ResearchPad - translational-science https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Cell Atlas technologies and insights into tissue architecture]]> https://www.researchpad.co/article/elastic_article_9194 Since Robert Hooke first described the existence of ‘cells’ in 1665, scientists have sought to identify and further characterise these fundamental units of life. While our understanding of cell location, morphology and function has expanded greatly; our understanding of cell types and states at the molecular level, and how these function within tissue architecture, is still limited. A greater understanding of our cells could revolutionise basic biology and medicine. Atlasing initiatives like the Human Cell Atlas aim to identify all cell types at the molecular level, including their physical locations, and to make this reference data openly available to the scientific community. This is made possible by a recent technology revolution: both in single-cell molecular profiling, particularly single-cell RNA sequencing, and in spatially resolved methods for assessing gene and protein expression. Here, we review available and upcoming atlasing technologies, the biological insights gained to date and the promise of this field for the future.

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<![CDATA[Recent advances in understanding prodrug transport through the SLC15 family of proton-coupled transporters]]> https://www.researchpad.co/article/elastic_article_9192 Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an important role in regulating the uptake of nutrients and vitamins from the diet, and in controlling the distribution of their metabolic intermediates within the cell. Several SLC families also play an important role in drug transport and strategies are being developed to hijack SLC transporters to control and regulate drug transport within the body. Through the addition of amino acid and peptide moieties several novel antiviral and anticancer agents have been developed that hijack the proton-coupled oligopeptide transporters, PepT1 (SCL15A1) and PepT2 (SLC15A2), for improved intestinal absorption and renal retention in the body. A major goal is to understand the rationale behind these successes and expand the library of prodrug molecules that utilise SLC transporters. Recent co-crystal structures of prokaryotic homologues of the human PepT1 and PepT2 transporters have shed important new insights into the mechanism of prodrug recognition. Here, I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition.

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<![CDATA[Post-translational modifications and stress adaptation: the paradigm of FKBP51]]> https://www.researchpad.co/article/elastic_article_9189 Adaptation to stress is a fundamental requirement to cope with changing environmental conditions that pose a threat to the homeostasis of cells and organisms. Post-translational modifications (PTMs) of proteins represent a possibility to quickly produce proteins with new features demanding relatively little cellular resources. FK506 binding protein (FKBP) 51 is a pivotal stress protein that is involved in the regulation of several executers of PTMs. This mini-review discusses the role of FKBP51 in the function of proteins responsible for setting the phosphorylation, ubiquitination and lipidation of other proteins. Examples include the kinases Akt1, CDK5 and GSK3β, the phosphatases calcineurin, PP2A and PHLPP, and the ubiquitin E3-ligase SKP2. The impact of FKBP51 on PTMs of signal transduction proteins significantly extends the functional versatility of this protein. As a stress-induced protein, FKBP51 uses re-setting of PTMs to relay the effect of stress on various signaling pathways.

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<![CDATA[Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases]]> https://www.researchpad.co/article/N00eda29b-3a72-4a58-833e-b43beac904cf Long-chain fatty acyl CoA synthetases (ACSLs) activate fatty acids by CoA addition thus facilitating their intracellular metabolism. Dysregulated ACSL expression features in several cancers and can affect processes such as ferroptosis, fatty acid β-oxidation, prostaglandin biosynthesis, steroidogenesis and phospholipid acyl chain remodelling. Here we investigate long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4) expression in liver malignancies. The expression and subcellular localisations of the ACSL3 and ACSL4 isoforms in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatic metastases were assessed by immunohistochemical analyses of multiple tumour tissue arrays and by subcellular fractionation of cultured HepG2 cells. The expression of both enzymes was increased in HCC compared with normal liver. Expression of ACSL3 was similar in HCC and hepatic metastases but lower in healthy tissue. Increased ACSL3 expression distinguished HCC from CCA with a sensitivity of 87.2% and a specificity of 75%. ACSL4 expression was significantly greater in HCC than in all other tumours and distinguished HCC from normal liver tissue with a sensitivity of 93.8% and specificity of 93.6%. Combined ACSL3 and ACSL4 staining scores distinguished HCC from hepatic metastases with 80.1% sensitivity and 77.1% specificity. These enzymes had partially overlapping intracellular distributions, ACSL4 localised to the plasma membrane and both isoforms associated with lipid droplets and the endoplasmic reticulum (ER). In conclusion, analysis of ACSL3 and ACSL4 expression can distinguish different classes of hepatic tumours.

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<![CDATA[Modulation of CRMP2 via (S)-Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6-Batten disease]]> https://www.researchpad.co/article/N12a57012-8ebd-4058-b121-c0cacf3f28c8

Abstract

CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.

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<![CDATA[Low efficacy of vaccination against serogroup B meningococci in patients with atypical hemolytic uremic syndrome]]> https://www.researchpad.co/article/N063b6d00-2073-4190-8d9a-fb913cdb54b6

Abstract

Background: The C5 complement inhibitor eculizumab is first-line treatment in atypical hemolytic uremic syndrome (aHUS) going along with a highly increased risk of meningococcal infections. Serogroup B meningococci (MenB) are the most frequently encountered cause for meningococcal infections in Europe. Efficacy of the protein-based MenB-vaccine Bexsero in aHUS has not been determined and testing is only possible in patients off-treatment with eculizumab as a human complement source is required.

Methods: Patients with aHUS were vaccinated with two doses of the protein-based MenB-vaccine Bexsero. Serum bactericidal antibody (SBA) titers against factor H binding protein (fHbp) of MenB were determined in 14 patients with aHUS off-treatment with eculizumab.

Results: Only 50% of patients showed protective human serum bactericidal antibody (hSBA) titers (≥1:4) against MenB following two vaccinations. Bactericidal antibody titers were relatively low (≤1:8) in three of seven patients with protective titers. While 71% of patients were on immunosuppressive treatment for either thrombotic microangiopathy or renal transplantation at either first or second vaccination, all four patients not receiving any immunosuppressive treatment showed protective bactericidal antibody response. Time between second vaccination and titer measurement was not significantly different between patients with protective titers compared with those with non-protective titers, while time between first and second vaccination was significantly longer in patients with protective titers going along with a tendency for reduction in immunosuppressive treatment.

Conclusions: Efficacy of vaccination against MenB is insufficient in patients with aHUS. Response to vaccination seems to be hampered by immunosuppression. Therefore, implementation of adequate antibiotic prophylaxis seems pivotal.

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<![CDATA[Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry disease]]> https://www.researchpad.co/article/Ncb67bb93-58cf-4196-99ee-9f62076d3ef2

The lysosomal storage disorder Fabry disease is characterized by a deficiency of the lysosomal enzyme α-Galactosidase A. The observation that missense variants in the encoding GLA gene often lead to structural destabilization, endoplasmic reticulum retention and proteasomal degradation of the misfolded, but otherwise catalytically functional enzyme has resulted in the exploration of alternative therapeutic approaches. In this context, we have investigated proteostasis regulators (PRs) for their potential to increase cellular enzyme activity, and to reduce the disease-specific accumulation of the biomarker globotriaosylsphingosine in patient-derived cell culture. The PRs also acted synergistically with the clinically approved 1-deoxygalactonojirimycine, demonstrating the potential of combination treatment in a therapeutic application. Extensive characterization of the effective PRs revealed inhibition of the proteasome and elevation of GLA gene expression as paramount effects. Further analysis of transcriptional patterns of the PRs exposed a variety of genes involved in proteostasis as potential modulators. We propose that addressing proteostasis is an effective approach to discover new therapeutic targets for diseases involving folding and trafficking-deficient protein mutants.

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<![CDATA[Identification of exosomal miR-455-5p and miR-1255a as therapeutic targets for breast cancer]]> https://www.researchpad.co/article/N88906e9c-1e83-4778-bba4-98e21aacfc94

Abstract

Accumulated evidence has demonstrated exosomes of cancer cells carry microRNAs (miRNAs) to non-malignant cells to induce metastasis. The present study aimed to identify crucial exosomal miRNAs for breast cancer (BC) using microarray data (GSE83669 and GSE50429) from Gene Expression Omnibus database, including exosomal samples from human BC cells (MCF7, MDA-MB-231) and normal mammary epithelial cell line (MCF10, MCF-10A), as well as original cell samples. Differentially expressed miRNAs (DEMs) were identified using EdgeR package, and mRNA targets were predicted using miRWalk2 database. The target genes were overlapped with BC genes from Comparative Toxicogenomics Database (CTD) to construct BC-related interaction network. Potential functions were analyzed by DAVID. The expression of crucial miRNAs and target genes were confirmed in other microarray datasets or TCGA sequencing data. Their associations with survival and other clinical characteristics were validated by Kaplan–Meier plotter and LinkedOmics database. As a result, 9 and 8 DEMs were identified to be shared in two datasets for exosomal and original cells, respectively. Further comparison showed that miR-455-5p was specifically differentially expressed in exosomes, and miR-1255a was commonly expressed in exosomal and original cells samples. miR-455-5p could interact with CDKN1B to influence cell cycle process and miR-1255a could regulate SMAD4 to participate in TGF-β signaling pathway. High expressed miR-455-5p (basal-like) and miR-1255a (overall) were associated with poor overall survival, while the high expression of their target genes was associated with excellent overall, recurrence-free or distant metastasis-free survival. In conclusion, the present study preliminarily indicates that exosomal miR-455-5p and miR-1255a may be novel therapeutic targets for BC.

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<![CDATA[2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury]]> https://www.researchpad.co/article/N3754d22e-423e-4038-bba7-89aa96f82518

Abstract

Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected against rhabdomyolysis-induced AKI with good safety. However, whether 23BB possessed favorable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by acute kidney dysfunction and pathological changes, companied by the overexpression of HDAC6 in tubular epithelial cells. Pharmacological inhibition of HDAC6 by the treatment of 23BB significantly attenuated sCr, BUN and renal tubular damage. Mechanistically, 23BB enhanced the acetylation of histone H3 to reduce the HDAC6 activity. Cisplatin-induced AKI triggered multiple signal mediators of endoplasmic reticulum (ER) stress including PERK, ATF6 and IRE1 pathway, as well as CHOP, GRP78, p-JNK and caspase 12 proteins. Oral administration of our HDAC6i 23BB at a dose of 40 mg/kg/d for 3 days notably improved above-mentioned responses in the injured kidney tissues. HDAC6 inhibition also reduced the number of TUNEL-positive tubular cells and regulated apoptosis-related protein expression. Overall, these data highlighted that HDAC6 inhibitor 23BB modulated apoptosis via the inhibition of ER stress in the tubular epithelial cells of cisplatin-induced AKI.

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<![CDATA[Abstract 125: ReflexiveVisual Inspection of Cleft Lip Faces - Analysis of Lookzone Focus Over Time]]> https://www.researchpad.co/article/5c014084d5eed0c484fcebb5 ]]> <![CDATA[Abstract 40: AMD3100 (Plerixafor) As A Single-Dose Stem Cell Mobilizing Agent In Vascularized Composite Tissue Allograft (VCA) Transplantation In A Canine Model]]> https://www.researchpad.co/article/5c014086d5eed0c484fcec07 ]]> <![CDATA[Abstract 100: Osteoclast Activity Required For Cranial Suture Patency]]> https://www.researchpad.co/article/5c014075d5eed0c484fce839 ]]> <![CDATA[Abstract 123: Functional Characterization of Fibroblasts Differentiated from Adipose-Derived Stem Cells]]> https://www.researchpad.co/article/5c013fb2d5eed0c484fcc22f ]]> <![CDATA[Abstract 37: Whole Eye Allograft Transplantation And Immunosuppression: Survival Of The Transplanted Rodent Eye Using Tacrolimus Monotherapy]]> https://www.researchpad.co/article/5c013fb7d5eed0c484fcc31f ]]> <![CDATA[Abstract 44: Successful Reduction of Radiation Associated Skin Injury Utilizing Topical DFO in a Murine Breast Reconstruction Model]]> https://www.researchpad.co/article/5c013fabd5eed0c484fcc0af ]]> <![CDATA[Abstract 104: Conformity of the Actual to Planned Result in Orthognathic Surgery]]> https://www.researchpad.co/article/5c013ff9d5eed0c484fccf12 ]]> <![CDATA[Abstract 62: Chlorhexidine Gluconate Surgical Preparation is Associated with Increases in the Proportion of Streptococcus Species and Enterobacteriaceae Genera in Skin Microbiome]]> https://www.researchpad.co/article/5c013fffd5eed0c484fcd035 ]]> <![CDATA[Abstract 105: Deferoxamine: A Regenerative Therapeutic with Antitumorigenic Potential]]> https://www.researchpad.co/article/5c014006d5eed0c484fcd1e4 ]]> <![CDATA[Abstract 83: Frustration and Emotional Regulation in Nonsyndromic Craniosynostosis: an fMRI Study]]> https://www.researchpad.co/article/5c01400fd5eed0c484fcd3d0 ]]> <![CDATA[Abstract 119: Designing a Murine Model of the Foreign Body Reaction]]> https://www.researchpad.co/article/5c01408bd5eed0c484fceda0 ]]>