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Cell and Tissue Banking Jun 2024An injury that affects the integrity of the skin, either inside or externally, is called a wound. Damaged tissue is repaired by a set of cellular and molecular...
An injury that affects the integrity of the skin, either inside or externally, is called a wound. Damaged tissue is repaired by a set of cellular and molecular mechanisms known as wound healing. Quercetin, a naturally occurring flavonoid, may hasten the healing of wounds. The study's objective was to investigate any potential impacts of quercetin on the wound-healing process. Human umbilical vein endothelial cells (HUVECs) were treated to varying dose ranges of quercetin (5-320 nM) for 24 and 48 h. Cultured cells were evaluated by using the MTT analysis, wound scratch assay and vascular tube formation. Furthermore the gene expression of VEGF and FGF were evaluated by qRT-PCR to determine the effects of quercetin on angiogenezis and wound repair. Positive effects of quercetin on cellular viability were demonstrated by the MTT experiment. In HUVECs quercetin promoted tube formation, migration, and proliferation while also averting wound breakage. Moreover, quercetin increased the expression of the FGF and VEGF genes, which aid in the healing of wounds in HUVECs. Quercetin may be bioactive molecule that successfully speeds up wound healing by regulating the vasculogenezis and healing cells.
PubMed: 38944663
DOI: 10.1007/s10561-024-10144-1 -
Nature Communications Jun 2024Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4 T cell...
Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4 T cell subsets remain unresolved. Here, we examine antigen-experienced CD4 T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic T cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with T/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4 T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4 T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.
Topics: Animals; Malaria; CD4-Positive T-Lymphocytes; Mice; Reinfection; Th1 Cells; Mice, Inbred C57BL; Spleen; Receptors, Antigen, T-Cell; Mice, Transgenic; Female; Immunologic Memory
PubMed: 38944658
DOI: 10.1038/s41467-024-49879-6 -
Nature Communications Jun 2024JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the...
JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the Drosophila intestine, the TNF-type ligand, Eiger (Egr), is expressed exclusively by intestinal stem cells (ISCs) and enteroblasts (EBs), where it is induced by stress and during aging. Egr preferentially activates JNK signaling in a paracrine fashion in differentiated enterocytes (ECs) via its receptor, Grindelwald (Grnd). N-glycosylation genes (Alg3, Alg9) restrain this activation, and stress-induced downregulation of Alg3 and Alg9 correlates with JNK activation, suggesting a regulatory switch. JNK activity in ECs induces expression of the intermembrane protease Rhomboid (Rho), driving secretion of EGFR ligands Keren (Krn) and Spitz (Spi), which in turn activate EGFR signaling in progenitor cells (ISCs and EBs) to stimulate their growth and division, as well as to produce more Egr. This study uncovers an N-glycosylation-controlled, paracrine JNK-EGFR-JNK feedforward loop that sustains ISC proliferation during stress-induced gut regeneration.
Topics: Animals; Drosophila Proteins; ErbB Receptors; Intestines; MAP Kinase Signaling System; Drosophila melanogaster; Enterocytes; Stem Cells; Intestinal Mucosa; Drosophila; Glycosylation; Receptors, Invertebrate Peptide; Cell Proliferation; JNK Mitogen-Activated Protein Kinases; Signal Transduction; Cell Communication; Cell Differentiation; Epidermal Growth Factor; Membrane Proteins
PubMed: 38944657
DOI: 10.1038/s41467-024-49786-w -
Communications Biology Jun 2024Macrolide antibiotics, pivotal in clinical therapeutics, are confronting resistance challenges mediated by enzymes like macrolide esterases, which are classified into...
Macrolide antibiotics, pivotal in clinical therapeutics, are confronting resistance challenges mediated by enzymes like macrolide esterases, which are classified into Ere-type and the less studied Est-type. In this study, we provide the biochemical confirmation of EstX, an Est-type macrolide esterase that initially identified as unknown protein in the 1980s. EstX is capable of hydrolyzing four 16-membered ring macrolides, encompassing both veterinary (tylosin, tidipirosin, and tilmicosin) and human-use (leucomycin A5) antibiotics. It uses typical catalytic triad (Asp233-His261-Ser102) from alpha/beta hydrolase superfamily for ester bond hydrolysis. Further genomic context analysis suggests that the dissemination of estX is likely facilitated by mobile genetic elements such as integrons and transposons. The global distribution study indicates that bacteria harboring the estX gene, predominantly pathogenic species like Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae, are prevalent in 74 countries across 6 continents. Additionally, the emergence timeline of the estX gene suggests its proliferation may be linked to the overuse of macrolide antibiotics. The widespread prevalence and dissemination of Est-type macrolide esterase highlight an urgent need for enhanced monitoring and in-depth research, underlining its significance as an escalating public health issue.
Topics: Esterases; Anti-Bacterial Agents; Macrolides; Humans; Bacterial Proteins; Phylogeny; Hydrolases
PubMed: 38944651
DOI: 10.1038/s42003-024-06473-2 -
American Journal of Surgery Jun 2024There has been tremendous effort to improve quality following colorectal surgery, including the proliferation of minimally invasive techniques, enhanced recovery...
BACKGROUND
There has been tremendous effort to improve quality following colorectal surgery, including the proliferation of minimally invasive techniques, enhanced recovery protocols, and surgical site infection prevention bundles. While these programs have demonstrated improved postoperative outcomes at the institutional level, it is unclear whether similar benefits are present on a national scale.
METHODS
American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Targeted Colectomy data from 2012 to 2020 were used to identify patients undergoing minimally invasive surgery (MIS) or open partial colectomy (CPT 44140, 44204) or low anterior resection (CPT 44145, 44207). Chronological cohorts as well as annual trends in 30-day postoperative outcomes including surgical site infection, venous thromboembolism, and length of stay were assessed using both univariable and multivariable regression analyses.
RESULTS
261,301 patients, 135,876 (52 %) female, with a median age of 62 (IQR 53-72) were included. Across all years, MIS partial colectomy was the most common procedure (37 %), followed by MIS low anterior resection (27 %), open partial colectomy (24 %), and open low anterior resection (12 %). MIS increased from 59 % in 2012-2014 to 66 % in 2018-2020 (p < 0.001). During this same period, postoperative length of stay decreased from a median of 5 days (IQR 4-7) in 2012-2014 to 4 days (IQR 3-6) in 2018-2020 (p < 0.001). Superficial surgical site infections decreased from 5.5 % in 2012-2014 to 2.9 % in 2018-2020 (p < 0.001). Deep surgical site infections similarly decreased from 1.1 % to 0.4 % between these periods (p < 0.001). Pulmonary embolism also decreased from 0.6 % to 0.5 % between periods (p = 0.02). 30-day mortality was unchanged at 1.7 % between 2012-2014 and 2018-2020 (p = 0.40). After adjustment for ACS NSQIP estimated probability of morbidity and mortality, undergoing a colectomy in 2020 compared to 2012 was associated with a 14 % decrease in postoperative length of stay (p < 0.001).
CONCLUSIONS
Between 2012 and 2020, significant improvements in postoperative outcomes after colectomy were observed in the United States. These results support the positive impact that the widespread adoption of quality improvement initiatives is having on colorectal patient care nationally.
PubMed: 38944622
DOI: 10.1016/j.amjsurg.2024.115808 -
Cancer Genomics & Proteomics 2024Metastatic prostate cancer (mPCa) results in high morbidity and mortality. Visceral metastases in particular are associated with a shortened survival. Our aim was to...
BACKGROUND/AIM
Metastatic prostate cancer (mPCa) results in high morbidity and mortality. Visceral metastases in particular are associated with a shortened survival. Our aim was to unravel the molecular mechanisms that underly pulmonary spread in mPCa.
MATERIALS AND METHODS
We performed a comprehensive transcriptomic analysis of PCa lung metastases, followed by functional validation of candidate genes. Digital gene expression analysis utilizing the NanoString technology was performed on mRNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissue from PCa lung metastases. The gene expression data from primary PCa and PCa lung metastases were compared, and several publicly available bioinformatic analysis tools were used to annotate and validate the data.
RESULTS
In PCa lung metastases, 234 genes were considerably up-regulated, and 78 genes were significantly down-regulated when compared to primary PCa. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) was identified as suitable candidate gene for further functional validation. CEACAM6 as a cell adhesion molecule has been implicated in promoting metastatic disease in several solid tumors, such as colorectal or gastric cancer. We showed that siRNA knockdown of CEACAM6 in PC-3 and LNCaP cells resulted in decreased cell viability and migration as well as enhanced apoptosis. Comprehensive transcriptomic analyses identified several genes of interest that might promote metastatic spread to the lung.
CONCLUSION
Functional validation revealed that CEACAM6 might play an important role in fostering metastatic spread to the lung of PCa patients via enhancing proliferation, migration and suppressing apoptosis in PC-3 and LNCaP cells. CEACAM6 might pose an attractive therapeutic target to prevent metastatic disease.
Topics: Humans; Male; Apoptosis; Cell Adhesion Molecules; Cell Proliferation; Cell Movement; Lung Neoplasms; Antigens, CD; Prostatic Neoplasms; GPI-Linked Proteins; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 38944419
DOI: 10.21873/cgp.20459 -
Clinica Chimica Acta; International... Jun 2024Breast cancer (BC) remains the most prevalent cancer among women worldwide, despite significant advancements in its prevention and treatment. The escalating incidence of...
Breast cancer (BC) remains the most prevalent cancer among women worldwide, despite significant advancements in its prevention and treatment. The escalating incidence of BC globally necessitates continued research into novel diagnostic and therapeutic strategies. Metabolomics, a burgeoning field, offers a comprehensive analysis of all metabolites within a cell, tissue, system, or organism, providing crucial insights into the dynamic changes occurring during cancer development and progression. This review focuses on the metabolic alterations associated with BC, highlighting the potential of metabolomics in identifying biomarkers for early detection, diagnosis, treatment and prognosis. Metabolomics studies have revealed distinct metabolic signatures in BC, including alterations in lipid metabolism, amino acid metabolism, and energy metabolism. These metabolic changes not only support the rapid proliferation of cancer cells but also influence the tumour microenvironment and therapeutic response. Furthermore, metabolomics holds great promise in personalized medicine, facilitating the development of tailored treatment strategies based on an individual's metabolic profile. By providing a holistic view of the metabolic changes in BC, metabolomics has the potential to revolutionize our understanding of the disease and improve patient outcomes.
PubMed: 38944408
DOI: 10.1016/j.cca.2024.119836 -
Biochemical Pharmacology Jun 2024Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA...
Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the proteasome. Inhibition of the PI3K/AKT signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.
PubMed: 38944395
DOI: 10.1016/j.bcp.2024.116398 -
Journal of Theoretical Biology Jun 2024The mechanisms underlying the formation of necrotic regions within avascular tumors are complex and poorly understood. In this paper, we investigate the formation of a...
The mechanisms underlying the formation of necrotic regions within avascular tumors are complex and poorly understood. In this paper, we investigate the formation of a necrotic core in a 3D tumor cell culture within a microfluidic device, considering oxygen, nutrients, and the microenvironment acidification by means of a computational-mathematical model. Our objective is to simulate cell processes, including proliferation and death inside a microfluidic device, according to the microenvironmental conditions. We employed approximation utilizing the finite element models taking into account glucose, oxygen, and hydrogen ions diffusion, consumption and production, as well as cell proliferation, migration and death, addressing how tumor cells evolve under different conditions. The resulting mathematical model was examined under different scenarios, being capable of reproducing cell death and proliferation under different cell concentrations, and the formation of a necrotic core, in good agreement with experimental data reported in the literature. This approach not only advances our fundamental understanding of necrotic core formation but also provides a robust computational platform to study personalized therapeutic strategies, offering an important tool in cancer research and treatment design.
PubMed: 38944380
DOI: 10.1016/j.jtbi.2024.111893 -
Journal of Theoretical Biology Jun 2024Regulation of cell proliferation is a crucial aspect of tissue development and homeostasis and plays a major role in morphogenesis, wound healing, and tumor invasion. A...
Regulation of cell proliferation is a crucial aspect of tissue development and homeostasis and plays a major role in morphogenesis, wound healing, and tumor invasion. A phenomenon of such regulation is contact inhibition, which describes the dramatic slowing of proliferation, cell migration and individual cell growth when multiple cells are in contact with each other. While many physiological, molecular and genetic factors are known, the mechanism of contact inhibition is still not fully understood. In particular, the relevance of cellular signaling due to interfacial contact for contact inhibition is still debated. Cellular automata (CA) have been employed in the past as numerically efficient mathematical models to study the dynamics of cell ensembles, but they are not suitable to explore the origins of contact inhibition as such agent-based models assume fixed cell sizes. We develop a minimal, data-driven model to simulate the dynamics of planar cell cultures by extending a probabilistic CA to incorporate size changes of individual cells during growth and cell division. We successfully apply this model to previous in-vitro experiments on contact inhibition in epithelial tissue: After a systematic calibration of the model parameters to measurements of single-cell dynamics, our CA model quantitatively reproduces independent measurements of emergent, culture-wide features, like colony size, cell density and collective cell migration. In particular, the dynamics of the CA model also exhibit the transition from a low-density confluent regime to a stationary postconfluent regime with a rapid decrease in cell size and motion. This implies that the volume exclusion principle, a mechanical constraint which is the only inter-cellular interaction incorporated in the model, paired with a size-dependent proliferation rate is sufficient to generate the observed contact inhibition. We discuss how our approach enables the introduction of effective bio-mechanical interactions in a CA framework for future studies.
PubMed: 38944379
DOI: 10.1016/j.jtbi.2024.111882