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Frontiers in Bioscience (Landmark... Apr 2024Sodium-glucose cotransporters 2 (SGLT2) are high-capacity, low-affinity transporters, expressed mainly in the early portion of the proximal renal tube, mediating up to... (Review)
Review
Sodium-glucose cotransporters 2 (SGLT2) are high-capacity, low-affinity transporters, expressed mainly in the early portion of the proximal renal tube, mediating up to 90% of renal glucose uptake, while SGLT1 receptors are found mainly in the small intestine, facilitating glucose absorption. SGLT2 inhibitors (SGLT2i) originally emerged as agents for the treatment of type 2 diabetes mellitus; however, they soon demonstrated remarkable cardio- and renoprotective actions that led to their licensed use for the treatment of heart failure and chronic kidney disease, regardless of the diabetic status. Cardiovascular remodelling represents an umbrella term that encompasses changes that occur in the cardiovascular system, from the molecular and cellular level, to tissue and organs after local injury, chronic stress, or pressure. SGLT modulation has been shown to positively affect many of these molecular and cellular changes observed during pathological remodelling. Among the different pathophysiological mechanisms that contribute to adverse remodelling, various stem and progenitor cells have been shown to be involved, through alterations in their number or function. Recent studies have examined the effects of SGLT2i on stem and progenitor cell populations and more specifically on endothelial progenitor cells (EPCs). Although some found no significant effect, others showed that SGLT2i can modulate the morphology and function of EPCs. These preliminary observations of the effect of SGLT2i on EPCs may be responsible for some of the beneficial effects of gliflozins on pathological remodelling and, by extension, on cardiovascular disease. The purpose of this narrative review is to critically discuss recent evidence on the cardioprotective effects of SGLT2is, in the context of cardiac remodelling.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Stem Cells; Animals; Diabetes Mellitus, Type 2; Ventricular Remodeling; Cardiovascular System; Sodium-Glucose Transporter 2; Cardiovascular Diseases; Heart Failure
PubMed: 38682194
DOI: 10.31083/j.fbl2904145 -
NPJ Precision Oncology Apr 2024In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus,...
In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significantly contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.
PubMed: 38637626
DOI: 10.1038/s41698-024-00578-x -
Radiology Case Reports Jun 2024Extramedullary hematopoiesis represents a clinical compensatory condition characterized by the growth of hematopoietic tissue outside the bone marrow. It can mainly...
Extramedullary hematopoiesis represents a clinical compensatory condition characterized by the growth of hematopoietic tissue outside the bone marrow. It can mainly occur in patient with myeloproliferative disorders where alteration or neoplastic invasion of the bone marrow causes ineffective production of blood cells with the recruitment of progenitrix blood cells in non-hematopoietic organs, including kidneys. Renal extramedullary hematopoiesis is a rare condition manifesting as parenchymal or perirenal soft tissue masses with different patterns mimicking neoplasms, infectious or vascular diseases. We describe a unique case of a patient affected by primary myelofibrosis underwent ultrasound and magnetic resonance examinations showing bilateral perirenal alterations to be related to hemopoietic tissue. We also focused on the pathophysiology of this condition with imaging correlation. The case we present emphasises the importance of recognising the main radiological features of renal extramedullary hematopoiesis. MR examination should become part of the diagnostic pathway of the patient with primary myelofibrosis.
PubMed: 38559653
DOI: 10.1016/j.radcr.2024.02.083 -
Magnetic Resonance in Medical Sciences... Feb 2024A chemically fixed Carnegie stage 23 (approximately 56 days of gestation) human embryo specimen was imaged using 3D spin-echo and gradient-echo sequences in a static...
A chemically fixed Carnegie stage 23 (approximately 56 days of gestation) human embryo specimen was imaged using 3D spin-echo and gradient-echo sequences in a static magnetic field strength of 4.74T, and a quantitative susceptibility map was calculated using the 3D gradient-echo image. The acquired 3D microscopic images (90 μm cube voxel size) clarified the relationship between R (transverse relaxation rate), R* (apparent transverse relaxation rate), and magnetic susceptibility in the heart, liver, kidney, and spinal cord. The results suggested that the R* and magnetic susceptibility in each tissue were probably due to paramagnetic iron ions originating from erythrocytes. The large R* (~130 s) and magnetic susceptibility (~0.122 ppm) in the liver were attributed to its hemopoietic function. A large magnetic susceptibility (~0.116 ppm) was also observed in the spinal cord, but we conclude that more detailed future studies are needed.
PubMed: 38417909
DOI: 10.2463/mrms.tn.2023-0149 -
Frontiers in Immunology 2024There is little information on the trajectory and developmental fate of LinCD34DNAM-1 CXCR4 progenitors exiting bone marrow during systemic inflammation.
BACKGROUND
There is little information on the trajectory and developmental fate of LinCD34DNAM-1 CXCR4 progenitors exiting bone marrow during systemic inflammation.
OBJECTIVE
To study LinCD34DNAM-1 CXCR4 cell circulation in cancer patients, to characterize their entry into involved lung tissue and to characterize their progenies.
METHODS
Flow cytometric analysis of PBMC from 18 patients with lung cancer on samples collected immediately before the first and the second treatment was performed to study LinCD34DNAM-1 CXCR4 precursors. Precursors were purified (>99%) and cultured from all patients. Paired PBMC and tissue samples from patients undergoing tumor resection were analyzed by flow cytometry to assess tissue entry and compare phenotype and developmental potential of LinCD34DNAM-1 CXCR4 cells in both compartments.
RESULTS
Significant circulation of LinCD34DNAM-1 CXCR4 precursors was observed 20d after the first treatment. Precursors express CXC3CR1, CXCR3, CXCR1 consistent with travel towards inflamed tissues. Flowcytometric analysis of lung tissue samples showed precursor presence in all patients in tumor and neighboring uninvolved areas. Successful purification and culture from both blood and lung tissue generates a minor proportion of maturing NK cells (<10%) and a predominant proportion (>85%) of α/β T-progenies with innate-like phenotype expressing NKG2D,NKp30,DNAM-1. Innate-like maturing T-cells are cytotoxic, can be triggered via NKR/TCR co-stimulation and display broad spectrum Th1,Th2 and Th1/Th17 cytokine production.
CONCLUSION
In advanced stage lung cancer CD34DNAM-1CXCR4 inflammatory precursors increase upon treatment, enter involved tissues, generate functional progenies and may thus represent an additional player contributing to immune balance in the highly SDF-1/CXCR4-biased pro-metastatic tumor microenvironment.
Topics: Humans; Leukocytes, Mononuclear; Killer Cells, Natural; Bone Marrow; Lung; Lung Neoplasms; Tumor Microenvironment; Receptors, CXCR4
PubMed: 38390333
DOI: 10.3389/fimmu.2024.1332781 -
Clinical & Translational Immunology 2024Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality,...
OBJECTIVES
Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes.
METHODS
Twenty-one patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling and whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB.
RESULTS
Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 h afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony-stimulating factor (G-CSF), a regulator of neutrophil production and function.
CONCLUSIONS
We identified neutrophils and G-CSF as major regulators of CPB-induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil-mediated inflammation and tissue damage in SIRS induced by CPB.
PubMed: 38375330
DOI: 10.1002/cti2.1490 -
Biomedicine & Pharmacotherapy =... Dec 2023Acquired aplastic anemia (AA) is a bone marrow failure (BMF) disease, characterized by fatty bone marrow (BM) and BM hypocellularity resulted from auto-immune...
Acquired aplastic anemia (AA) is a bone marrow failure (BMF) disease, characterized by fatty bone marrow (BM) and BM hypocellularity resulted from auto-immune dysregulated T cells-mediated destruction of BM haemopoietic stem cells (HPSC). The objective of this study was to investigate potential therapeutic effect of irisin, a molecule involved in adipose tissue transition, on AA mouse model. Our results showed that the concentration of irisin in serum was lower in AA patients than in healthy controls, suggesting a role of irisin in the pathogenesis of AA. In the AA mice, irisin administration prolonged the survival rate, prevented or attenuated peripheral pancytopenia, and preserved HPSC in the BM. Moreover, irisin also markedly reduced BM adipogenesis. In vitro results showed that irisin increased both cell proliferation and colony numbers of HPSC. Furthermore, our results demonstrated that irisin upregulated the expression of mitochondrial ATPase Inhibitory Factor 1 (IF1) in HPSC, inhibited the activation of mitochondrial fission protein (DRP1) and enhanced aerobic glycolysis. Taken together, our findings indicate novel roles of irisin in the pathogenesis of AA, and in the protection of HPSC through stimulation of proliferation and regulation of mitochondria function, which provides a proof-of-concept for the application of irisin in AA therapy.
Topics: Animals; Humans; Mice; Anemia, Aplastic; Bone Marrow; Bone Marrow Cells; Fibronectins; Pancytopenia; Hematopoietic Stem Cells
PubMed: 37952356
DOI: 10.1016/j.biopha.2023.115863 -
Nature Nov 2023Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I...
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs), conferring a predisposition to life-threatening COVID-19 pneumonia. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52/IκBδ). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52/IκBδ) or gain-of-function of p52 (hereafter, p52/IκBδ). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
Topics: Humans; Autoantibodies; COVID-19; Gain of Function Mutation; Genetic Predisposition to Disease; Heterozygote; I-kappa B Proteins; Interferon Type I; Loss of Function Mutation; NF-kappa B; NF-kappa B p52 Subunit; Pneumonia, Viral; Thymus Gland; Thyroid Epithelial Cells; AIRE Protein; NF-kappaB-Inducing Kinase
PubMed: 37938781
DOI: 10.1038/s41586-023-06717-x -
Journal of Translational Medicine Oct 2023Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not... (Review)
Review
Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-β, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.
Topics: Humans; Bone Marrow; Primary Myelofibrosis; Cytokines; Fibrosis; Chemokines; Hormones
PubMed: 37814319
DOI: 10.1186/s12967-023-04393-z -
Cancer Immunology, Immunotherapy : CII Oct 2023The macrophage colony-stimulating factor 1 (CSF1) is a chemokine essential for the survival, proliferation, and differentiation of mononuclear phagocytes from...
The macrophage colony-stimulating factor 1 (CSF1) is a chemokine essential for the survival, proliferation, and differentiation of mononuclear phagocytes from hemopoietic stem cells. In addition to its essential physiological role in normal tissues, the CSF1/CSF1 receptor axis is known to be overexpressed in many tumor types and associated with poor prognosis. High levels of CSF1 within the tumor microenvironment have been shown to recruit and reeducate macrophages to produce factors that promote tumor invasiveness and accelerate metastasis. In this study, we demonstrate, for the first time, that treating established syngeneic murine colon and breast carcinoma tumors with a CSF1R-blocking antibody also promotes the expansion of neoepitope-specific T cells. To assess the role of tumor-derived CSF1 in these model systems, we generated and characterized CSF1 CRISPR-Cas9 knockouts. Eliminating tumor-derived CSF1 results in decreased tumor growth and enhanced immunity against tumor-associated neoepitopes, potentially promoting an immune permissive tumor microenvironment in tumor-bearing mice. The combination of neoepitope vaccine with anti-PDL1 in the MC38 CSF1-/- tumor model significantly decreased tumor growth in vivo. Moreover, anti-CSF1R therapy combined with the adeno-TWIST1 vaccine resulted in tumor control, decreased metastasis, and a synergistic increase in CD8 T cell infiltration in 4T1 mammary tumors. Analysis of the tumor microenvironment demonstrated greater CD8 T cell infiltration and a reduction in tumor-associated macrophages following CSF1R inhibition in both tumor models. Our findings thus add to the therapeutic potential of CSF1 targeting agents by employing combinations with vaccines to modulate anti-neoepitope responses in the tumor microenvironment.
Topics: Mice; Animals; Macrophage Colony-Stimulating Factor; Tumor Microenvironment; Macrophages; Neoplasms
PubMed: 37505292
DOI: 10.1007/s00262-023-03496-2