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Development (Cambridge, England) Jul 2024The bromodomain and extra-terminal (BET) family of proteins reads epigenetic histone acetylation marks on the genome and regulates the transcriptional machinery. In...
The bromodomain and extra-terminal (BET) family of proteins reads epigenetic histone acetylation marks on the genome and regulates the transcriptional machinery. In their study, Carole LaBonne and colleagues reveal the role of BET protein activity in the maintenance of pluripotency and establishment of the neural crest in Xenopus laevis. To know more about their work, we spoke to the first author Paul Huber and the corresponding author Carole LaBonne, Developmental and Stem Cell Biologist at Northwestern University.
Topics: Animals; Xenopus laevis; History, 21st Century; Humans; History, 20th Century; Neural Crest; Developmental Biology
PubMed: 38958074
DOI: 10.1242/dev.203151 -
Arteriosclerosis, Thrombosis, and... Jul 2024Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the...
BACKGROUND
Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes.
METHODS
Rapamycin and adeno-associated virus carrying short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA.
RESULTS
Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2.
CONCLUSIONS
Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification.
REGISTRATION
URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2200064155.
PubMed: 38957984
DOI: 10.1161/ATVBAHA.123.319993 -
Extracellular Vesicle Jun 2024Mesenchymal stem cells (MSCs) have been studied for decades as candidates for cellular therapy, and their secretome, including secreted extracellular vesicles (EVs), has...
Mesenchymal stem cells (MSCs) have been studied for decades as candidates for cellular therapy, and their secretome, including secreted extracellular vesicles (EVs), has been identified to contribute significantly to regenerative and reparative functions. Emerging evidence has suggested that MSC-EVs alone, could be used as therapeutics that emulate the biological function of MSCs. However, just as with MSCs, MSC-EVs have been shown to vary in composition, depending on the tissue source of the MSCs as well as the protocols employed in culturing the MSCs and obtaining the EVs. Therefore, the importance of careful choice of cell sources and culture environments is receiving increasing attention. Many factors contribute to the therapeutic potential of MSC-EVs, including the source tissue, isolation technique, and culturing conditions. This review illustrates the molecular landscape of EVs derived from different types of MSC cells along with culture strategies. A thorough analysis of publicly available omic datasets was performed to advance the precision understanding of MSC-EVs with unique tissue source-dependent molecular characteristics. The tissue-specific protein and miRNA-driven Reactome ontology analysis was used to reveal distinct patterns of top Reactome ontology pathways across adipose, bone marrow, and umbilical MSC-EVs. Moreover, a meta-analysis assisted by an AI technique was used to analyze the published literature, providing insights into the therapeutic translation of MSC-EVs based on their source tissues.
PubMed: 38957857
DOI: 10.1016/j.vesic.2024.100034 -
Cureus Apr 2024Introduction Cancer exerts a substantial influence on the body's metabolism through varied mechanisms, instigating a metabolic reprogramming that maintains the unchecked...
Introduction Cancer exerts a substantial influence on the body's metabolism through varied mechanisms, instigating a metabolic reprogramming that maintains the unchecked growth and survival of cancer cells, consequently perturbing diverse metabolic parameters. The introduction of positron emission tomography-computed tomography (PET/CT), delivering detailed insights into both metabolic and morphological aspects, has brought about a revolutionary shift in modern cancer detection. Exploring the potential connection between PET-CT metabolic features and the metabolic parameters of liver enzymes in an individual can unveil novel avenues for cancer diagnosis and prognosis. Materials and methods This study conducted a retrospective analysis of patient records from our institution, covering the period from January 2021 to September 2023, focusing on individuals with various malignancies. The data included information on gender, age, clinical history, and liver serum parameters, which were compiled into tables. Additionally, inflammatory indicators such as ALT (alanine transaminase), ALP (alkaline phosphatase), total protein (TP), ALT/AST ratio, and SUVmax were collected and plotted. The study used Pearson correlation analysis to assess the relationship between each inflammatory variable and SUV (max) as determined by PET-CT. Results In breast cancer, there was a statistically significant positive correlation (R2=0.0651) between serum ALP levels and SUVmax as determined by regression analysis. Hodgkin lymphoma, on the other hand, showed a statistically significant negative correlation between the ALT-to-AST ratio (ALT/AST) and SUVmax (r = -0.45, R2 = 0.204). In non-Hodgkin lymphoma patients, total protein (TP) was negatively correlated with SUVmax (R2=-0.081, r= -0.28), while in lung cancer patients, there was a significant positive correlation with regression correlation coefficients (R2 = 0.026, 0.024, 0.024, and 0.018 for ALT/AST, TP, ALP, albumin, and ALT, respectively). Conclusion Aligning with these results, it can be a recent addition to acknowledge that both the tumor metabolic parameter (SUVmax) and the levels of liver serum enzymes exhibit a potential for predicting patient prognosis in various cancers.
PubMed: 38957833
DOI: 10.7759/cureus.58532 -
Frontiers in Cellular and Infection... 2024Tuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of...
BACKGROUND
Tuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of drug resistance. Therefore, the development of novel therapeutic strategies is critical. This study focuses on the role of immune checkpoint molecules (ICs) and functions of CD8+ T cells in the search for new potential targets against TB.
METHODS
We conducted differential expression genes analysis and CD8+ T cell functional gene analysis on 92 TB samples and 61 healthy individual (HI) samples from TB database GSE83456, which contains data on 34,603 genes. The GSE54992 dataset was used to validated the findings. Additionally, a cluster analysis on single-cell data from primates infected with mycobacterium tuberculosis and those vaccinated with BCG was performed.
RESULTS
The overexpression of LAG-3 gene was found as a potentially important characteristic of both pulmonary TB (PTB) and extrapulmonary TB (EPTB). Further correlation analysis showed that LAG-3 gene was correlated with GZMB, perforin, IL-2 and IL-12. A significant temporal and spatial variation in LAG-3 expression was observed in T cells and macrophages during TB infection and after BCG vaccination.
CONCLUSION
LAG-3 was overexpressed in TB samples. Targeting LAG-3 may represent a potential therapeutic target for tuberculosis.
Topics: Lymphocyte Activation Gene 3 Protein; Humans; Mycobacterium tuberculosis; CD8-Positive T-Lymphocytes; Tuberculosis; Animals; Antigens, CD; BCG Vaccine; Macrophages; Interleukin-2; Gene Expression Profiling; Tuberculosis, Pulmonary; Interleukin-12; Perforin; Male
PubMed: 38957797
DOI: 10.3389/fcimb.2024.1410015 -
Ghana Medical Journal Sep 2023To assess the inter-laboratory comparability and intra-assay reproducibility of full blood count (FBC) results.
OBJECTIVE
To assess the inter-laboratory comparability and intra-assay reproducibility of full blood count (FBC) results.
DESIGN
Exploratory cross-sectional study.
SETTING
Three and two selected medical laboratories in the northern and southern zones, respectively.
PARTICIPANTS
Forty-nine individuals per zone; 16 type 2 diabetes mellitus, 16 with HbAS haemoglobin type and 17 normal samples.
INTERVENTION
Each sample was run eleven times through the analysers in the participating laboratories to evaluate intra-laboratory reproducibility and comparability of FBC results.
MAIN OUTCOME MEASURE
Intra-laboratory reproducibility was evaluated using %coefficient variation (%CV). Interlaboratory comparisons were assessed through t-test or One-Way ANOVA for two-sample and three-sample tests. All statistical testing was undertaken using the two-tailed assumption.
RESULT
Statistically significantly different haemoglobin levels were estimated in both northern and southern zones (mean difference 0.00 g/dL to 3.75 g/dL vs 0.18 g/dL to 1.92 g/dL respectively). Also, total WBC counts significantly differed across laboratories in both northern and southern zones (mean difference 0.15 ×10/L - 3.86 ×10/L vs 0.02 ×10/L to 1.39 ×10/L respectively). Furthermore, platelet counts significantly differed across the participating laboratories in the northern and southern zones (mean difference 0.40 ×10/L to 299.76 ×10/L vs 5.7 ×10/L to 76.9 ×10/L respectively). Moreover, there was evidence of non-reproducibility of results within the respective laboratories in each zone as the respective %CV were outside the acceptable limits.
CONCLUSION
The intra-laboratory non-reproducibility and inter-laboratory non-comparability of FBC results highlight the need to establish a national quality assessment scheme to harmonise laboratory practices nationwide.
FUNDING
This study was funded by the University of Cape Coast Individual-Led Research Support Grant (RSG-INDI-CoHAS-2019-107).
Topics: Humans; Ghana; Cross-Sectional Studies; Reproducibility of Results; Blood Cell Count; Diabetes Mellitus, Type 2; Hemoglobins; Laboratories, Clinical; Consensus; Hematology
PubMed: 38957675
DOI: 10.4314/gmj.v57i3.8 -
Ghana Medical Journal Sep 2023To determine if the number of vaso-occlusive events in SCD relates to plasma concentration of fucosyltransferase 7 (FUT7), which catalyses the synthesis of selectin...
OBJECTIVE
To determine if the number of vaso-occlusive events in SCD relates to plasma concentration of fucosyltransferase 7 (FUT7), which catalyses the synthesis of selectin ligands.
DESIGN
A prospective, analytical study.
SETTING
Haematology and Chemical Pathology Departments of tertiary healthcare centres.
PARTICIPANTS
Steady state HbSS individuals aged 13-45 years, 20 had 3 or more vaso-occlusive crises that required hospital admission in the previous year (with or without complications of SCD); 17 other HbSS persons had 0-1 vaso-occlusive crisis that required hospital admission in the previous year and no disease complications.
INTERVENTION
Steady-state plasma concentrations of FUT7 measured by ELISA were compared between SCD patients who had one vaso-occlusive crisis requiring hospital treatment in the previous year but no disease complications and those who had >3 crises with or without complications.
MAIN OUTCOME MEASURES
Plasma level of FUT7and the number of vaso-occlusive events in each HbSS patient.
RESULTS
Mean + standard deviation plasma concentration of FUT7 was 8.6 + 2.7 ng/ml in patients with >3 vasoocclusive crises in the previous year and 7.3 + 1.7 ng/ml in those with 0-1 crisis and no complications; independent sample t-test, p > 0.05, not significantly different.
CONCLUSION
Plasma concentration of fucosyltransferase7 is not associated with the number of vaso-occlusive events in sickle cell disease.
FUNDING
None declared.
Topics: Humans; Fucosyltransferases; Anemia, Sickle Cell; Adult; Female; Male; Prospective Studies; Adolescent; Young Adult; Middle Aged; Vascular Diseases; Enzyme-Linked Immunosorbent Assay; Biomarkers
PubMed: 38957672
DOI: 10.4314/gmj.v57i3.6 -
Dental Research and Oral Health 2024Topoisomerase IIα (TOP2A), is an enzyme involved in DNA replication, transcription, recombination, and chromatin remodeling and is found in a variety of cancers....
BACKGROUND
Topoisomerase IIα (TOP2A), is an enzyme involved in DNA replication, transcription, recombination, and chromatin remodeling and is found in a variety of cancers. However, the role of TOP2A regulation in oral cancer progression is not fully explained. We investigated the effect of TOP2A inhibition on cell survival, metabolism, and cancer stem cell self-renewal function in oral cancer cells.
METHODS
Oral carcinoma cell line SCC25 was cultured in complete DMEM/F12 media and treated with 5μM of Etoposide (Topoisomerase II inhibitor) for 48h. The critical parameters of cellular metabolism, including extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate of cancer cells were assessed using Seahorse assay. Western blotting was performed to assess the proteins that are associated with proliferation (Survivin, IL-6) and cancer stem cell function (Oct4, Sox2) in cell lysates prepared from control and etoposide treated groups. Statistical analysis was performed using One-way ANOVA with Dunnett's multiple comparisons test.
RESULTS
The protein expression of TOP2A was significantly (P<0.05) inhibited by etoposide. Additionally, TOP2A inhibition decreased the mitochondrial respiratory parameters including basal respiration, maximal respiration and ATP production. However, TOP2A inhibition has no impact on glycolytic function. Moreover, the proliferative marker survivin and IL-6 showed a significant (P<0.05) decrease after TOP2A inhibition. Conversely, the protein expression of cancer stem cell markers Oct-4 and Sox 2 were not altered.
CONCLUSION
These results indicate that inhibition of TOP2A is more efficacious by decreasing the mitochondrial metabolic reprogramming and thereby downregulating the key anti-apoptotic and pro-survival mediators. Thus, TOP2A represents an ideal therapeutic target and offers a potential treatment strategy for OSCC.
PubMed: 38957610
DOI: 10.26502/droh.0076 -
Frontiers in Immunology 2024Sepsis is a life-threatening organ dysfunction and lack of effective measures in the current. Exosomes from mesenchymal stem cells (MSCs) reported to alleviate...
Exosome-shuttled miR-150-5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis.
RATIONALE
Sepsis is a life-threatening organ dysfunction and lack of effective measures in the current. Exosomes from mesenchymal stem cells (MSCs) reported to alleviate inflammation during sepsis, and the preconditioning of MSCs could enhance their paracrine potential. Therefore, this study investigated whether exosomes secreted by lipopolysaccharide (LPS)-pretreated MSCs exert superior antiseptic effects, and explored the underlying molecular mechanisms.
METHODS
Exosomes were isolated and characterized from the supernatants of MSCs. The therapeutic efficacy of normal exosomes (Exo) and LPS-pretreated exosomes (LPS-Exo) were evaluated in terms of survival rates, inflammatory response, and organ damage in an LPS-induced sepsis model. Macrophages were stimulated with LPS and treated with Exo or LPS-Exo to confirm the results of the studies, and to explain the potential mechanisms.
RESULTS
LPS-Exo were shown to inhibit aberrant pro-inflammatory cytokines, prevent organ damages, and improve survival rates of the septic mice to a greater extent than Exo. , LPS-Exo significantly promoted the M2 polarization of macrophages exposed to inflammation. miRNA sequencing and qRT-PCR analysis identified the remarkable expression of miR-150-5p in LPS-Exo compared to that in Exo, and exosomal miR-150-5p was transferred into recipient macrophages and mediated macrophage polarization. Further investigation demonstrated that miR-150-5p targets Irs1 in recipient macrophages and subsequently modulates macrophage plasticity by down-regulating the PI3K/Akt/mTOR pathway.
CONCLUSION
The current findings highly suggest that exosomes derived from LPS pre-conditioned MSCs represent a promising cell-free therapeutic method and highlight miR-150-5p as a novel molecular target for regulating immune hyperactivation during sepsis.
Topics: MicroRNAs; Animals; Exosomes; Mesenchymal Stem Cells; Sepsis; TOR Serine-Threonine Kinases; Mice; Proto-Oncogene Proteins c-akt; Lipopolysaccharides; Macrophages; Insulin Receptor Substrate Proteins; Signal Transduction; Phosphatidylinositol 3-Kinases; Male; Mice, Inbred C57BL; Macrophage Activation; Disease Models, Animal
PubMed: 38957471
DOI: 10.3389/fimmu.2024.1397722 -
Frontiers in Immunology 2024
Review
Topics: Humans; Oxidation-Reduction; Inflammation; Animals; Growth Hormone-Releasing Hormone
PubMed: 38957466
DOI: 10.3389/fimmu.2024.1403124