scholarly journals The Role of Cystinosin in the Intermediary Thiol Metabolism and Redox Homeostasis in Kidney Proximal Tubular Cells

Antioxidants ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 179 ◽  
Author(s):  
Rodolfo Sumayao ◽  
Philip Newsholme ◽  
Tara McMorrow
Keyword(s):  
Redox Homeostasis ◽  
In Vitro Models ◽  
Cellular Redox ◽  
Tubular Cells ◽  
Thiol Metabolism ◽  
Proximal Tubular ◽  
Kidney Proximal Tubular Cells

Cystinosin is a lysosomal transmembrane protein which facilitates transport of the disulphide amino acid cystine (CySS) from the lysosomes of the cell. This protein is encoded by the CTNS gene which is defective in the lysosomal storage disorder, cystinosis. Because of the apparent involvement of cystinosin in the intermediary thiol metabolism, its discovery has fuelled investigations into its role in modulating cellular redox homeostasis. The kidney proximal tubular cells (PTCs) have become the focus of various studies on cystinosin since the protein is highly expressed in these cells and kidney proximal tubular transport dysfunction is the foremost clinical manifestation of cystinosis. The lysosomal CySS pool is a major source of cytosolic cysteine (Cys), the limiting amino acid for the synthesis of an important antioxidant glutathione (GSH) via the γ-glutamyl cycle. Therefore, loss of cystinosin function is presumed to lead to cytosolic deficit of Cys which may impair GSH synthesis. However, studies using in vitro models lacking cystinosin yielded inconsistent results and failed to establish the mechanistic role of cystinosin in modulating GSH synthesis and redox homeostasis. Because of the complexity of the metabolic micro- and macro-environment in vivo, using in vitro models alone may not be able to capture the complete sequence of biochemical and physiological events that occur as a consequence of loss of cystinosin function. The coexistence of pathways for the overall handling and disposition of GSH, the modulation of CTNS gene by intracellular redox status and the existence of a non-canonical isoform of cystinosin may constitute possible rescue mechanisms in vivo to remediate redox perturbations in renal PTCs. Importantly, the mitochondria seem to play a critical role in orchestrating redox imbalances initiated by cystinosin dysfunction. Non-invasive techniques such as in vivo magnetic resonance imaging with the aid of systems biology approaches may provide invaluable mechanistic insights into the role of cystinosin in the essential intermediary thiol metabolism and in the overall regulation cellular redox homeostasis.

scholarly journals The Role of Biomimetic Hypoxia on Cancer Cell Behaviour in 3D Models: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1334
Author(s):  
Ye Liu ◽  
Zahra Mohri ◽  
Wissal Alsheikh ◽  
Umber Cheema
Keyword(s):  
Systematic Review ◽  
Cellular Response ◽  
3D Culture ◽  
3D Models ◽  
In Vitro Models ◽  
Research Findings ◽  
Tissue Models

The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features into 3D models informs us of how each component feature alters specific cellular response. We conducted a systematic review of research papers where the focus was the introduction of key biomimetic features into in vitro models of cancer, including 3D culture and hypoxia. We analysed outcomes from these and compiled our findings into distinct groupings to ascertain which biomimetic parameters correlated with specific responses. We found a number of biomimetic features which primed cancer cells to respond in a manner which matched in vivo response.

The Use of Erythropoietin in the Treatment of Post-bone Marrow Transplatation Anemia

1993 ◽  
Vol 16 (5_suppl) ◽  
pp. 8-12 ◽  
Author(s):  
A.M. Vannucchi ◽  
A. Bosi ◽  
A. Grossi ◽  
S. Guidi ◽  
R. Saccardi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Bone Marrow Transplantation ◽  
Blood Transfusion ◽  
In Vitro Models ◽  
Immunosuppressive Drug ◽  
Number Of Patients

The issue of the role of erythropoietin (Epo) in the erythroid reconstitution after bone marrow transplantation (BMT) has been addressed in several recent studies. A defective Epo production in response to anemia has been shown to occur in patients undergoing allogeneic BMT unlike in most of those subjected to an autologous rescue. The factors involved in the inadeguate Epo production in BMT are discussed, with particular attention to the role of the immunosuppressive drug cyclosporin-A, which has been shown to inhibit Epo production in both in vivo and in vitro models. The observation of defective Epo production eventually led to the development of clinical trials of recombinant human Epo (rhEpo) administration in BMT patients; the aims of these studies were to stimulate erythroid engraftment, hence reducing blood transfusion exposure. Although the number of patients studied up to now is relatively small, a benefit from rhEpo administration in terms of accelerated erythroid engraftment seems very likely, and it may also be associated with decreased transfusional needs in most treated patients. However, further studies are needed to better define indications, dosages and schedules of rhEpo in BMT patients.

scholarly journals N-Acetylcysteine as Modulator of the Essential Trace Elements Copper and Zinc

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1117
Author(s):  
Theresa Wolfram ◽  
Maria Schwarz ◽  
Michaela Reuß ◽  
Kristina Lossow ◽  
Mario Ost ◽  
...  
Keyword(s):  
Trace Elements ◽  
Redox Homeostasis ◽  
Redox Balance ◽  
Cellular Redox ◽  
Essential Trace Elements ◽  
Nrf2 Activation ◽  
Zn And Cu In ◽  
Cu And Zn

N-acetylcysteine (NAC) is a frequently prescribed drug and known for its metal chelating capability. However, to date it is not well characterized whether NAC intake affects the homeostasis of essential trace elements. As a precursor of glutathione (GSH), NAC also has the potential to modulate the cellular redox homeostasis. Thus, we aimed to analyze effects of acute and chronic NAC treatment on the homeostasis of copper (Cu) and zinc (Zn) and on the activity of the redox-sensitive transcription factor Nrf2. Cells were exposed to 1 mM NAC and were co-treated with 50 μM Cu or Zn. We showed that NAC treatment reduced the cellular concentration of Zn and Cu. In addition, NAC inhibited the Zn-induced Nrf2 activation and limited the concomitant upregulation of cellular GSH concentrations. In contrast, mice chronically received NAC via drinking water (1 g NAC/100 mL). Cu and Zn concentrations were decreased in liver and spleen. In the duodenum, NQO1, TXNRD, and SOD activities were upregulated by NAC. All of them can be induced by Nrf2, thus indicating a putative Nrf2 activation. Overall, NAC modulates the homeostasis of Cu and Zn both in vitro and in vivo and accordingly affects the cellular redox balance.

scholarly journals Intestinal miRNAs regulated in response to dietary lipids

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Judit Gil-Zamorano ◽  
João Tomé-Carneiro ◽  
María-Carmen Lopez de las Hazas ◽  
Lorena del Pozo-Acebo ◽  
M. Carmen Crespo ◽  
...  
Keyword(s):  
Small Intestine ◽  
Lipid Metabolism ◽  
Chronic Exposure ◽  
Potential Role ◽  
In Vitro Models ◽  
Dietary Lipids ◽  
Metabolism Regulation

Abstract The role of miRNAs in intestinal lipid metabolism is poorly described. The small intestine is constantly exposed to high amounts of dietary lipids, and it is under conditions of stress that the functions of miRNAs become especially pronounced. Approaches consisting in either a chronic exposure to cholesterol and triglyceride rich diets (for several days or weeks) or an acute lipid challenge were employed in the search for intestinal miRNAs with a potential role in lipid metabolism regulation. According to our results, changes in miRNA expression in response to fat ingestion are dependent on factors such as time upon exposure, gender and small intestine section. Classic and recent intestinal in vitro models (i.e. differentiated Caco-2 cells and murine organoids) partially mirror miRNA modulation in response to lipid challenges in vivo. Moreover, intestinal miRNAs might play a role in triglyceride absorption and produce changes in lipid accumulation in intestinal tissues as seen in a generated intestinal Dicer1-deletion murine model. Overall, despite some variability between the different experimental cohorts and in vitro models, results show that some miRNAs analysed here are modulated in response to dietary lipids, hence likely to participate in the regulation of lipid metabolism, and call for further research.

scholarly journals The effect of proteinuria-mediated endothelin-1 downregulation of PKCα signalling in proximal tubular cells and its successful/INS; treatment is measurable using microRNA15a as biomarker in vitro and in vivo

Life Sciences ◽  
2013 ◽  
Vol 93 (25-26) ◽  
pp. e5-e6
Author(s):  
Heike Loeser ◽  
Melanie von Brandenstein ◽  
Maike Wittersheim ◽  
Volker Burst ◽  
Claudia Richter ◽  
...  
Keyword(s):  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Endothelin 1 ◽  
Proximal Tubular

In vitro metabolism of 5-fluoro-2-glutathionyl-nitrobenzene by kidney proximal tubular cells studied by 19F-NMR

1995 ◽  
Vol 98 (2) ◽  
pp. 97-112 ◽  
Author(s):  
H.E.M.G. Haenen ◽  
I.M.C.M. Rietjens ◽  
J. Vervoort ◽  
J.H.M. Temmink ◽  
P.J. van Bladeren
Keyword(s):  
In Vitro Metabolism ◽  
19F Nmr ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Kidney Proximal Tubular Cells

scholarly journals Staphylococcus aureususes the bacilliredoxin (BrxAB)/ bacillithiol disulfide reductase (YpdA) redox pathway to defend against oxidative stress under infections

2019 ◽  
Author(s):  
Nico Linzner ◽  
Vu Van Loi ◽  
Verena Nadin Fritsch ◽  
Quach Ngoc Tung ◽  
Saskia Stenzel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Defense Mechanism ◽  
Redox Homeostasis ◽  
Stress Monitoring ◽  
Macrophage Infection ◽  
Disulfide Reductase ◽  
Mixed Disulfides

ABSTRACTStaphylococcus aureusis a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections. The low molecular weight thiol bacillithiol (BSH) is an important defense mechanism ofS. aureusfor detoxification of ROS and HOCl stress to maintain the reduced state of the cytoplasm. Under HOCl stress, BSH forms mixed disulfides with proteins, termed asS-bacillithiolations, which are reduced by bacilliredoxins (BrxA and BrxB). The NADPH-dependent flavin disulfide reductase YpdA is phylogenetically associated with the BSH synthesis and BrxA/B enzymes and was proposed to function as BSSB reductase. Here, we investigated the role of the bacilliredoxin BrxAB/BSH/YpdA pathway inS. aureusCOL under oxidative stress and macrophage infection conditionsin vivoand in biochemical assaysin vitro. Using HPLC thiol metabolomics, a strongly enhanced BSSB level and a decreased BSH/BSSB ratio were measured in theS. aureusCOLypdAdeletion mutant under control and NaOCl stress. Monitoring the BSH redox potential (EBSH) using the Brx-roGFP2 biosensor revealed that YpdA is required for regeneration of the reducedEBSHupon recovery from oxidative stress. In addition, theypdAmutant was impaired in H2O2detoxification as measured with the novel H2O2-specific Tpx-roGFP2 biosensor. Phenotype analyses further showed that BrxA and YpdA are required for survival under NaOCl and H2O2stressin vitroand inside murine J-774A.1 macrophages in infection assaysin vivo. Finally, NADPH-coupled electron transfer assays provide evidence for the function of YpdA in BSSB reduction, which depends on the conserved Cys14 residue. YpdA acts together with BrxA and BSH in de-bacillithiolation ofS-bacilithiolated GapDH. In conclusion, our results point to a major role of the BrxA/BSH/YpdA pathway in BSH redox homeostasis inS. aureusduring recovery from oxidative stress and under infections.

Therapeutics and Research Related to Glioblastoma: Advancements and Future Targets

2020 ◽  
Vol 21 (3) ◽  
pp. 186-198 ◽  
Author(s):  
Vishal Chavda ◽  
Vimal Patel ◽  
Dhananjay Yadav ◽  
Jigar Shah ◽  
Snehal Patel ◽  
...  
Keyword(s):  
Treatment Options ◽  
Graphene Quantum Dots ◽  
Primary Brain Tumor ◽  
In Vitro Models ◽  
Molecular Pathways ◽  
Dismal Prognosis ◽  
Novel Drugs

Glioblastoma, the most common primary brain tumor, has been recognized as one of the most lethal and fatal human tumors. It has a dismal prognosis, and survival after diagnosis is less than 15 months. Surgery and radiotherapy are the only available treatment options at present. However, numerous approaches have been made to upgrade in vivo and in vitro models with the primary goal of assessing abnormal molecular pathways that would be suitable targets for novel therapeutic approaches. Novel drugs, delivery systems, and immunotherapy strategies to establish new multimodal therapies that target the molecular pathways involved in tumor initiation and progression in glioblastoma are being studied. The goal of this review was to describe the pathophysiology, neurodegeneration mechanisms, signaling pathways, and future therapeutic targets associated with glioblastomas. The key features have been detailed to provide an up-to-date summary of the advancement required in current diagnosis and therapeutics for glioblastoma. The role of nanoparticulate system graphene quantum dots as suitable therapy for glioblastoma has also been discussed.

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