidney disease, cardiovascular disease, and premature death.
AIM
The aim of the study was to determine the profile of essential and toxic trace elements in erythrocytes of patients with end-stage renal disease (ESRD) and their relationship with selected anthropometric and biochemical parameters.
METHODS
The present study compared the profiles of trace elements, including toxic sub-stances, in the erythrocytes of 80 hemodialysis patients with CKD with 40 healthy subjects. All patients had stage 5 CKD. The levels of Cd and Pb were determined by graphite furnace atomic absorption spectrometry and levels of Fe, Mn, Zn, Cu Cr, Ni, and Li by inductively coupled plasma atomic emission spectrometry.
RESULTS
The ESRD patients demonstrated significantly lower Fe and Zn concentrations and significantly higher Mn and Li and toxic Pb and Cd concentrations in erythrocytes compared to those of the healthy controls. Negative correlations were observed, among others, between the concentrations of Cu, Li, and creatinine; Cu and phosphates; Mn, Pb, and transferrin saturation while positive correlations were noted between Cu, Cr, and transferrin and Pb, Cr, and the normalized protein catabolism rate.
CONCLUSIONS
The higher concentrations of toxic elements present in the erythrocytes of CKD patients might have resulted from the reduced ability of the kidneys to excrete them. Moreover, differences in the concentrations of essential elements (Fe, Mn, Zn) between the two groups indicated that their resorption in the kidneys of CKD patients was impaired. Patients with CKD might benefit from interventions intended to reduce high, toxic concentrations of Pb and Cd and Li and Mn as an alternative supportive treatment. Iron and zinc supplementation should be a component for the treatment of anemia in CKD patients.
PubMed: 38943837
DOI: 10.1016/j.jtemb.2024.127491 -
Journal of Pharmaceutical and... Jun 2024Oxylipins are important low abundant signaling molecules in living organisms. In platelets they play a primary role in platelet activation and aggregation in the course...
Non-enantioselective, enantioselective, and two-dimensional liquid chromatography coupled with tandem mass spectrometry for the study of stereochemical disposition of oxylipins in cGMP-regulated hemin-treated platelets.
Oxylipins are important low abundant signaling molecules in living organisms. In platelets they play a primary role in platelet activation and aggregation in the course of thrombotic events. In vivo, they are enzymatically synthesized by cyclooxygenases, lipoxygenases, or cytochrome P450 isoenzmes, resulting in diverse polyunsaturated fatty acid (FA) metabolites including hydroxy-, epoxy-, oxo-FAs, and endoperoxides with pro-thrombotic or anti-thrombotic effects. In a recent study, it was reported that hemin induces platelet death which was accompanied by enhanced reactive oxygen species (ROS) production (measured by flow cytometry) and lipid peroxidation (as determined by proxy using flow cytometry with BODIPY-C11 as sensor). Lipidomic studies further indicated significant changes of the platelet lipidome upon ex vivo hemin treatment, amongst others oxylipins were increased. The effect could be (at least partly) reversed by riociguat/diethylamine NONOate diethylammonium salt (DEA/NO) which modulates the soluble guanylate cyclase(sGC)-cGMP-cGMP-dependent protein kinase I(cGKI) signaling axis. In the original work, oxylipins were measured by a non-enantioselective UHPLC-tandem-MS assay which may not give the full picture whether oxylipin elevation is due to ROS or by enzymatic processes. We present here the study of the stereochemical disposition of hemin-induced platelet lipidome alterations using Chiralpak IA-U column with amylose tris(3,5-dimethylphenylcarbamate) chiral selector immobilized on 1.6 µm silica particles. It was found that the major platelet oxylipins 12-HETE, 12-HEPE and 14-HDoHE (from 12-LOX) and 12-HHT (from COX-1) were present in S-configuration indicating their enzymatic formation. On the other hand, both R and S enantiomers of 9- and 13-HODE, 11- and 15-HETE were detected, possibly due to enzyme promiscuity rather than non-specific oxidation (by ROS or autoxidation), as confirmed by multi-loop based two-dimensional LC-MS using selective comprehensive mode with achiral RPLC in the 1st dimension and chiral LC in the 2nd using a multiple heart-cutting interface. For 12-HETrE, a peak at the retention time of the R-enantiomer was ruled out as isobaric interference by 2D-LC-MS. In particular, arachidonic acid derivates 12(S)-HHT, 11(R)-HETE and 15(S)-HETE were found to be sensitive to hemin and cGMP modulation.
PubMed: 38943819
DOI: 10.1016/j.jpba.2024.116328 -
Poultry Science May 2024The proliferation and death of granulosa cells (GCs) in poultry play a decisive role in follicular fate and egg production. The follicular fluid (FF) contains a variety...
The proliferation and death of granulosa cells (GCs) in poultry play a decisive role in follicular fate and egg production. The follicular fluid (FF) contains a variety of nutrients and genetic substances to ensure the communication between follicular cells. Exosomes, as a new intercellular communication, could carry and transport the proteins, RNA, and lipids to react on GCs, which had been found in FF of various domestic animals. Whether exosomes of FF in poultry play a similar role is unclear. In this study, geese, a poultry with low egg production, were chosen, and the effect of FF exosomes on the proliferation and death of GCs was investigated. Firstly, there were not only a large number of healthy small yellow follicles (HSYFs) but also some atresia small yellow follicles (ASYFs) in the egg-laying stage. Also, the GC layers of ASYFs became loose interconnections, inward detachment, and diminished survival rate than that of HSYFs. Besides, compared to HSYFs, the contents of E2, P4, and the mRNA expression levels of ferroptosis-related genes GPX4, FPN1, and FTH1 were significantly decreased, while COX2, NCOA4, VDAC3 mRNA were significantly increased, and the structure of mitochondrial cristae disappeared and the outer membrane broke in the GC layers of ASYFs. Moreover, the ROS, MDA, and oxidation levels in the GC layers of ASYFs were significantly higher than those of HSYFs. All these hinted that ferroptosis might result in a large number of GCs death and involvement in follicle atresia. Secondly, FF exosomes were isolated from HSYFs and ASYFs, respectively, and identified by TEM, NTA, and detection of exosome marker proteins. Also, we found the exosomes were phagocytic by GCs by tracking CM-Dil. Moreover, the addition of ASYF-FF exosomes significantly elevated the MDA content, Fe levels, and the mitochondrial membrane potential (MMP) in GCs, thus significantly inhibiting the proliferation of GCs, which was restored by the ferroptosis inhibitor ferrostatin-1. Thirdly, the proteomic sequencing was performed between FF-derived exosomes of HSYFs and ASYFs. We obtained 1615 differentially expressed proteins, which were mainly enriched in the protein transport and ferroptosis pathways. Among them, HMOX1 was enriched in the ferroptosis pathway based on differential protein-protein interaction network analysis. Finally, the role of HMOX1 in regulating ferroptosis in GCs was further explored. The highly expressed HMOX1 was observed in the exosomes of ASYF-FF than that in HSYF-FF. Overexpression of HMOX1 increased ATG5, LC3II, and NCOA4 expression and reduced the expression of FTH1, GPX4, PCBP2, FPN1 in the ferroptosis pathway, also promoted intracellular Fe accumulation and MDA surge, which drove ferroptosis in GCs. The effects of HMOX1 on ferroptosis could be blocked by its inhibitor Znpp. Taken together, the important protein HMOX1 was identified in FF, which could be delivered to GCs via exosomes, triggering ferroptosis and thus determining the fate of follicles.
PubMed: 38943808
DOI: 10.1016/j.psj.2024.103912 -
Injury Jun 2024Homicides using knives or other sharp objects are the most common type of homicide in Europe, and the second most common type of homicide worldwide. In contrast,...
INTRODUCTION
Homicides using knives or other sharp objects are the most common type of homicide in Europe, and the second most common type of homicide worldwide. In contrast, suicides using sharp objects are rarer, constituting only a few per cent of all suicides in western countries. We investigated single stab injuries to the trunk in both homicides and suicides to assess differences in extent of injuries and in medical care, which could be of value for trauma management, public health and forensic assessment.
METHODS
We identified all cases in Sweden between 2010 and 2021 that died of a single stab to the trunk, in either a homicide (n = 94) or a suicide (n = 45), and that were the subject of a forensic autopsy. We obtained data on demographics, hospital care and injured structures. To assess the severity of injuries, we applied AIS (Abbreviated Injury Score) and NISS (New Injury Severity Score). The inter-rater reliability of NISS between two raters was evaluated with intra-class correlation (ICC), with 95 % confidence intervals (CI). The data was analysed using Fisher's exact test, Mann-Whitney U test and logistic regression models.
RESULTS
The inter-rater reliability between the two NISS raters showed an ICC of 0.87 (95 % CI 0.68-0.95). We observed a larger variation of injuries in suicides, with a higher proportion of both unsurvivable (NISS 75) and minor injuries (NISS ≤ 8) (66.7 % and 8.9 % respectively) compared to in homicides (46.8 % and 0 % respectively). We observed a larger proportion of injuries to the heart in suicides (68.9% vs. 46.8 %, p = 0.018). In homicides, injuries involving vessels (52.1% vs. 13.3 %, p < 0.001) and hospital care (56.4 % vs. 8.9 %, p < 0.001) were significantly more common compared to suicides.
DISCUSSION AND CONCLUSION
Causation (self-inflicted or assaults) seems to be associated with characteristics of injury and the likelihood of receiving hospital care. These findings could potentially be valuable for trauma management and forensic assessment of manner of death, however, determining the mortality of the injuries would require a comparison group comprising injured survivors.
PubMed: 38943797
DOI: 10.1016/j.injury.2024.111694 -
Injury Jun 2024Animal-related injuries are among the major causes of morbidity and mortality all over the world, especially in rural areas. This study aims to determine the...
BACKGROUND
Animal-related injuries are among the major causes of morbidity and mortality all over the world, especially in rural areas. This study aims to determine the characteristic features of animal-related injury cases presented to the emergency department and to evaluate their temporal trends and relationships with climatic factors.
METHODS
Among the animal-related injury cases, those who applied between January 1, 2017, and December 31, 2021, in a small seaside town in Turkey were included in the study. Application date, age, gender, ICD code, and prognosis constitute the variables from the hospital information management system within the relevant date range. Meteorological data were taken from Hatay Meteorological Directorate as average daily temperature ( °C) and humidity (g/m). Descriptive statistics are presented using mean, standard error, number, percentage, and ratio. Kruskal-Wallis, Pearson correlation analysis, linear trend analysis, chi-square, and t-test were used in the analyses. The statistical significance level was accepted as p < 0.05.
RESULTS
A total of 6634 animal-related injuries were included in the study. The average age of the injured was 26.1 ± 21.1 years and 60.3 % were male. Injuries were most frequently observed in the 0-9 age group (29.9 %). Of all the cases, around 0.1 % were hospitalized and there were no reported deaths. Injuries caused by mammalian species accounted for 85 % of the cases. The number of recorded cases was lowest in 2018 and highest in 2021. Over the five years, animal-related injuries showed an increase trend which was not statistically significant (R2 = 0.216, p= 0.430). The injury cases showed a marked seasonality; numbers tended to increase in March and reached the highest level between June and September. While a significant and positive relationship was observed between the daily average temperature and the number of cases (r = 0.428, p < 0.001), there was no correlation between the average relative humidity and the injury numbers (p = 0.537).
CONCLUSION
This study revealed that animal-related injuries were commonly seen in children and young middle-aged adult groups and during warmer seasons. Based on the results of the study, we suggest several strategies to reduce the public health impact of animal-induced injuries, such as region-specific intervention programs adapted to animal species and seasonal changes, educational campaigns targeting children during the warmer seasons, and improved data recording systems for the cases.
PubMed: 38943796
DOI: 10.1016/j.injury.2024.111688