scholarly journals Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis

2021 ◽  
Author(s):  
Maria Bartosova ◽  
Conghui Zhang ◽  
Betti Schaefer ◽  
Rebecca Herzog ◽  
David Ridinger ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Peritoneal Dialysis ◽  
Endothelial Cell ◽  
Cell Junction ◽  
Cytoskeleton Organization ◽  
Cell Counts ◽  
Lumen Narrowing ◽  
The Impact

Rationale: Patients with chronic kidney disease (CKD) have an exceedingly high cardiovascular risk; which further increases in patients on peritoneal dialysis (PD). The pathophysiological role of reactive metabolites accumulating in CKD such as glucose degradation products (GDP) is uncertain. Objective: Delineating the impact of GDP present in PD fluids in accelerated vasculopathy development in patients with CKD. Methods and Results: Omental and parietal peritoneal tissues were obtained from 107 children with CKD prior to dialysis, and 90 children on chronic PD with PD fluids containing very low or high concentrations of GDP. Omental arterioles, protected from local PD fluid exposure by surrounding fat, were microdissected for multi-omics analyses. High-GDP exposed omental arterioles exhibited three-fold higher advanced glycation endproduct concentrations and upregulated genes involved in cell death/apoptosis and suppressed genes related to cell viability/survival, cytoskeleton organization and immune response biofunctions. Vasculopathy associated canonical pathways concordantly regulated on gene- and protein level with high-GDP exposure included cell death/proliferation, apoptosis, cytoskeleton organization, metabolism and detoxification, cell junction signaling, and immune response. Parietal peritoneal arterioles of patients exposed to high-GDP fluids exhibited lumen narrowing compared to patients with CKD5 and patients on low-GDP PD, intima thickness was increased. Protein quantification verified increased proapoptotic activity and cytoskeleton disintegration, single-molecule-localization microscopy demonstrated arteriolar endothelial zonula occludens-1 (ZO-1) disruption. Absolute and per endoluminal surface length, arteriolar endothelial cell counts inversely correlated with GDP exposure, caspase-3, TGF-ß induced pSMAD2/3, interleukin-6, ZO-1 abundance and lumen narrowing. In vitro, 3,4-dideoxyglucosone-3-ene reduced lamin-A/C and membrane ZO-1 assembly, increased pSMAD2/3, and ionic and 4- and 10kDa permeability of arterial endothelial cells. Conclusions: Our findings indicate a fundamental role of GDP in PD associated vasculopathy, exerted by endothelial cell junction and cytoskeleton disruption, and induction of apoptosis. They should redirect the focus of research and intervention on targeting reactive metabolite overload in CKD and PD.

FC 109GLUCOSE DERIVATIVE INDUCED VASCULOPATHY IN CHILDREN ON PERITONEAL DIALYSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Maria Bartosova ◽  
Betti Schaefer ◽  
Conghui Zhang ◽  
Rebecca Herzog ◽  
David Ridinger ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Peritoneal Dialysis ◽  
Endothelial Cell ◽  
Tight Junction ◽  
Protein Abundance ◽  
Localization Microscopy ◽  
Cytoskeleton Organization ◽  
Canonical Pathways

Abstract Background and Aims Patients with chronic kidney disease patients (CKD) have an exceedingly high cardiovascular risk. While vasculopathy is further accelerated during peritoneal dialysis (PD), the pathophysiological role of reactive metabolites such as glucose degradation products (GDP) is uncertain. Method Omental and parietal peritoneal tissues from 100 non-CKD individuals, 107 children with CKD5, 60 children treated with neutral pH, low GDP, and 30 children treated with acidic pH, high GDP PD fluids underwent standardized digital histomorphometry. Omental arterioles localized within the fat tissue, protected from direct PD fluid exposure were microdissected for multi-omics analysis. Key regulated pathways were validated by quantitative immunostaining, with localization microscopy in peritoneal tissues of matched cohorts and in vitro in human umbilical vein endothelial cells. Results Arterioles from children with CKD5 exhibited reduced lumen to vessel ratio (L/V) and reduced endothelial telomere length compared to non-CKD individuals; gene ontology analysis identified enrichment of arteriolar genes associated with nuclear telomere cap complex and focal adhesion. Pathway analysis of arteriolar cross-omics identified top canonical pathways including telomere extension by telomerase, actin cytoskeleton, integrin and tight junction signalling. Peritoneal vasculopathy progressed with PD vintage and was more pronounced with high versus low GDP exposure (p<0.001). Compared to CKD5, low GDP-PD upregulated 145/110 and downregulated 38/34 arteriolar genes/proteins, high GDP-PD upregulated 684/137 and supressed 1560/55 genes/proteins (p<0.01). High GDP milieu induced upregulation of arteriolar genes involved in cell death/apoptosis and suppressed genes related to cell viability/survival, cytoskeleton organization and immune response biofunctions. Vasculopathy associated canonical pathways concordantly regulated on arteriolar gene and protein level with high GDP exposure included cell death/proliferation, apoptosis, cytoskeleton organization, metabolism and detoxification, cell junction signalling, and immune response. Quantitative validation in PD cohorts with similar PD vintage, dialytic glucose exposure and age (n=15 / group) verified increased proapoptotic activity and cytoskeleton disintegration with high-GDP exposure; single-molecule-localization microscopy demonstrated arteriolar endothelial zonula occludens-1 (ZO-1) disruption. Absolute and relative to endoluminal surface length, arteriolar endothelial cell counts were inversely correlated with GDP exposure, with apoptosis marker caspase-3, TGF-ß induced pSMAD2/3, interleukin-6, ZO-1 protein abundance and the degree of vasculopathy. In vitro, exposure to GDP 3,4-dideoxyglucosone-3-ene dose-dependently reduced nuclear endothelial lamin-A/C and membrane ZO-1 assembly. Transendothelial electrical resistance was decreased. ZO-1 and sealing tight junction claudin-5 protein abundance were decreased in cells after incubation with high GDP compared to low GDP PD fluid and culture media. On nanoscale level GDP reduced junction cluster formation in the membrane area. Conclusion Multi-omics analysis of omental arterioles from children without pre-existing vasculopathy and life-style related confounders identified key mechanisms of vascular aging in CKD5 and the major contribution of GDP to accelerated vasculopathy during PD, i.e. disruption of endothelial cell junctions and cytoskeleton and induction of apoptosis.

scholarly journals NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2999
Author(s):  
Deborah Reynaud ◽  
Roland Abi Nahed ◽  
Nicolas Lemaitre ◽  
Pierre-Adrien Bolze ◽  
Wael Traboulsi ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Major Gene ◽  
Critical Role ◽  
Orthotopic Model ◽  
Independent Manner ◽  
Maternal Immune Response ◽  
The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

Effects of Mitomycin C on Corneal Endothelial Cell Counts in Pterygium Surgery: Role of Application Location

2011 ◽  
Vol 151 (3) ◽  
pp. 488-493 ◽  
Author(s):  
Ahmad Kheirkhah ◽  
Ali Izadi ◽  
Mohammad Yaser Kiarudi ◽  
Rahman Nazari ◽  
Hesam Hashemian ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Mitomycin C ◽  
Corneal Endothelial Cell ◽  
Cell Counts ◽  
Pterygium Surgery ◽  
Endothelial Cell Counts

scholarly journals The Role of Micronutrients in Support of the Immune Response against Viral Infections

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3198 ◽  
Author(s):  
Francesco Pecora ◽  
Federica Persico ◽  
Alberto Argentiero ◽  
Cosimo Neglia ◽  
Susanna Esposito
Keyword(s):  
Fatty Acids ◽  
Immune Response ◽  
Immune System ◽  
Viral Infections ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Optimal Function ◽  
The Impact

Viral infections are a leading cause of morbidity and mortality worldwide, and the importance of public health practices including handwashing and vaccinations in reducing their spread is well established. Furthermore, it is well known that proper nutrition can help support optimal immune function, reducing the impact of infections. Several vitamins and trace elements play an important role in supporting the cells of the immune system, thus increasing the resistance to infections. Other nutrients, such as omega-3 fatty acids, help sustain optimal function of the immune system. The main aim of this manuscript is to discuss of the potential role of micronutrients supplementation in supporting immunity, particularly against respiratory virus infections. Literature analysis showed that in vitro and observational studies, and clinical trials, highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in modulating the immune response. Supplementation with vitamins, omega 3 fatty acids and zinc appears to be a safe and low-cost way to support optimal function of the immune system, with the potential to reduce the risk and consequences of infection, including viral respiratory infections. Supplementation should be in addition to a healthy diet and fall within recommended upper safety limits set by scientific expert bodies. Therefore, implementing an optimal nutrition, with micronutrients and omega-3 fatty acids supplementation, might be a cost-effective, underestimated strategy to help reduce the burden of infectious diseases worldwide, including coronavirus disease 2019 (COVID-19).

scholarly journals Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

2020 ◽  
Author(s):  
Qiang Liu ◽  
Yihang Qi ◽  
Jie Zhai ◽  
Xiangyi Kong ◽  
Xiangyu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cell ◽  
Immune Checkpoints ◽  
Cell Populations ◽  
Potential Biomarker ◽  
The Impact

Abstract Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer. Furthermore, we estimated the landscape of relationship between LAG3 and ten types of cell populations in breast cancer. Gene ontology analysis revealed LAG3 were strongly correlated with immune response and inflammatory activities. We investigated the correlation pattern between LAG3 and immune modulators in pan-cancer, especially the synergistic role of LAG3 with other immune checkpoints members in breast cancer. Conclusions LAG3 expression was closely related to malignancy of breast cancer and might serve as a potential biomarker; LAG3 might plays an important role in regulating tumor immune microenvironment, not only T cells, but also other immune cells. More importantly, LAG3 might synergize with CTLA4, PD1/ PDL1 and other immune checkpoints, thereby lending more evidences to combination cancer immunotherapy by targeting LAG3, PD1/PDL1, and CTLA4 together.

scholarly journals Autophagy Function and Regulation in Kidney Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 100 ◽  
Author(s):  
Gur P. Kaushal ◽  
Kiran Chandrashekar ◽  
Luis A. Juncos ◽  
Sudhir V. Shah
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Therapeutic Approaches ◽  
Regulated Necrosis ◽  
Atg Genes ◽  
Cellular Components ◽  
The Impact

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

scholarly journals Peritoneal Microbiome in End-Stage Renal Disease Patients and the Impact of Peritoneal Dialysis Therapy

2020 ◽  
Vol 8 (2) ◽  
pp. 173
Author(s):  
Liliana Simões-Silva ◽  
Ricardo Araujo ◽  
Manuel Pestana ◽  
Isabel Soares-Silva ◽  
Benedita Sampaio-Maia
Keyword(s):  
Peritoneal Dialysis ◽  
Human Microbiome ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Peritoneal Tissue ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Impact

Factors influencing the occurrence of peritoneal dialysis (PD)-related infections are still far from fully understood. Recent studies described the existence of specific microbiomes in body sites previously considered microbiome-free, unravelling new microbial pathways in the human body. In the present study, we analyzed the peritoneum of end-stage kidney disease (ESKD) patients to determine if they harbored a specific microbiome and if it is altered in patients on PD therapy. We conducted a cross-sectional study where the peritoneal microbiomes from ESKD patients with intact peritoneal cavities (ESKD non-PD, n = 11) and ESKD patients undergoing PD therapy (ESKD PD, n = 9) were analyzed with a 16S rRNA approach. Peritoneal tissue of ESKD patients contained characteristically low-abundance microbiomes dominated by Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Patients undergoing PD therapy presented lower species richness, with dominance by the Pseudomonadaceae and Prevotelaceae families. This study provides the first characterization of the peritoneal microbiome in ESKD patients, bringing new insight to the human microbiome. Additionally, PD therapy may induce changes in this unique microbiome. The clinical relevance of these observations should be further explored to uncover the role of the peritoneal microbiome as a key element in the onset or aggravation of infection in ESKD patients, especially those undergoing PD.

scholarly journals Dysfunction of Heterotrimeric Kinesin-2 in Rod Photoreceptor Cells and the Role of Opsin Mislocalization in Rapid Cell Death

2010 ◽  
Vol 21 (23) ◽  
pp. 4076-4088 ◽  
Author(s):  
Vanda S. Lopes ◽  
David Jimeno ◽  
Kornnika Khanobdee ◽  
Xiaodan Song ◽  
Bryan Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Outer Segment ◽  
Photoreceptor Cell ◽  
Photoreceptor Cells ◽  
Cell Loss ◽  
Rod Photoreceptor ◽  
Retinal Degenerations ◽  
Cell Counts ◽  
And Function

Due to extensive elaboration of the photoreceptor cilium to form the outer segment, axonemal transport (IFT) in photoreceptors is extraordinarily busy, and retinal degeneration is a component of many ciliopathies. Functional loss of heterotrimeric kinesin-2, a major anterograde IFT motor, causes mislocalized opsin, followed by rapid cell death. Here, we have analyzed the nature of protein mislocalization and the requirements for the death of kinesin-2-mutant rod photoreceptors. Quantitative immuno EM showed that opsin accumulates initially within the inner segment, and then in the plasma membrane. The light-activated movement of arrestin to the outer segment is also impaired, but this defect likely results secondarily from binding to mislocalized opsin. Unlike some other retinal degenerations, neither opsin–arrestin complexes nor photoactivation were necessary for cell loss. In contrast, reduced rod opsin expression provided enhanced rod and cone photoreceptor survival and function, as measured by photoreceptor cell counts, apoptosis assays, and ERG analysis. The cell death incurred by loss of kinesin-2 function was almost completely negated by Rho−/−. Our results indicate that mislocalization of opsin is a major cause of photoreceptor cell death from kinesin-2 dysfunction and demonstrate the importance of accumulating mislocalized protein per se, rather than specific signaling properties of opsin, stemming from photoactivation or arrestin binding.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Graziella Curtale ◽  
Franca Citarella ◽  
Claudia Carissimi ◽  
Marina Goldoni ◽  
Nicoletta Carucci ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

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