Human Mesenchymal Stem Cell Secretome Driven T Cell Immunomodulation Is IL-10 Dependent

Financial support was provided by the Ministry of Higher Education and Scientific Research, Iraq (S1443) and the Guy Hilton Asthma Trust.Peer reviewedPublisher PD

Physoxia alters human mesenchymal stem cell secretome

The human mesenchymal stem cell (hMSC) secretome has pleiotropic effects which underpin their therapeutic potential. hMSC serum-free conditioned media (SFCM) has been determined to contain a variety of cytokines with roles in regeneration and suppression of inflammation. Physiological oxygen (physoxia) has been demonstrated to impact upon a number of facets of hMSC biology and we hypothesized that the secretome would be similarly modified. We tested a range of oxygen conditions; 21% O-2 (air oxygen (AO)), 2% O-2 (intermittent hypoxia (IH)) and 2% O-2 Workstation (physoxia (P)) to evaluate their effect on hMSC secretome profiles. Total protein content of secretome was upregulated in IH and P (>3 fold vs AO) and IH (>1 fold vs P). Focused cytokine profiling indicated global upregulation in IH of all 31 biomolecules tested in comparison to AO and P with basic-nerve growth factor (bNGF) and granulocyte colony-stimulating factor (GCSF) (>3 fold vs AO) and bNGF and Rantes (>3 fold vs P) of note. Similarly, upregulation of interferon gamma-induced protein 10 (IP10) was noted in P (>3 fold vs AO). Interleukin-2 (IL2) and Rantes (in AO and P) and adiponectin, IL17a, and epidermal growth factor (EGF) (in AO only) were entirely absent or below detection limits. Quantitative analysis validated the pattern of IH-induced upregulation in vascular endothelial growth factor (VEGF), placental growth factor-1 (PIGF1), Tumor necrosis factor alpha (TNFa), IL2, IL4, and IL10 when compared to AO and P. In summary, modulation of environmental oxygen alters both secretome concentration and composition. This consideration will likely impact on delivering improved mechanistic understanding and potency effects of hMSC-based therapeutics

Human Mesenchymal Stem Cell Secretome Driven T Cell Immunomodulation Is IL-10 Dependent

The Human Mesenchymal Stem Cell (hMSC) secretome has pleiotropic effects underpinning its therapeutic potential. hMSC serum-free conditioned media (SFCM) contains a variety of cytokines, with previous studies linking a changed secretome composition to physoxia. The Jurkat T cell model allowed the efficacy of SFCM vs. serum-free media (SFM) in the suppression of immunological aspects, including proliferation and polarisation, to be explored. Cell growth in SFM was higher [(21% O2 = 5.3 × 105 ± 1.8 × 104 cells/mL) and (2% O2 = 5.1 × 105 ± 3.0 × 104 cells/mL)], compared to SFCM [(21% O2 = 2.4 × 105 ± 2.5 × 104 cells/mL) and (2% O2 = 2.2 × 105 ± 5.8 × 103 cells/mL)]. SFM supported IL-2 release following activation [(21% O2 = 5305 ± 211 pg/mL) and (2% O2 = 5347 ± 327 pg/mL)] whereas SFCM suppressed IL-2 secretion [(21% O2 = 2461 ± 178 pg/mL) and (2% O2 = 1625 ± 159 pg/mL)]. Anti-inflammatory cytokines, namely IL-4, IL-10, and IL-13, which we previously confirmed as components of hMSC SFCM, were tested. IL-10 neutralisation in SFCM restored proliferation in both oxygen environments (SFM/SFCM+antiIL−10 ~1-fold increase). Conversely, IL-4/IL-13 neutralisation showed no proliferation restoration [(SFM/SFM+antiIL−4 ~2-fold decrease), and (SFM/SFCM+antiIL−13 ~2-fold decrease)]. Present findings indicate IL-10 played an immunosuppressive role by reducing IL-2 secretion. Identification of immunosuppressive components of the hMSC secretome and a mechanistic understanding of their action allow for the advancement and refinement of potential future cell-free therapies.</jats:p

Chorionic and amniotic membrane-derived stem cells have distinct, and gestational diabetes mellitus independent, proliferative, differentiation, and immunomodulatory capacities

Placental membrane-derived mesenchymal stem cells (MSCs), with the advantages of being non-invasive and having fewer ethical issues, are a promising source for cell therapy. Gestational diabetes (GDM) alters the uterine environment and may affect the therapeutic potential of MSCs derived from placenta. Therefore, we evaluated the biological properties of amniotic (AMSCs) and chorionic membrane MSCs (CMSCs) from human GDM placenta in order to explore their therapeutic potential. In comparison of GDM-/Healthy- CMSCs and AMSCs, the immunophenotypes and typical stellate morphology of MSC were similar in CMSCs irrespective of disease state while the MSC morphology in GDM-AMSCs was less evident. GDM- and Healthy- CMSCs displayed an enhanced proliferation rate and tri-lineage differentiation capacity compared with AMSCs. Notably, GDM-CMSCs had a significantly increased adipogenic ability than Healthy-CMSCs accompanied by increased transcriptional responsiveness of PPARγ and ADIPOQ induction. The secretome effect of Healthy- and GDM- CMSCs/AMSCs by using conditioned media and coculture experiments, suggests that GDM- and Healthy- CMSCs provided an equivalent immunoregulatory effect on suppressing T-cells activation but a reduced effect of GDM-CMSCs on macrophage regulation. However, Healthy- and GDM- CMSCs displayed a superior immunomodulatory capacity in regulation of both T-cells and macrophages than AMSCs. In summary, we highlight the importance of the maternal GDM intrauterine environment during pregnancy and its impact on CMSCs/AMSCs proliferation ability, CMSCs adipogenic potential, and macrophage regulatory capacity

La evaluación de las incidencias de toxicidad ocular y hallazgos oculares causados por el compuesto quelante de hierro

Introduction: The current article mainly attempts to evaluate the incidences of ocular toxicity and ocular findings stemming from the iron-chelating compound, deferasirox in patients with beta-thalassemia receiving recurrent blood transfusions. Patients and methods: Nearly sixty cases with ß-thalassemia major participated as case subjects, while an additional sixty otherwise healthy volunteers were engaged as control subjects. All of the subjects were age and sex-matched, and all of the volunteers were included as case subjects. Results: Despite the fact that all of the cases with beta-thalassemia did not have any signs or symptoms of eye disease, abnormal visual features (dry eye (35%), retinal pigment changes and retinal epithelium degeneration (15%), and ocular abnormalities (36.2%) were observed in 67% of thalassemia patients, indicating that the disease is not contagious, given the findings. The incidence of visual anomalies in the control group was 18.2 %, which was significantly subtler in comparison to thalassemia patients (P≤0.001). A non-significant link exists between ocular defects and serum ferritin (P=0.543) or blood hemoglobin (P=0.265). A statistically significant connection between the frequency of blood transfusions and ocular abnormalities was discovered (P=0.001). Conclusion: Based on the results, thalassemia patients should go through regular ophthalmological examination to detect early anomalies in their visual system when using an iron chelator.Introducción: El presente artículo intenta principalmente evaluar las incidencias de toxicidad ocular y los hallazgos oculares derivados del compuesto quelante de hierro deferasirox en pacientes con beta-talasemia que reciben transfusiones de sangre recurrentes. Pacientes y métodos: Casi sesenta casos con ß-talasemia mayor participaron como sujetos de casos, mientras que otros sesenta voluntarios sanos participaron como sujetos de control. Todos los sujetos tenían la misma edad y sexo, y todos los voluntarios se incluyeron como sujetos de casos. Resultados: Apesar de que todos los casos con beta-talasemia no tenían ningún signo o síntoma de enfermedad ocular, características visuales anormales (ojo seco (35%), cambios en la pigmentación retiniana y degeneración del epitelio retiniano (15%) y se observaron anomalías visuales (36,2%) en el 67% de los pacientes con talasemia, lo que indica que la enfermedad no es contagiosa, dados los hallazgos. La incidencia de anomalías visuales en el grupo control fue del 18,2 %, que fue significativamente más sutil en comparación con los pacientes con talasemia (P≤0,001). Existe una relación no significativa entre los defectos oculares y la ferritina sérica (P=0,543) o la hemoglobina en sangre (P=0,265). Se descubrió una conexión estadísticamente significativa entre la frecuencia de las transfusiones de sangre y las anomalías oculares (P=0,001) Conclusión: En base a los resultados, es recomendable que los pacientes con talasemia se realicen un examen oftalmológico periódico para detectar tempranamente anomalías en su sistema visual al utilizar un quelante de hierro

Effect of esomeprazole on lipid profile in patients with peptic ulcer

Esomeprazole; a newly introduced PPI has been widely prescribed by healthcare providers due to its improved pharmacokinetic profile. Most users could have other diseases and the PPIs are indicated as acid-suppressor to minimize gastric side effects of polypharmacy. A high percentage of users could suffer from cardiovascular diseases and lipid dysmetabolism. Hence, this study was designed to determine the impact of long-term use of esomeprazole on lipid profile in a normal subject other than having peptic ulcer for which esomeprazole has been indicated. Results confirmed that esomeprazole reduced triglyceride and HDL levels and elevated total cholesterol level and correspondingly LDL level was elevated, however, no effect was noticed with VLDL. To sum up, esomeprazole impaired lipid metabolism in apparently normal healthy individuals apart from having peptic ulcer for which the esomeprazole was indicated, this finding rise a caution during prescribing esomeprazole for the patient with multiple diseases and polypharmacy including cardiovascular ailments

Cytotoxic effect of PEI-coated magnetic nanoparticles on the regulation of cellular focal adhesions and actin stress fibres

The biocompatibility of surface-coated magnetic nanoparticles (MNPs) is key to their successful use in biomedical applications. Polyethyleneimine-coated MNPs (MNP-PEIs) provide improved in vitro nucleic acid transfection efficiency and are safer compared to conventional chemicals. Commercial cell toxicity assays are useful for end-point and high-throughput screening, however, they only reports cells that have undergone an extreme toxic response leading to cell death. Cell toxicity is a complex process which can be expressed in many forms, through morphological, metabolic, and epigenetic changes. This study explores the effect of magnetic transfection with MNP-PEIs and an external magnetic field on cell toxicity, by studying particle internalization, changes in cellular morphology, and cell adhesion. We show that MNP-PEIs induce cell stress through a dose-dependent increase in cell adhesion via the overexpression of vinculin and formation of actin stress fibres. While the presence of PEI was the main contributor to increased cell stress, free PEI polyplexes induced higher toxicity compared to PEI bound to MNPs. MNPs without PEI coating however did not adversely affect cells, suggesting a chemical effect instead of a mechanical one. In addition, genes identified as being associated with actin fibre regulation and cell adhesion showed significant increases in expression from MNP-PEI internalization. From these results, we identify anomalous cell behaviour, morphology, and gene expression after interaction with MNP-PEIs, as well as a safe dosage to reduce acute cell toxicity

Nivel de troponina sérica modulada por alopurinol en pacientes con cálculos renales

Cardiovascular diseases are aggravated by various factors, including chronic use of certain medications. There are worldwide reported cases of sudden strokes or myocardial infarction in previously non-ischemic patients while using medications for other chronic diseases, such as diabetes, gout, hypertension, and endocrine diseases. The mechanism is quite complicated, and the underlying causes were obscure. In line with this reported toxicity are patients with hyperuricemia on uric acid lowering therapy. The goal of the present investigation was to assess the cardiotoxic effect of allopurinol based on the levels of troponin that were quantified by fully automated COBAS technique in apparently healthy renal stone patients. To do so, serum samples were collected from these patients at baseline (before starting allopurinol therapy), and at the end of the course of the therapy. The troponin level was significantly elevated after allopurinol therapy compared to baseline. The study concluded that allopurinol could have a significant cardiotoxic effect in heart tissues and should be used cautiously in patients with pre-existing ischemic cardiac diseases.Las enfermedades cardiovasculares se ven agravadas por varios factores, incluido el uso crónico de ciertos medicamentos. Se han reportado casos en todo el mundo de accidentes cerebrovasculares repentinos o infarto de miocardio en pacientes previamente no isquémicos mientras usaban medicamentos para otras enfermedades crónicas, como diabetes, gota, hipertensión y enfermedades endocrinas. El mecanismo es bastante complicado y las causas subyacentes son oscuras. En consonancia con esta toxicidad reportada están los pacientes con hiperuricemia con tratamiento para reducir el ácido úrico. El objetivo de la presente investigación fue evaluar el efecto cardiotóxico del alopurinol en función de los niveles de troponina, cuantificados mediante la técnica COBAS totalmente automatizada en pacientes con cálculos renales aparentemente sanos. Para ello, se recolectaron muestras de suero de estos pacientes al inicio (antes de comenzar la terapia con alopurinol) y al final del curso de la terapia. El nivel de troponina incrementó significativamente en los pacientes que recibieron tratamiento con alopurinol &nbsp;&nbsp;en comparación con el valor inicial. El estudio concluyó que el alopurinol podría tener un efecto cardiotóxico significativo en los tejidos cardíacos y debería usarse con precaución en pacientes con enfermedades cardíacas isquémicas preexistentes

Silent hyperlipidaemia modulated vascular endothelial markers

The aetiology of ischemic heart diseases is mainly based on atherosclerosis of coronary artery. Inflammation and oxidative reactions are initiating and aggravating the illness resulting in pathological remodelling of vasculaturze at site of injury. Endothelium lining of blood vessels participated in the reaction biochemically through releasing some proteins into circulatory system which further complicate the condition. The aim of this study was to determine early diagnosed hyperlipidaemia-associated changes of the plasma level of some of these endothelial biomolecules. Compared to healthy control, hyperlipidaemic patients have significantly increased arginase, metalloendopeptidase, peroxidase, myeloperoxidase, and peroxynitrite with concomitant reduction in arylesterase and nitric oxide. The present study concluded that hyperlipidaemia play a great role in modulation of certain plasma protein markers which might be directly related to patient pathological condition or could be used as a tool for diagnosis or patient follow up indicating the stage of vasculature remodelling, healing, inflammation or resolution