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Journal of Gastrointestinal and Liver... Jun 2024
Response to Letter to Editor on "Reduction of Fecal Calprotectin Levels Induced by a Short Course of Escherichia Coli Nissle is Associated with a Lower Likelihood of Disease Flares in Patients with Ulcerative Colitis in Clinical Remission".
Topics: Humans; Leukocyte L1 Antigen Complex; Colitis, Ulcerative; Feces; Escherichia coli; Remission Induction; Symptom Flare Up; Probiotics; Biomarkers
PubMed: 38944863
DOI: 10.15403/jgld-5660 -
Journal of Extracellular Vesicles Jul 2024Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains...
Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains poorly understood. Here, we demonstrate the involvement of β-hexosaminidase B (HEXB) in mediating EV release in response to oxidative stress, thereby promoting the development of hepatocellular carcinoma (HCC). Mechanistically, reactive oxygen species (ROS) stimulate the nuclear translocation of transcription factor EB (TFEB), leading to the upregulation of both HEXB and its antisense lncRNA HEXB-AS. HEXB-AS can bind HEXB to form a protein/RNA complex, which elevates the protein stability of HEXB. The stabilized HEXB interacts with lysosome-associated membrane glycoprotein 1 (LAMP1), disrupting lysosome-multivesicular body (MVB) fusion, which protects EVs from degradation. Knockdown of HEXB efficiently inhibits EV release and curbs HCC growth both in vitro and in vivo. Moreover, targeting HEXB by M-31850 significantly inhibits HCC growth, especially when combined with GW4869, an inhibitor of exosome release. Our results underscore the critical role of HEXB as a modulator that promotes EV release during HCC development.
Topics: Extracellular Vesicles; Carcinoma, Hepatocellular; Animals; Oxidative Stress; Humans; Liver Neoplasms; Mice; Up-Regulation; Cell Line, Tumor; Cell Proliferation; RNA, Long Noncoding; Reactive Oxygen Species; Gene Expression Regulation, Neoplastic; Male; Mice, Nude
PubMed: 38944674
DOI: 10.1002/jev2.12468 -
Journal of Extracellular Vesicles Jul 2024Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour...
Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour development. Here, the role of in vitro generated B16F10 tumour cell-derived extracellular vesicles (tEVs) as indirect cellular communicators, participating in tumour-induced dysregulation of haematopoiesis, was explored. The isolated tEVs displayed features of small EVs with a size range of 100-200 nm, expressed the common EV markers CD63, CD9, and Alix, and had a spherical shape with a lipid bilayer membrane. Proteomic profiling revealed significant levels of angiogenic factors, particularly vascular endothelial growth factor (VEGF), osteopontin, and tissue factor, associated with the tEVs. Systemic administration of these tEVs in syngeneic mice induced splenomegaly and disrupted haematopoiesis, leading to extramedullary haematopoiesis, expansion of splenic immature erythroid progenitors, reduced bone marrow cellularity, medullary expansion of granulocytic myeloid suppressor cells, and the development of anaemia. These effects closely mirrored those observed in tumour-bearing mice and were not seen after heat inactivating the tEVs. In vitro studies demonstrated that tEVs independently induced the expansion of bone marrow granulocytic myeloid suppressor cells and B cells while reducing the frequency of cells in the erythropoietic lineage. These effects of tEVs were significantly abrogated by the blockade of VEGF or heat inactivation. Our findings underscore the important role of tEVs in dysregulating haematopoiesis during the immune escape phase of cancer immunoediting, suggesting their potential as targets for addressing immune evasion and reinstating normal hematopoietic processes.
Topics: Animals; Extracellular Vesicles; Mice; Hematopoiesis; Melanoma, Experimental; Mice, Inbred C57BL; Vascular Endothelial Growth Factor A; Cell Line, Tumor
PubMed: 38944672
DOI: 10.1002/jev2.12471 -
Journal of Medical Case Reports Jun 2024Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest...
BACKGROUND
Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies).
CASE PRESENTATION
We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of β-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process.
CONCLUSION
The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy.
Topics: Humans; Female; Pregnancy; Lung Neoplasms; Choriocarcinoma; Uterine Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Methotrexate; Vincristine; Dactinomycin; Etoposide; Chorionic Gonadotropin, beta Subunit, Human; Cyclophosphamide; Dyspnea; Pregnancy Complications, Neoplastic
PubMed: 38944668
DOI: 10.1186/s13256-024-04615-y -
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 -
Nature Communications Jun 2024IncX3 plasmids carrying the New Delhi metallo-β-lactamase-encoding gene, bla, are rapidly spreading globally in both humans and animals. Given that carbapenems are...
IncX3 plasmids carrying the New Delhi metallo-β-lactamase-encoding gene, bla, are rapidly spreading globally in both humans and animals. Given that carbapenems are listed on the WHO AWaRe watch group and are prohibited for use in animals, the drivers for the successful dissemination of Carbapenem-Resistant Enterobacterales (CRE) carrying bla-IncX3 plasmids still remain unknown. We observe that E. coli carrying bla-IncX3 can persist in chicken intestines either under the administration of amoxicillin, one of the largest veterinary β-lactams used in livestock, or without any antibiotic pressure. We therefore characterise the bla-IncX3 plasmid and identify a transcription regulator, VirBR, that binds to the promoter of the regulator gene actX enhancing the transcription of Type IV secretion systems (T4SS); thereby, promoting conjugation of IncX3 plasmids, increasing pili adhesion capacity and enhancing the colonisation of bla-IncX3 transconjugants in animal digestive tracts. Our mechanistic and in-vivo studies identify VirBR as a major factor in the successful spread of bla-IncX3 across one-health AMR sectors. Furthermore, VirBR enhances the plasmid conjugation and T4SS expression by the presence of copper and zinc ions, thereby having profound ramifications on the use of universal animal feeds.
Topics: Animals; Plasmids; beta-Lactamases; Chickens; Humans; Escherichia coli; Anti-Bacterial Agents; Conjugation, Genetic; Escherichia coli Proteins; Type IV Secretion Systems; Transcription Factors; Amoxicillin; Promoter Regions, Genetic; Escherichia coli Infections; Gene Expression Regulation, Bacterial; Intestines
PubMed: 38944647
DOI: 10.1038/s41467-024-49800-1 -
NPJ Biofilms and Microbiomes Jun 2024Gut metaproteomics can provide direct evidence of microbial functions actively expressed in the colonic environments, contributing to clarify the role of the gut... (Meta-Analysis)
Meta-Analysis
Gut metaproteomics can provide direct evidence of microbial functions actively expressed in the colonic environments, contributing to clarify the role of the gut microbiota in human physiology. In this study, we re-analyzed 10 fecal metaproteomics datasets of healthy individuals from different continents and countries, with the aim of identifying stable and variable gut microbial functions and defining the contribution of specific bacterial taxa to the main metabolic pathways. The "core" metaproteome included 182 microbial functions and 83 pathways that were identified in all individuals analyzed. Several enzymes involved in glucose and pyruvate metabolism, along with glutamate dehydrogenase, acetate kinase, elongation factors G and Tu and DnaK, were the proteins with the lowest abundance variability in the cohorts under study. On the contrary, proteins involved in chemotaxis, response to stress and cell adhesion were among the most variable functions. Random-effect meta-analysis of correlation trends between taxa, functions and pathways revealed key ecological and molecular associations within the gut microbiota. The contribution of specific bacterial taxa to the main biological processes was also investigated, finding that Faecalibacterium is the most stable genus and the top contributor to anti-inflammatory butyrate production in the healthy gut microbiota. Active production of other mucosal immunomodulators facilitating host tolerance was observed, including Roseburia flagellin and lipopolysaccharide biosynthetic enzymes expressed by members of Bacteroidota. Our study provides a detailed picture of the healthy human gut microbiota, contributing to unveil its functional mechanisms and its relationship with nutrition, immunity, and environmental stressors.
Topics: Humans; Gastrointestinal Microbiome; Proteomics; Bacteria; Feces; Bacterial Proteins; Healthy Volunteers; Proteome; Metabolic Networks and Pathways
PubMed: 38944645
DOI: 10.1038/s41522-024-00526-4 -
The Journal of Biological Chemistry Jun 2024One of seven natural CO fixation pathways, the anaerobic Wood-Ljungdahl Pathway (WLP) is unique in generating CO as a metabolic intermediate, operating through...
One of seven natural CO fixation pathways, the anaerobic Wood-Ljungdahl Pathway (WLP) is unique in generating CO as a metabolic intermediate, operating through organometallic intermediates, and in conserving (versus utilizing) net ATP. The key enzyme in the WLP is acetyl-CoA synthase (ACS), which uses an active site [2Ni-4Fe-4S] cluster (A-cluster), a CO tunnel, and an organometallic (Ni-CO, Ni-methyl, and Ni-acetyl) reaction sequence to generate acetyl-CoA. Here we reveal that an alcove, which interfaces the tunnel and the A-cluster, is essential for CO fixation and autotrophic growth by the WLP. In vitro spectroscopy, kinetics, binding, and in vivo growth experiments reveal that a Phe229A substitution at one wall of the alcove decreases CO affinity thirty-fold and abolishes autotrophic growth; however, a F229W substitution enhances CO binding 80-fold. Our results indicate the structure of the alcove is exquisitely tuned to concentrate CO near the A-cluster; protect ACS from CO loss during catalysis, provide a haven for inhibitory CO, and stabilize the tetrahedral coordination at the Ni site where CO binds. The directing, concentrating, and protective effects of the alcove explain the inability of F209A to grow autotrophically. The alcove also could help explain current controversies over whether ACS binds CO and methyl through a random or ordered mechanism. Our work redefines what we historically refer to as the metallocenter "active site". The alcove is so crucial for enzymatic function that we propose it is part of the active site. The community should now look for such alcoves in all "gas handling" metalloenzymes.
PubMed: 38944127
DOI: 10.1016/j.jbc.2024.107503