scholarly journals Human leucocyte antigen G (HLA-G) and its murine homologue Qa-2 protect from pregnancy loss

2021 ◽  
Author(s):  
Stefanie Dietz ◽  
Julian Schwarz ◽  
Ana Velic ◽  
Irene Gonzalez Menendez ◽  
Leticia Quintanilla-Martinez ◽  
...  
Keyword(s):  
Pregnancy Loss ◽  
Therapeutic Potential ◽  
Suppressor Cells ◽  
Late Pregnancy ◽  
Immunological Tolerance ◽  
Growth Restriction ◽  
Maternal Immune System ◽  
Murine Homologue ◽  
The Impact

Abstract During pregnancy, the maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. The MHC-Ib molecule HLA-G is well known to mediate immunological tolerance. However, no in-vivo studies have yet demonstrated a beneficial role of HLA-G for pregnancy success. Myeloid derived suppressor cells (MDSC) are suppressively acting immune cells accumulating during pregnancy and mediating maternal-fetal tolerance. Here, we analyzed the impact of Qa-2, the murine homologue to HLA-G, on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by changes in uterine gene expression, altered spiral artery remodeling and protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused decreased accumulation of MDSC and impaired MDSC function. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for the treatment of immunological pregnancy complications.

scholarly journals Human Leucocyte Antigen G and Murine Qa-2 Are Critical for Myeloid Derived Suppressor Cell Expansion and Activation and for Successful Pregnancy Outcome

2022 ◽  
Vol 12 ◽  
Author(s):  
Stefanie Dietz ◽  
Julian Schwarz ◽  
Ana Velic ◽  
Irene González-Menéndez ◽  
Leticia Quintanilla-Martinez ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Late Pregnancy ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
The Impact

During pregnancy, maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. In the present study we analyzed the impact of the murine MHC class Ib molecule Qa-2 on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by a disturbed trophoblast invasion and altered spiral artery remodeling as well as protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused imbalanced immunological adaptation to pregnancy with altered immune cell and especially T-cell homeostasis, reduced Treg numbers and decreased accumulation and functional activation of myeloid-derived suppressor cells. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for treatment of immunological pregnancy complications.

scholarly journals Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure

2016 ◽  
Vol 231 (2) ◽  
pp. R47-R60 ◽  
Author(s):  
Baiba Steinbrekera ◽  
Robert Roghair
Keyword(s):  
Intrauterine Growth Restriction ◽  
Therapeutic Potential ◽  
Growth Restriction ◽  
Neuronal Regulation ◽  
Antenatal Steroid ◽  
Life Threatening ◽  
Neurodevelopmental Impairment ◽  
The Impact ◽  
Circulating Levels ◽  
Regulation Of Blood Pressure

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction–adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

Evaluation of Chemical, Antipsoriatic and Antiangiogenic Properties of Salt from Lonar Crater Lake Water

2019 ◽  
Vol 4 (3) ◽  
pp. 159-165
Author(s):  
Prakash Bansode ◽  
Indumathi Somasundaram ◽  
Apurva Birajdar ◽  
Sanjay Mishra ◽  
Dhanashree Patil ◽  
...  
Keyword(s):  
Lake Water ◽  
Crater Lake ◽  
Skin Diseases ◽  
Therapeutic Potential ◽  
Chorioallantoic Membrane ◽  
Soda Lake ◽  
Antiangiogenic Activity ◽  
The Impact ◽  
Lonar Crater

Lonar Crater lake was created by the impact of a massive meteor during the Pleistocene Epoch. Being a hypersaline and hyperalkaline soda lake, rich microbial diversity is reported earlier. Lonar lake water is used by local people and tribals against skin diseases. These observations prompted us to investigate the therapeutic potential of lake water against skin diseases. In this context, we have conducted pilot study to assess the antipsoriatic and antiangiogenic activity of the salt obtained from lake water using THP1 cell line by MTT assay and antiangiogenic activity by in vivo chicken chorioallantoic membrane (CAM) assay, as there is a close relation between psoriasis and angiogenesis. The results revealed that salt possess remarkable antipsoriatic and antiangiogenic activity.

scholarly journals Insights into Host–Pathogen Interactions in Biofilm-Infected Wounds Reveal Possibilities for New Treatment Strategies

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 396
Author(s):  
Hannah Trøstrup ◽  
Anne Sofie Boe Laulund ◽  
Claus Moser
Keyword(s):  
Wound Healing ◽  
Host Response ◽  
Chronic Wounds ◽  
Therapeutic Potential ◽  
Recent Observation ◽  
Treatment Strategies ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
The Impact

Normal wound healing occurs in three phases—the inflammatory, the proliferative, and the remodeling phase. Chronic wounds are, for unknown reasons, arrested in the inflammatory phase. Bacterial biofilms may cause chronicity by arresting healing in the inflammatory state by mechanisms not fully understood. Pseudomonas aeruginosa, a common wound pathogen with remarkable abilities in avoiding host defense and developing microbial resistance by biofilm formation, is detrimental to wound healing in clinical studies. The host response towards P. aeruginosa biofilm-infection in chronic wounds and impact on wound healing is discussed and compared to our own results in a chronic murine wound model. The impact of P. aeruginosa biofilms can be described by determining alterations in the inflammatory response, growth factor profile, and count of leukocytes in blood. P. aeruginosa biofilms are capable of reducing the host response to the infection, despite a continuously sustained inflammatory reaction and resulting local tissue damage. A recent observation of in vivo synergism between immunomodulatory and antimicrobial S100A8/A9 and ciprofloxacin suggests its possible future therapeutic potential.

Pharmacologic Replacement of BIM BH3 Reactivates Apoptosis in Hematologic Cancer and Lymphoproliferative Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 524-524
Author(s):  
James L. LaBelle ◽  
Jill K. Fisher ◽  
Samuel G. Katz ◽  
Gregory H. Bird ◽  
Chelsea E. Lawrence ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Models ◽  
Therapeutic Potential ◽  
Control Point ◽  
Lymphoproliferative Disease ◽  
Critical Control Point ◽  
Hematologic Cancer ◽  
Apoptotic Proteins ◽  
The Impact

Abstract Selective targeting of deregulated apoptotic protein networks is a promising pharmacologic strategy for subverting diseases of unrestrained cellular survival, such as cancer. BCL-2 family protein interactions constitute a critical control point for the regulation of apoptosis. Whereas multidomain anti-apoptotic proteins such as BCL-2 guard against cell death, multidomain pro-apoptotic proteins such as BAX constitute a gateway to cell death through mitochondrial damage. The BH3-only proteins function as death sentinels situated throughout the cell, poised to transmit signals of cellular injury to multidomain members. BH3-only proteins deliver their death messages via their conserved alpha-helical BH3 domains. Whereas the indirect activator class of BH3-only proteins (e.g. BAD) counteract anti-apoptotic proteins, the direct activator subgroup (e.g. BIM) is believed to trigger apoptosis both by neutralizing anti-apoptotics and by directly activating the mitochondrial executioners BAX and BAK. The essential roles of BH3-only proteins in maintaining cellular homeostasis is highlighted by the development of autoimmune disease and cancer in mouse models of BH3-only protein deficiency. By inserting hydrocarbon “staples” into native BH3 peptide sequences, we have produced a chemical toolbox of stabilized alpha-helices of BCL-2 domains (SAHBs) to dissect apoptotic signaling pathways in vivo and explore the pharmacodynamic effects of “BH3 replacement” in cancer cells and mouse models of deregulated apoptosis. Whereas SAHBs display high affinity binding to anti-apoptotic targets, BID and BIM SAHBs also directly engage BAX and are thus especially potent in inducing apoptosis of a panel of leukemia and lymphoma cell lines. To evaluate the impact of selective BH3 replacement in vivo, we tested the capacity of BIM SAHB to reactivate apoptosis in the lymphoproliferative disease of Bim-/- mice. Strikingly, Bim-/- mice treated with BIM SAHB displayed marked influx of tingible-body macrophages into the lymphoid infiltrates of affected organs, with scattered cells throughout the infiltrate robustly positive for activated caspase-3, suggestive of SAHB induced apoptosis induction. Our studies highlight the therapeutic potential of BH3 replacement to circumvent apoptotic blockade and restore the death pathway in hematologic cancer and lymphoproliferative disease.

scholarly journals Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

2021 ◽  
Vol 9 ◽  
Author(s):  
Mariana A. Antunes ◽  
Cassia L. Braga ◽  
Tainá B. Oliveira ◽  
Jamil Z. Kitoko ◽  
Ligia L. Castro ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Chronic Obstructive ◽  
Severe Emphysema ◽  
Arginase 1 ◽  
The Impact

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

scholarly journals Chronic sodium bromide relieves autistic-like deficits in the Oprm1 mouse model of autism and modulates the activity of serotonin and dopamine receptors in vitro

2020 ◽  
Author(s):  
Cécile Derieux ◽  
Sébastien Roux ◽  
Thierry Plouvier ◽  
Audrey Léauté ◽  
Agathe Brugoux ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dopamine Receptors ◽  
Therapeutic Potential ◽  
Autism Spectrum ◽  
Chloride Ions ◽  
Sodium Bromide ◽  
Bromide Ion ◽  
The Impact

Chronic sodium bromide relieves autistic-like deficits in the Oprm1 mouse model of autism and modulates the activity of serotonin and dopamine receptors in vitro C. DERIEUX 1 , S. ROUX 1 , A. LEAUTE 1 , T. PLOUVIER 2 , J.A.J. BECKER 1 , J. LE MERRER 1 1 Déficits de Récompense, GPCRs et Sociabilité, Physiologie de la Reproduction et des Comportements, INRA UMR0085, CNRS UMR7247, Université de Tours, Inserm ; 37380 Nouzilly, France 2 Térali Innov, 37230 Fondettes, France Corresponding author : [email protected] Autism spectrum disorders (ASD) are complex neurodevelopmental diseases whose diagnosis lies on the detection of impaired social skills together with restricted and repetitive behavior and interests (DSM-5). Although the etiology of ASD remains mostly unknown, impaired excitation/inhibition ratio appears as a common mechanistic feature. Bromide ion is known to reduce hyperexcitability, possibly by competing with chloride ions at channels and transporters and may thus have therapeutic potential in ASD. Aims : We evaluated the therapeutic potential of bromide ion in the Oprm1 -/- mouse model of ASD and the molecular mechanisms involved in bromide treatment, notably effects on GPCRs. Methods : In vivo , we first assessed the effect of chronically administered sodium bromide on autistic-like behavioral deficits and performed RT-qPCR on brain structures known to be involved in ASD. In vitro , we evaluated the impact of bromide ion on G-protein mediated signaling of serotonin and dopamine receptors. Results : In vivo , sodium bromide (30 to 500 mg/Kg) dose-dependently improved social interaction and preference, reduced stereotypies and decreased anxiety. Bromide also impacts the expression of genes coding for some GPCRs, chloride transporters and GABA A subunits. In vitro , bromide behaves as a positive allosteric modulator of 5-HT 6 , 5-HT 7 and D1 receptors but not 5-HT 4 and D2 receptors. Conclusions : The beneficial effects of bromide administration in a genetic murine model of ASD and its impact on both gene expression and GPCR pharmacology predicts high translational potential in patients with autism, despite high heterogeneity in etiology and symptoms.

scholarly journals The Impact of CRISPR/Cas9 Technology on Cardiac Research: From Disease Modelling to Therapeutic Approaches

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Benedetta M. Motta ◽  
Peter P. Pramstaller ◽  
Andrew A. Hicks ◽  
Alessandra Rossini
Keyword(s):  
Genome Editing ◽  
Ethical Issues ◽  
Therapeutic Potential ◽  
Gene Knockout ◽  
Model Systems ◽  
Large Deletions ◽  
Induced Pluripotent ◽  
The Impact

Genome-editing technology has emerged as a powerful method that enables the generation of genetically modified cells and organisms necessary to elucidate gene function and mechanisms of human diseases. The clustered regularly interspaced short palindromic repeats- (CRISPR-) associated 9 (Cas9) system has rapidly become one of the most popular approaches for genome editing in basic biomedical research over recent years because of its simplicity and adaptability. CRISPR/Cas9 genome editing has been used to correct DNA mutations ranging from a single base pair to large deletions in both in vitro and in vivo model systems. CRISPR/Cas9 has been used to increase the understanding of many aspects of cardiovascular disorders, including lipid metabolism, electrophysiology and genetic inheritance. The CRISPR/Cas9 technology has been proven to be effective in creating gene knockout (KO) or knockin in human cells and is particularly useful for editing induced pluripotent stem cells (iPSCs). Despite these progresses, some biological, technical, and ethical issues are limiting the therapeutic potential of genome editing in cardiovascular diseases. This review will focus on various applications of CRISPR/Cas9 genome editing in the cardiovascular field, for both disease research and the prospect of in vivo genome-editing therapies in the future.

scholarly journals Enhanced anti-inflammatory effects of mesenchymal stromal cells mediated by the transient ectopic expression of CXCR4 and IL10

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rosario Hervás-Salcedo ◽  
María Fernández-García ◽  
Miriam Hernando-Rodríguez ◽  
Oscar Quintana-Bustamante ◽  
Jose-Carlos Segovia ◽  
...  
Keyword(s):  
Transient Expression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Ectopic Expression ◽  
In Vivo Studies ◽  
Anti Inflammatory ◽  
The Impact

Abstract Background Mesenchymal stromal cells (MSCs) constitute one of the cell types most frequently used in cell therapy. Although several studies have shown the efficacy of these cells to modulate inflammation in different animal models, the results obtained in human clinical trials have been more modest. Here, we aimed at improving the therapeutic properties of MSCs by inducing a transient expression of two molecules that could enhance two different properties of these cells. With the purpose of improving MSC migration towards inflamed sites, we induced a transient expression of the C-X-C chemokine receptor type 4 (CXCR4). Additionally, to augment the anti-inflammatory properties of MSCs, a transient expression of the anti-inflammatory cytokine, interleukin 10 (IL10), was also induced. Methods Human adipose tissue-derived MSCs were transfected with messenger RNAs carrying the codon-optimized versions of CXCR4 and/or IL10. mRNA-transfected MSCs were then studied, first to evaluate whether the characteristic phenotype of MSCs was modified. Additionally, in vitro and also in vivo studies in an LPS-induced inflamed pad model were conducted to evaluate the impact associated to the transient expression of CXCR4 and/or IL10 in MSCs. Results Transfection of MSCs with CXCR4 and/or IL10 mRNAs induced a transient expression of these molecules without modifying the characteristic phenotype of MSCs. In vitro studies then revealed that the ectopic expression of CXCR4 significantly enhanced the migration of MSCs towards SDF-1, while an increased immunosuppression was associated with the ectopic expression of IL10. Finally, in vivo experiments showed that the co-expression of CXCR4 and IL10 increased the homing of MSCs into inflamed pads and induced an enhanced anti-inflammatory effect, compared to wild-type MSCs. Conclusions Our results demonstrate that the transient co-expression of CXCR4 and IL10 enhances the therapeutic potential of MSCs in a local inflammation mouse model, suggesting that these mRNA-modified cells may constitute a new step in the development of more efficient cell therapies for the treatment of inflammatory diseases.

scholarly journals Targeting abundant survivin expression in liposarcoma: subtype dependent therapy responses to YM155 treatment

2021 ◽  
Author(s):  
Christian Vay ◽  
Philipp M. Schlünder ◽  
Levent Dizdar ◽  
Irene Esposito ◽  
Markus P. H. Ghadimi ◽  
...  
Keyword(s):  
Cell Viability ◽  
Therapeutic Potential ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Survivin Expression ◽  
Tissue Microarrays ◽  
In Vivo Models ◽  
The Impact

Abstract Purpose Liposarcoma (LPS) represent the largest group of malignant soft tissue tumours comprising a heterogeneous group of subtypes in which the degrees of chemoresistance and radiosensitivity strongly vary. Consequently, it is of utmost interest to establish novel therapeutic regimens based on molecular targets. Methods Immunohistochemical staining of survivin was performed in tissue microarrays comprising 49 primary LPS specimens. LPS cell lines were treated with survivin antagonist YM155 and doxorubicin or etoposide alone as well as in combination. Changes in cell viability were investigated and the synergistic effect of a combined therapy analysed. Results Immunohistochemistry revealed an abundant expression of survivin in LPS that significantly concurred with less-differentiated tumour subtypes and grading. In vitro, we demonstrated the impact of the survivin inhibitor YM155 on dedifferentiated LPS (DDLPS) and, even more imposing, pleomorphic LPS (PLS) tumour cell viability with a strong induction of apoptosis. A combined treatment of doxorubicin or etoposide with YM155 augmented the cytotoxic effects on DDLPS and PLS cells. Conclusion These findings support the significant role of survivin in the oncogenesis and progression of LPS subtypes providing a rationale to target survivin in eligible in-vivo models and to pioneer clinical applications of survivin-specific substances unfolding their therapeutic potential in LPS patients prospectively.

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