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Asian Pacific Journal of Cancer... Jun 2024Breast cancer represents one of the leading causes of death worldwide. Apart from genetic factors, the sex hormone estrogen plays a pivotal role in breast cancer...
BACKGROUND
Breast cancer represents one of the leading causes of death worldwide. Apart from genetic factors, the sex hormone estrogen plays a pivotal role in breast cancer development. We are exposed to a plethora of estrogen mimics on a daily basis via various routes. Nevertheless, how xenoestrogens, the exogenous estrogen mimics, modulate cancer-associated signaling pathways and interact with specific genes is still underexplored. Hence, this study aims to explore the direct or indirect binding partners of xenoestrogens and their expression upon exposure to these estrogenic compounds.
METHODS
The collection of genes linked to the xenoestrogens Octylphenol, Nonylphenol, Bisphenol-A, and 2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane were gathered from the Comparative Toxicogenomics Database. Venny 2.1 was utilized to pinpoint the genes shared by these xenoestrogens. Subsequently, the shared genes underwent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery bioinformatics resource. A xenoestrogen-protein interaction network was constructed using Search Tool for Interactions of Chemicals. The expressions of common genes were studied with the microarray dataset GSE5200 from the Gene Expression Omnibus database. Also, the expression of a common gene set within different breast cancer subtypes was identified using the University of California, Santa Cruz Xena.
RESULTS
The genes linked to xenoestrogens were identified, and 13 genes were found to interact with all four xenoestrogens. Through DAVID analysis, the genes chosen are found to be enriched for various functions and pathways, including pathways in cancer, chemical carcinogenesis-receptor activation, and estrogen signaling pathways. The results of the Comparative Toxicogenomics Database and the chemical-protein interaction network derived from STITCH were similar. Microarray data analysis showed significantly high expression of all 13 genes in another study, with Bisphenol-A and Nonylphenol treated MCF-7 cells, most of the genes are expressed in luminal A or basal breast cancer subtype.
CONCLUSION
In summary, the genes associated with the four xenoestrogens were mostly linked to pathways related to tumorigenesis, and the expression of these genes was found to be higher in breast cancer.
Topics: Humans; Breast Neoplasms; Estrogens; Female; Computational Biology; Computer Simulation; Protein Interaction Maps; Signal Transduction; Gene Expression Regulation, Neoplastic; Benzhydryl Compounds
PubMed: 38918670
DOI: 10.31557/APJCP.2024.25.6.2077 -
Aging Jun 2024Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages...
Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages gastric tissue, which is susceptible to inflammation. Luteolin has powerful anti-inflammatory and regulatory potential for cellular ferroptosis. We aimed to clarify the involvement of luteolin in inflammation and ferroptosis during CAG. Luteolin targets were searched to identify intersecting genes in the chronic atrophic gastritis disease database. The AGE-RAGE pathway is a potential target of luteolin for the treatment of chronic atrophic gastritis and a binding site between luteolin and RAGE was predicted through a computer simulation of molecular docking. We established a CAG rat model using N-methyl-N-nitro-N-nitroguanidine. The therapeutic effect of luteolin on CAG was detected using western blotting, qPCR, hematoxylin and eosin staining, lipid oxidation (MDA), and Fe assays. Luteolin inhibited the AGE-RAGE signaling pathway and reduced the inflammatory response in gastric tissues. Additionally, luteolin downregulated the concentration of (MDA) and Fe, and CAG downregulated the expression levels of ACSL4 and NOX1 and upregulated the expression levels of FIH1 and GPX4 ferroptosis-related proteins, thus inhibiting the ferroptosis of gastric tissue cells, which had a therapeutic effect on CAG.
PubMed: 38917486
DOI: 10.18632/aging.205969 -
PloS One 2024Previous research has indicated the suitability of behavioural activation (BA) as an intervention for reducing depression in older adults. However, little research has...
Previous research has indicated the suitability of behavioural activation (BA) as an intervention for reducing depression in older adults. However, little research has investigated the potential of BA to increase active engagement and well-being in older adults. The current pilot study sought to investigate the usefulness and acceptability of BA to promote well-being in a group of non-clinical older adults. Participants (N = 18) aged between 65 and 86 (M = 77.82, SD = 5.59) who were retired and living independently in the community were provided a 6-week BA program predominantly delivered online. Treatment retention, self-ratings, and participants' compliance to treatment principles indicate preliminary feasibility for the use of BA as an approach for increasing active engagement in older adult populations. Participants also provided feedback on their experiences with the program post-intervention via individual structured interviews. Thematic analysis of these data revealed that participants found the program to be beneficial in terms of increased self-awareness and social engagement, and provided several recommendations for improving acceptability of the program and workbook. The unexpected events relating to the first wave of the novel coronavirus (COVID-19) led to necessary adaptations to delivery modalities, and provided the researchers with an opportunity to investigate the use of a structured well-being program on a high-risk population during a pandemic. Our findings support the proposition that BA is a suitable intervention for increasing engagement and well-being in older adults, provide insight into adapting programs for older adults, and suggest next steps for testing intervention efficacy.
Topics: Humans; Aged; Pilot Projects; Male; Female; Aged, 80 and over; COVID-19; SARS-CoV-2; Depression; Behavior Therapy
PubMed: 38917213
DOI: 10.1371/journal.pone.0305908 -
MBio Jun 2024The cAMP receptor proteins (CRPs) play a critical role in bacterial environmental adaptation by regulating global gene expression levels via cAMP binding. Here, we...
The cAMP receptor proteins (CRPs) play a critical role in bacterial environmental adaptation by regulating global gene expression levels via cAMP binding. Here, we report the structure of DdrI, a CRP family protein from . Combined with biochemical, kinetic, and molecular dynamics simulations analyses, our results indicate that DdrI adopts a DNA-binding conformation in the absence of cAMP and can form stable complexes with the target DNA sequence of classical CRPs. Further analysis revealed that the high-affinity cAMP binding pocket of DdrI is partially filled with Tyr113-Arg55-Glu65 sidechains, mimicking the -cAMP-mediated allosteric transition. Moreover, the second -cAMP binding site of DdrI at the protein-DNA interface is more negatively charged compared to that of classical CRPs, and manganese ions can enhance its DNA binding affinity. DdrI can also bind to a target sequence that mimics another transcription factor, DdrO, suggesting potential cross-talk between these two transcription factors. These findings reveal a class of CRPs that are independent of cAMP activation and provide valuable insights into the environmental adaptation mechanisms of .IMPORTANCEBacteria need to respond to environmental changes at the gene transcriptional level, which is critical for their evolution, virulence, and industrial applications. The cAMP receptor protein (CRP) of (ecCRP) senses changes in intracellular cAMP levels and is a classic example of allosteric effects in textbooks. However, the structures and biochemical activities of CRPs are not generally conserved and there exist different mechanisms. In this study, we found that the proposed CRP from , DdrI, exhibited DNA binding ability independent of cAMP binding and adopted an apo structure resembling the activated CRP. Manganese can enhance the DNA binding of DdrI while allowing some degree of freedom for its target sequence. These results suggest that CRPs can evolve to become a class of cAMP-independent global regulators, enabling bacteria to adapt to different environments according to their characteristics. The first-discovered CRP family member, ecCRP (or CAP) may well not be typical of the family and be very different to the ancestral CRP-family transcription factor.
PubMed: 38916345
DOI: 10.1128/mbio.01144-24 -
Frontiers in Plant Science 2024Rapid industrialization and urbanization have caused severe soil contamination with cadmium (Cd) necessitating effective remediation strategies. Phytoremediation is a...
Rapid industrialization and urbanization have caused severe soil contamination with cadmium (Cd) necessitating effective remediation strategies. Phytoremediation is a widely adopted technology for remediating Cd-contaminated soil. Previous studies have shown that has a high Cd accumulation capacity and tolerance indicating its potential for Cd soil remediation. However, the mechanisms underlying its response to Cd stress remain unclear. In this study, physiological, transcriptomic, and metabolomic analyses were conducted to explore the response of roots to Cd stress at different time points. The results revealed that Cd stress significantly increased malondialdehyde (MDA) levels in , which simultaneously activated its antioxidant defense system, enhancing the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) by 19.73%-50%, 22.87%-38.89%, and 32.31%-45.40% at 12 h, 36 h, 72 h, and 7 days, respectively, compared with those in the control (CK). Moreover, transcriptomic and metabolomic analyses revealed 245, 5,708, 9,834, and 2,323 differentially expressed genes (DEGs), along with 66, 62, 156, and 90 differentially expressed metabolites (DEMs) at 12 h, 36 h, 72 h, and 7 days, respectively. Through weighted gene coexpression network analysis (WGCNA) of physiological indicators and transcript expression, eight hub genes involved in phenylpropanoid biosynthesis, signal transduction, and metal transport were identified. In addition, integrative analyses of metabolomic and transcriptomic data highlighted the activation of lipid metabolism and phenylpropanoid biosynthesis pathways under Cd stress suggesting that these pathways play crucial roles in the detoxification process and in enhancing Cd tolerance in . This comprehensive study provides detailed insights into the response mechanisms of to Cd toxicity.
PubMed: 38916029
DOI: 10.3389/fpls.2024.1389207 -
Frontiers in Medicine 2024The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune...
BACKGROUND
The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively.
OBJECTIVES
We investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease.
METHODS
For this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping.
RESULTS
Thirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 μg/L, ADAMTS13 activity ≤ 50%, Von.
CONCLUSION
A combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection.
PubMed: 38915768
DOI: 10.3389/fmed.2024.1399335 -
BioRxiv : the Preprint Server For... Jun 2024Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of ATP from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of...
Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of ATP from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of the C-terminus promotes the opening of the Panx1 channel by unplugging the pore. However, this simple pore- plugging mechanism alone cannot account for the observation that a Panx1 construct ending before the caspase cleavage site remains closed. Here, we show that a helical region located immediately before the caspase cleavage site, referred to as the "C-terminal activating domain (CAD)," plays a pivotal role in facilitating Panx1 activation. Electrophysiology and mutagenesis studies uncovered that two conserved leucine residues within the CAD plays a pivotal role. Cryo- EM analysis of the construct ending before reaching the CAD demonstrated that the N-terminus extends into an intracellular pocket. In contrast, the construct including the CAD revealed that this domain occupies the intracellular pocket, causing the N-terminus to flip upward within the pore. Analysis of electrostatic free energy landscape in the closed conformation indicated that the intracellular side of the ion permeation pore may be occupied by anions like ATP, creating an electrostatic barrier for anions attempting to permeate the pore. When the N-terminus flips up, it diminishes the positively charged surface, thereby reducing the drive to accumulate anions inside the pore. This dynamic change in the electrostatic landscape likely contributes to the selection of permeant ions. Collectively, these experiments put forth a novel mechanism in which C-terminal cleavage liberates the CAD, causing the repositioning of the N-terminus to promote Panx1 channel opening.
PubMed: 38915727
DOI: 10.1101/2024.06.13.598903 -
BioRxiv : the Preprint Server For... Jun 2024related dilated cardiomyopathy ( -DCM) is one of the most severe forms of DCM. The incomplete understanding of the molecular disease mechanisms results in lacking...
related dilated cardiomyopathy ( -DCM) is one of the most severe forms of DCM. The incomplete understanding of the molecular disease mechanisms results in lacking treatment options, leading to high mortality amongst patients. Here, using an inducible, cardiomyocyte-specific lamin A/C depletion mouse model, we conducted a comprehensive transcriptomic study, combining both bulk and single nucleus RNA sequencing, and spanning -DCM disease progression, to identify potential disease drivers. Our refined analysis pipeline identified 496 genes already misregulated early in disease. The expression of these genes was largely driven by disease specific cardiomyocyte sub-populations and involved biological processes mediating cellular response to DNA damage, cytosolic pattern recognition, and innate immunity. Indeed, DNA damage in -DCM hearts was significantly increased early in disease and correlated with reduced cardiomyocyte lamin A levels. Activation of cytosolic pattern recognition in cardiomyocytes was independent of cGAS, which is rarely expressed in cardiomyocytes, but likely occurred downstream of other pattern recognition sensors such as IFI16. Altered gene expression in cardiac fibroblasts and immune cell infiltration further contributed to tissue-wide changes in gene expression. Our transcriptomic analysis further predicted significant alterations in cell-cell communication between cardiomyocytes, fibroblasts, and immune cells, mediated through early changes in the extracellular matrix (ECM) in the -DCM hearts. Taken together, our work suggests a model in which nuclear damage in cardiomyocytes leads to activation of DNA damage responses, cytosolic pattern recognition pathway, and other signaling pathways that activate inflammation, immune cell recruitment, and transcriptional changes in cardiac fibroblasts, which collectively drive -DCM pathogenesis.
PubMed: 38915720
DOI: 10.1101/2024.06.11.598511 -
BioRxiv : the Preprint Server For... Jun 2024Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity...
Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in topdown modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.
PubMed: 38915683
DOI: 10.1101/2024.06.13.598957 -
BioRxiv : the Preprint Server For... Jun 2024The fungus is an opportunistic pathogen of people that reprograms its translatome to facilitate adaptation and virulence within the host. We studied the role of...
UNLABELLED
The fungus is an opportunistic pathogen of people that reprograms its translatome to facilitate adaptation and virulence within the host. We studied the role of Hog1/p38 in reprogramming translation during thermal stress adaptation, and found that this pathway acts on translation via crosstalk with the Gcn2 pathway, a well-studied regulator of general translation control. Using a combination of molecular assays and phenotypic analysis, we show that increased output from the Gcn2 pathway in a Hog1 deletion mutant is associated with rescue of thermal stress adaptation at both molecular and phenotypic scales. We characterize known outputs of the Hog1 pathway during thermal stress as either Gcn2-dependent or Gcn2-independent, and demonstrate that Hog1 activation regulates the Gcn2 pathway even in the absence of thermal stress. Finally, we implicate this phenomenon in another Hog1-regulated process, morphogenesis, and recapitulate Hog1-Gcn2 crosstalk in the distantly related fungal pathogen, Our results point to an important link between the stress response machinery and translation control, and clarify the etiology of phenotypes associated with Hog1 deletion. More broadly, this study highlights complex interplay between core conserved signal transduction pathways and the utility of molecular assays to better understand how these pathways are connected.
IMPORTANCE
is an opportunistic pathogen of people that causes deadly cryptococcal meningitis, which is is responsible for an estimated 19% of AIDS-related mortality. When left untreated, cryptococcal meningitis is uniformly fatal, and in patients receiving the most effective antifungal regimens, mortality remains high. Thus, there is a critical need to identify additional targets that play a role in adaptation to the human host and virulence. This study explores the role of the stress response kinases Hog1 and Gcn2 in thermoadaptation, which is pre-requisite for virulence. Our results show that compensatory signaling occurs via the Gcn2 pathway when Hog1 is deleted, and that disruption of both pathways increases sensitivity to thermal stress. Importantly, our study highlights the insufficiency of using single gene deletion mutants to study gene function, since many phenotypes associated with Hog1 deletion were driven by Gcn2 signaling in this background, rather than loss of direct Hog1 activity.
PubMed: 38915642
DOI: 10.1101/2024.06.11.598457