Search results for: α1β2γ2 GABAA receptors

Authors: Yong H Sheng, Beatriz Garcillán, Eden Whitlock, Yukli Freedman, SiLing Yang, M Arifur Rahman, Nicholas Weber, Fabienne Mackay

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Chronic lymphocytic leukemia (CLL) is closely associated with immune dysfunction, yet the mechanisms underlying this immune deficiency remain poorly understood. Transmembrane Activator and CAML Interactor (TACI), a receptor known for its role in IL-10 regulation and autoimmunity, to the best of our knowledge has not been investigated in the context of anti-tumor immunity or its impact on CLL progression. This study addresses the gap by exploring the role of TACI in regulating CLL cells within the tumor microenvironment and its broader effects on disease progression and immune competence. We utilized the Eµ-TCL1 mouse model to generate CLL mice deficient in TACI and examined the consequences of TACI loss in adoptive transfer models over a five-week period. Comprehensive transcriptomic analysis, including RNA sequencing and microarray, was employed to determine TACI’s influence on the CLL gene expression profile. Additionally, we studied TACI’s direct role in CLL cell migration and immune modulation using patient-derived CLL cells in culture and Patient-Derived Xenograph (PDX) models. Our findings demonstrate that TACI signaling plays a pivotal role in promoting CLL progression and immune suppression. Loss of TACI signaling significantly inhibited CLL development and enhanced immune functionality. When TACI+/+ or TACI-/- TCL1 CLL cells were transferred into wild-type recipient mice, those receiving TACI-deficient cells showed reduced disease progression and lower incidence of CLL. Mice with TACI-/- CLL cells exhibited normalized serum levels of pro-inflammatory cytokines IL-6 and IL-10, restored proportions of T-cell subsets, and improved immune compartment function compared to counterparts with TACI+/+ CLL cells. Mechanistically, TACI-deficient CLL cells expressed significantly lower levels of IL-10, TNF, and inhibitory receptors such as PD-L1 and PD-L2. These cells also display restored circulating immunoglobulin levels and responses to T cell-dependent antigens, highlighting a recovery of immune competence. Further mechanistic studies revealed that TACI signaling drives CLL cell migration and homing to the spleen, where these cells actively establish an immunosuppressive microenvironment that supports immune evasion and tumor growth. Patient-derived CLL cells and PDX models confirmed TACI’s direct role in enhancing CLL cell migration and fostering immune suppression, emphasizing its critical function in the tumor microenvironment. By disrupting TACI signaling, we observed a reduction in CLL-associated immune suppression and tumor progression, offering a promising therapeutic avenue. This study establishes, for the first time, that targeting TACI disrupts key mechanisms underlying CLL progression while preserving vital immune functions. Unlike existing treatments that often impair immunity and lead to infection-related complications, TACI inhibition offers the dual benefit of controlling disease and maintaining immune homeostasis. These findings provide a strong rationale for developing therapeutic strategies that inhibit TACI as a means to improve outcomes in CLL patients. Beyond its implications for CLL, this research underscores the broader importance of TACI in regulating immune-tumor interactions, paving the way for future studies into its role in other malignancies.

Keywords: chronic lymphocytic leukemia, TACI, IL-10, immune suppression

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Authors: David A. Olasehinde, Peter I. Olasehinde, Segun M. A. Adelana, Dapo O. Olasehinde

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An investigation was carried out on underground water system dynamics within Ilorin metropolis to monitor the subsurface flow and its corresponding pollution. Africa population growth rate is the highest among the regions of the world, especially in urban areas. A corresponding increase in waste generation and a change in waste composition from predominantly organic to non-organic waste has also been observed. Percolation of leachate from non-engineered landfills, the chief means of waste disposal in many of its cities, constitutes a threat to the underground water bodies. Ilorin city, a transboundary town in southwestern Nigeria, is a ready microcosm of Africa’s unique challenge. In spite of the fact that groundwater is naturally protected from common contaminants such as bacteria as the subsurface provides natural attenuation process, groundwater samples have been noted to however possesses relatively higher dissolved chemical contaminants such as bicarbonate, sodium, and chloride which poses a great threat to environmental receptors and human consumption. The Geographic Information System (GIS) was used as a tool to illustrate, subsurface dynamics and the corresponding pollutant indicators. Forty-four sampling points were selected around known groundwater pollutant, major old dumpsites without landfill liners. The results of the groundwater flow directions and the corresponding contaminant transport were presented using expert geospatial software. The experimental results were subjected to four descriptive statistical analyses, namely: principal component analysis, Pearson correlation analysis, scree plot analysis, and Ward cluster analysis. Regression model was also developed aimed at finding functional relationships that can adequately relate or describe the behaviour of water qualities and the hypothetical factors landfill characteristics that may influence them namely; distance of source of water body from dumpsites, static water level of groundwater, subsurface permeability (inferred from hydraulic gradient), and soil infiltration. The regression equations developed were validated using the graphical approach. Underground water seems to flow from the northern portion of Ilorin metropolis down southwards transporting contaminants. Pollution pattern in the study area generally assumed a bimodal pattern with the major concentration of the chemical pollutants in the underground watershed and the recharge. The correlation between contaminant concentrations and the spread of pollution indicates that areas of lower subsurface permeability display a higher concentration of dissolved chemical content. The principal component analysis showed that conductivity, suspended solids, calcium hardness, total dissolved solids, total coliforms, and coliforms were the chief contaminant indicators in the underground water system in the study area. Pearson correlation revealed a high correlation of electrical conductivity for many parameters analyzed. In the same vein, the regression models suggest that the heavier the molecular weight of a chemical contaminant of a pollutant from a point source, the greater the pollution of the underground water system at a short distance. The study concludes that the associative properties of landfill have a significant effect on groundwater quality in the study area.

Keywords: dumpsite, leachate, groundwater pollution, linear regression, principal component

Procedia PDF Downloads 118

Authors: Nada Al-Qallaf, Aisha Al-Barood, Djamel Lekmine, Srinivasan Vedhapuri

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Kuwait Oil Company (KOC) under the supervision of Kuwait National Focal Point (KNFP) is planning to remediate 26 million (M) m3 of oil-contaminated soil in oil fields of Kuwait as a direct and indirect fallout of the Gulf War during 1990-1991. This project is funded by the United Nations Compensation Commission (UNCC) under the Kuwait Environmental Remediation Program (KERP). Oil-contamination of the soil occurred due to the destruction of the oil wells and spilled crude oil across the land surface and created ‘oil lakes’ in low lying land. Aerial fall-out from oil spray and combustion products from oil fires combined with the sand and gravel on the ground surface to form a layer of hardened ‘Tarcrete’. The unique fresh groundwater lenses present in the Raudhatain and Sabriya subsurface areas had been impacted by the discharge and/or spills of dissolved petroleum constituents. These fresh groundwater aquifers were used for drinking water purposes until 1990, prior to invasion. This has significantly damages altered the landscape, ecology and habitat of the flora and fauna and in Kuwait Desert. Under KERP, KOC is fully responsible for the planning and execution of the remediation and restoration projects in KOC oil fields. After the initial recommendation of UNCC to construct engineered landfills for containment and disposal of heavily contaminated soils, two landfills were constructed, one in North Kuwait and another in South East Kuwait of capacity 1.7 million m3 and 0.5 million m3 respectively. KOC further developed the Total Remediation Strategy in conjunction with KNFP and has obtained UNCC approval. The TRS comprises of elements such as Risk Based Approach (RBA), Bioremediation of low Contaminated Soil levels, Remediation Treatment Technologies, Sludge Disposal via Beneficial Recycling or Re-use and Engineered landfills for Containment of untreatable materials. Risk Based Assessment as a key component to avoid any unnecessary remedial works, where it can be demonstrated that human health and the environment are sufficiently protected in the absence of active remediation. This study demonstrates on the risks of tarcrete materials spread over areas 20 Km2 on the fresh Ground water lenses/catchment located beneath the Sabriyah and Raudhatain oil fields in North Kuwait. KOC’s primary objective is to provide justification of using RBA, to support a case with the Kuwait regulators to leave the tarcrete material in place, rather than seek to undertake large-scale removal and remediation. The large-scale coverage of the tarcrete in the oil fields and perception that the residual contamination associated with this source is present in an environmentally sensitive area essentially in ground water resource. As part of this assessment, conceptual site model (CSM) and complete risk-based and fate and transport modelling was carried out which includes derivation of site-specific assessment criteria (SSAC) and quantification of risk to identified waters resource receptors posed by tarcrete impacted areas. The outcome of this assessment was determined that the residual tarcrete deposits across the site area shall not create risks to fresh groundwater resources and the remedial action to remove and remediate the surficial tarcrete deposits is not warranted.

Keywords: conceptual site model, fresh groundwater, oil-contaminated soil, tarcrete, risk based assessment

Procedia PDF Downloads 175

Authors: Michelle C. S. Azevedo, Priscila M. Colavite, Carolina F. Francisconi, Ana P. Trombone, Gustavo P. Garlet

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VIP (vasoactive intestinal peptide) know as a potential protective factor in the view of its marked immunosuppressive properties. In this work, we investigated a possible association of VIP with the clinical status of experimental periapical granulomas and the association with expression markers in the lesions potentially associated with periapical lesions pathogenesis. C57BL/6WT mice were treated or not with recombinant VIP. Animals with active/progressive (N=40), inactive/stable (N=70) periapical granulomas and controls (N=50) were anesthetized and the right mandibular first molar was surgically opened, allowing exposure of dental pulp. Endodontic pathogenic bacterial strains were inoculated: Porphyromonas gingivalis, Prevotella nigrescens, Actinomyces viscosus, and Fusobacterium nucleatum subsp. polymorphum. The cavity was not sealed after bacterial inoculation. During lesion development, animals were treated or not with recombinant VIP 3 days post infection. Animals were killed after 3, 7, 14, and 21 days of infection and the jaws were dissected. The extraction of total RNA from periodontal tissues was performed and the integrity of samples was checked. qPCR reaction using TaqMan chemistry with inventoried primers were performed in ViiA7 equipment. The results, depicted as the relative levels of gene expression, were calculated in reference to GAPDH and β-actin expression. Periodontal tissues from upper molars were vested and incubated supplemented RPMI, followed by processing with 0.05% DNase. Cell viability and couting were determined by Neubauer chamber analysis. For flow cytometry analysis, after cell counting the cells were stained with the optimal dilution of each antibody; (PE)-conjugated and (FITC)-conjugated antibodies against CD4, CD25, FOXP3, IL-4, IL-17 and IFN-γ antibodies, as well their respective isotype controls. Cells were analyzed by FACScan and CellQuest software. Results are presented as the number of cells in the periodontal tissues or the number of positive cells for each marker in the CD4+FOXp3+, CD4+IL-4+, CD4+IFNg+ and CD4+IL-17+ subpopulations. The levels mRNA were measured by qPCR. The VIP expression was predominated in inactive lesions, as well part of the clusters of cytokine/Th markers identified as protective factors and a negative correlation between VIP expression and lesion evolution was observed. A quantitative analysis of IL1β, IL17, TNF, IFN, MMP2, RANKL, OPG, IL10, TGFβ, CTLA4, COL5A1, CTGF, CXCL11, FGF7, ITGA4, ITGA5, SERP1 and VTN expression was measured in experimental periapical lesions treated with VIP 7 and 14 days after lesion induction and healthy animals. After 7 days, all targets presented a significate increase in comparison to untreated animals. About migration kinetics, profile of chemokine receptors expression of TCD4+ subsets and phenotypic analysis of Tregs, Th1, Th2 and Th17 cells during the course of experimental periodontal disease evaluated by flow cytometry and depicted as the number of positive cells for each marker. CD4+IFNg+ and CD4+FOXp3+ cells migration were significate increased 7 days post VIP treatment. CD4+IL17+ cells migration were significate increased 7 and 14 days post VIP treatment, CD4+IL4+ cells migration were significate increased 14 and 21 days post VIP treatment compared to the control group. In conclusion, our experimental data support VIP involvement in determining the inactivity of periapical lesions. Financial support: FAPESP #2015/25618-2.

Keywords: chronic inflammation, cytokines, osteolytic lesions, VIP (Vasoactive Intestinal Peptide)

Procedia PDF Downloads 194

Authors: Mohammadjavad Sotoudeheian, Navid Farahmandian

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Cardiac hypertrophy arises in response to persistent increases in hemodynamic loads. In comparison, diabetic cardiomyopathy is defined by an abnormal myocardial changes without other cardiac-related risk factors. Pathological cardiac hypertrophy and myocardial remodeling are hallmarks of cardiovascular diseases and are risk factors for heart failure. The transcription factor forkhead box class O (FOXOs) can protect heart tissue by hostile oxidative stress and stimulating apoptosis and autophagy. FOXO proteins, as sensitive elements and mediators in response to environmental changes, have been revealed to prevent and inverse cardiac hypertrophy. FOXOs are inhibited by insulin and are critical mediators of insulin action. Insulin deficiency and uncontrolled diabetes lead to a catabolic state. FOXO1 acts downstream of the insulin-dependent pathways, which are dysregulated in diabetes. It regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K/Akt activation, which are critical regulators of cardiac hypertrophy. The complex network of signaling pathways comprising insulin/IGF-1 signaling, AMPK, JNK, and Sirtuins regulate the development of cardiovascular dysfunction by modulating the activity of FOXOs. Insulin receptors and IGF1R act via the PI3k/Akt and the MAPK/ERK pathways. Activation of Akt in response to insulin or IGF-1 induces phosphorylation of FOXOs. Increased protein synthesis induced by activation of the IGF-I/Akt/mTOR signaling pathway leads to hypertrophy. This pathway and the myostatin/Smad pathway are potent negative muscle development regulators. In cardiac muscle, insulin receptor substrates (IRS)-1 or IRS-2 activates the Akt signaling pathway and inactivate FOXO1. Under metabolic stress, p38 MAPK promotes degradation of IRS-1 and IRS-2 in cardiac myocytes and activates FOXO1, leading to cardiomyopathy. Sirt1 and FOXO1 interaction play an essential role in starvation-induced autophagy in cardiac metabolism. Inhibition of Angiotensin-II induced cardiomyocyte hypertrophy is associated with reduced FOXO1 acetylation and activation of Sirt1. The NF-κB, ERK, and FOXOs are de-acetylated by SIRT1. De-acetylation of FOXO1 induces the expression of genes involved in autophagy and stimulates autophagy flux. Therefore, under metabolic stress, FOXO1 can cause diabetic cardiomyopathy. The overexpression of FOXO1 leads to decreased cardiomyocyte size and suppresses cardiac hypertrophy through inhibition of the calcineurin–NFAT pathway. Diabetes mellitus is associated with elevation of O-GlcNAcylation. Some of its binding partners regulate the substrate selectivity of O-GlcNAc transferase (OGT). O-GlcNAcylation of essential contractile proteins may inhibit protein-protein interactions, reduce calcium sensitivity, and modulate contractile function. Uridine diphosphate (UDP)-GlcNAc is the obligatory substrate of OGT, which catalyzes a reversible post-translational protein modification. The increase of O-GlcNAcylation is accompanied by impaired cardiac hypertrophy in diabetic hearts. Inhibition of O-GlcNAcylation blocks activation of ERK1/2 and hypertrophic growth. O-GlcNAc modification on NFAT is required for its translocation from the cytosol to the nucleus, where NFAT stimulates the transcription of various hypertrophic genes. Inhibition of O-GlcNAcylation dampens NFAT-induced cardiac hypertrophic growth. Transcriptional activity of FOXO1 is enriched by improved O-GlcNAcylation upon high glucose stimulation or OGT overexpression. In diabetic conditions, the modification of FOXO1 by O-GlcNAc is promoted in cardiac troponin I and myosin light chain 2. Therefore targeting O-GlcNAcylation represents a potential therapeutic option to prevent hypertrophy in the diabetic heart.

Keywords: diabetes, cardiac hypertrophy, O-GlcNAcylation, FOXO1, Akt, PI3K, AMPK, insulin

Procedia PDF Downloads 108