Publications by authors named "Mario Falchi"

137 Publications

O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function.

J Am Soc Nephrol 2021 Jun 14. Epub 2021 Jun 14.

M Falchi, Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom of Great Britain and Northern Ireland.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerular disease worldwide, and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. While both types of human IgA (IgA1 and IgA2) have several -glycans as posttranslational modification, only IgA1 features extensive hinge-region -glycosylation. IgA1 galactose-deficiency on the -glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA - and -glycosylation in IgAN. To gain insights into the complex - and -glycosylation of serum IgA1 and IgA2 in IgAN, we employed liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 IgAN patients and 244 age and sex-matched healthy controls. Multiple structural features of -glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and -glycan complexity. Moreover, IgA1 -glycan sialylation was associated with both disease risk and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. Our high-resolution data suggest that IgA - and -glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020081208DOI Listing
June 2021

Fragile X mental retardation protein in intrahepatic cholangiocarcinoma: regulating the cancer cell behavior plasticity at the leading edge.

Oncogene 2021 Jun 20;40(23):4033-4049. Epub 2021 May 20.

Research Unit of Microscopic and Ultrastructural Anatomy, Department of Medicine, Campus Bio-Medico University, Rome, Italy.

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy of the intrahepatic biliary tract with a very poor prognosis. Although some clinicopathological parameters can be prognostic factors for iCCA, the molecular prognostic markers and potential mechanisms of iCCA have not been well investigated. Here, we report that the Fragile X mental retardation protein (FMRP), a RNA binding protein functionally absent in patients with the Fragile X syndrome (FXS) and also involved in several types of cancers, is overexpressed in human iCCA and its expression is significantly increased in iCCA metastatic tissues. The silencing of FMRP in metastatic iCCA cell lines affects cell migration and invasion, suggesting a role of FMRP in iCCA progression. Moreover, we show evidence that FMRP is localized at the invasive front of human iCCA neoplastic nests and in pseudopodia and invadopodia protrusions of migrating and invading iCCA cancer cells. Here FMRP binds several mRNAs encoding key proteins involved in the formation and/or function of these protrusions. In particular, we find that FMRP binds to and regulates the expression of Cortactin, a critical regulator of invadopodia formation. Altogether, our findings suggest that FMRP could promote cell invasiveness modulating membrane plasticity and invadopodia formation at the leading edges of invading iCCA cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-021-01824-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195741PMC
June 2021

Extensive weight loss reduces glycan age by altering IgG N-glycosylation.

Int J Obes (Lond) 2021 Jul 3;45(7):1521-1531. Epub 2021 May 3.

Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.

Background: Obesity, a major global health problem, is associated with increased cardiometabolic morbidity and mortality. Protein glycosylation is a frequent posttranslational modification, highly responsive to inflammation and ageing. The prospect of biological age reduction, by changing glycosylation patterns through metabolic intervention, opens many possibilities. We have investigated whether weight loss interventions affect inflammation- and ageing-associated IgG glycosylation changes, in a longitudinal cohort of bariatric surgery patients. To support potential findings, BMI-related glycosylation changes were monitored in a longitudinal twins cohort.

Methods: IgG N-glycans were chromatographically profiled in 37 obese patients, subjected to low-calorie diet, followed by bariatric surgery, across multiple timepoints. Similarly, plasma-derived IgG N-glycan traits were longitudinally monitored in 1680 participants from the TwinsUK cohort.

Results: Low-calorie diet induced a marked decrease in the levels of IgG N-glycans with bisecting GlcNAc, whose higher levels are usually associated with ageing and inflammatory conditions. Bariatric surgery resulted in extensive alterations of the IgG N-glycome that accompanied progressive weight loss during 1-year follow-up. We observed a significant increase in digalactosylated and sialylated glycans, and a substantial decrease in agalactosylated and core fucosylated IgG N-glycans (adjusted p value range 7.38 × 10-3.94 × 10). This IgG N-glycan profile is known to be associated with a younger biological age and reflects an enhanced anti-inflammatory IgG potential. Loss of BMI over a 20 year period in the TwinsUK cohort validated a weight loss-associated agalactosylation decrease (adjusted p value 1.79 × 10) and an increase in digalactosylation (adjusted p value 5.85 × 10).

Conclusions: Altogether, these findings highlight that weight loss substantially affects IgG N-glycosylation, resulting in reduced glycan and biological age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-021-00816-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236401PMC
July 2021

Immune Trait Shifts in Association With Tobacco Smoking: A Study in Healthy Women.

Front Immunol 2021 9;12:637974. Epub 2021 Mar 9.

Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.

Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.637974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985448PMC
March 2021

Symptom clusters in COVID-19: A potential clinical prediction tool from the COVID Symptom Study app.

Sci Adv 2021 03 19;7(12). Epub 2021 Mar 19.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, MA, USA.

As no one symptom can predict disease severity or the need for dedicated medical support in coronavirus disease 2019 (COVID-19), we asked whether documenting symptom time series over the first few days informs outcome. Unsupervised time series clustering over symptom presentation was performed on data collected from a training dataset of completed cases enlisted early from the COVID Symptom Study Smartphone application, yielding six distinct symptom presentations. Clustering was validated on an independent replication dataset between 1 and 28 May 2020. Using the first 5 days of symptom logging, the ROC-AUC (receiver operating characteristic - area under the curve) of need for respiratory support was 78.8%, substantially outperforming personal characteristics alone (ROC-AUC 69.5%). Such an approach could be used to monitor at-risk patients and predict medical resource requirements days before they are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abd4177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978420PMC
March 2021

Association Between Medication-Taking and Refractive Error in a Large General Population-Based Cohort.

Invest Ophthalmol Vis Sci 2021 02;62(2):15

Section of Ophthalmology, School of Life Course Sciences, King's College London, United Kingdom.

Purpose: Refractive errors, particularly myopia, are common and a leading cause of blindness. This study aimed to explore associations between medications and refractive error in an aging adult cohort and to determine whether childhood-onset refractive errors predict future medication use to provide novel insights into disease mechanisms.

Methods: The study compared the spherical equivalent values measured in 102,318 UK Biobank participants taking the 960 most commonly used medications. The strengths of associations were evaluated against the self-reported age of spectacle wear. The causality of refractive error changes was inferred using sensitivity and Mendelian randomization analyses.

Results: Anti-glaucoma drugs were associated with 1 to 2 diopters greater myopic refraction, particularly in subjects who started wearing correction in the first two decades of life, potentially due to the association of higher intraocular pressure since early years with both myopia and, later in life, glaucoma. All classes of pain-control medications, including paracetamol, opiates, non-steroidal antiinflammatory drugs, and gabapentinoids, were associated with greater hyperopia (+0.68-1.15 diopters), after correction for deprivation, education, and polypharmacy and sensitivity analyses for common diagnoses. Oral hypoglycemics (metformin, gliburonide) were associated with myopia, as was allopurinol, and participants using bronchodilators (ipratropium and salbutamol) were more hyperopic.

Conclusions: This study finds for the first time, to our knowledge, that medication use is associated with refractive error in adults. The novel finding that analgesics are associated with hyperopic refraction, and the possibility that multisite chronic pain predisposes to hyperopia, deserves further research. Some drugs, such as antihyperglycemic or bronchodilators, may directly alter refractive error. Intraocular pressure appears causative for myopia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.62.2.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900881PMC
February 2021

Phagocytosis and activation of bone marrow-derived macrophages by Plasmodium falciparum gametocytes.

Malar J 2021 Feb 10;20(1):81. Epub 2021 Feb 10.

Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, via Pascal 36, 20133, Milan, Italy.

Background: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed.

Methods: Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes.

Results: The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2.

Conclusions: These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12936-021-03589-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874634PMC
February 2021

Ethnic-specific association of amylase gene copy number with adiposity traits in a large Middle Eastern biobank.

NPJ Genom Med 2021 Feb 9;6(1). Epub 2021 Feb 9.

Department of Human Genetics, Sidra Medicine, Doha, Qatar.

Studies assessing the impact of amylase genes copy number (CN) on adiposity report conflicting findings in different global populations, likely reflecting the impact of ancestral and ethnic-specific environment and lifestyle on selection at the amylase loci. Here, we leverage population size and detailed adiposity measures from a large population biobank to resolve confounding effects and determine the relationship between salivary (AMY1) and pancreatic (AMY2A) amylase genes CN and adiposity in 2935 Qatari individuals who underwent whole-genome sequencing (WGS) as part of the Qatar Genome Programme. We observe a negative association between AMY1 CNs and trunk fat percentage in the Qatari population (P = 7.50 × 10) and show that Qataris of Arab descent have significantly lower CN at AMY1 (P = 1.32 × 10) as well as less favorable adiposity and metabolic profiles (P < 1.34 × 10) than Qataris with Persian ancestry. Indeed, lower AMY1 CN was associated with increased total and trunk fat percentages in Arabs (P < 4.60 × 10) but not in Persians. Notably, overweight and obese Persians reported a significant trend towards dietary restraint following weight gain compared to Arabs (P = 4.29 × 10), with AMY1 CN showing negative association with dietary self-restraint (P = 3.22 × 10). This study reports an association between amylase gene CN and adiposity traits in a large Middle Eastern population. Importantly, we leverage rich biobank data to demonstrate that the strength of this association varies with ethnicity, and may be influenced by population-specific behaviors that also contribute to adiposity traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-021-00170-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873199PMC
February 2021

Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus.

Int J Mol Sci 2021 Feb 6;22(4). Epub 2021 Feb 6.

Pharmacological Research and Experimental Therapy Unit, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to "self" nucleic acids, LL37 acts as "danger signal," leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while "fully-citrullinated" LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated "adjuvant-like" properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to "fully citrullinated-LL37," "fully carbamylated-LL37" maintains both innate and adaptive immune-cells' stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915858PMC
February 2021

Self-Reported Symptoms of COVID-19, Including Symptoms Most Predictive of SARS-CoV-2 Infection, Are Heritable.

Twin Res Hum Genet 2020 12;23(6):316-321

Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, UK.

Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n = 3261) completing the C-19 COVID-19 symptom tracker app allowed classical twin studies of COVID-19 symptoms, including predicted COVID-19, a symptom-based algorithm to predict true infection, derived from app users tested for SARS-CoV-2. We found heritability of 49% (32-64%) for delirium; 34% (20-47%) for diarrhea; 31% (8-52%) for fatigue; 19% (0-38%) for anosmia; 46% (31-60%) for skipped meals and 31% (11-48%) for predicted COVID-19. Heritability estimates were not affected by cohabiting or by social deprivation. The results suggest the importance of host genetics in the risk of clinical manifestations of COVID-19 and provide grounds for planning genome-wide association studies to establish specific genes involved in viral infectivity and the host immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/thg.2020.85DOI Listing
December 2020

Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy.

mSystems 2021 Jan 12;6(1). Epub 2021 Jan 12.

Renal Division, Peking University First Hospital, Beijing, People's Republic of China.

The gut microbiota has been implicated in immunoglobin A nephropathy (IgAN) because the intestinal immune response is assumed to be one of the disease triggers. Since the microbial composition is heritable, we hypothesize that genetic variants controlling gut microbiota composition may be associated with susceptibility to IgAN or clinical phenotypes. A total of 175 gut-microbiome-associated genetic variants were retrieved from the Genome-Wide Association Study (GWAS) Catalog. Genetic associations were examined in 1,511 patients with IgAN and 4,469 controls. Subphenotype associations and microbiome annotations were undertaken for a better understanding of how genes shaped phenotypes. Likely candidate microbes suggested in genetic associations were validated using 16S rRNA gene sequencing in two independent data sets with 119 patients with IgAN and 45 controls in total. Nine genetic variants were associated with susceptibility to IgAN. Risk genotypes of were associated with higher serum levels of galactose-deficient IgA1 (Gd-IgA1). Other significant findings included the associations between the risk genotype of and early age at onset, and worse kidney function, and AL365503.1 and more severe hematuria. Besides, risk genotypes of and were associated with decreased abundances of and , respectively. Risk genotypes of and were associated with increased abundances of and , respectively. 16S data validated a decreased tendency for and an increased tendency for in IgAN. In this pilot study, our results provided preliminary evidence that the gut microbiota in IgAN was affected by host genetics and shed new light on candidate bacteria for future pathogenesis studies. The gut microbiota and host genetics are implicated in the pathogenesis of IgAN. Recent studies have confirmed that microbial compositions are heritable (microbiome quantitative trait loci [QTL]). The relationship between host genetics and the microbiota and the role of the microbiota in IgAN are unclear. We retrieved the GWAS Catalog and associated microbiome QTL in IgAN, observing that nine genetic variants were associated with IgAN susceptibility and some clinical phenotypes. In a consistent way, the decreased abundance of was associated with higher serum levels of Gd-IgA1, and 16S rRNA gene analysis confirmed the decreased abundance of in IgAN. These data provided preliminary evidence that the gut microbiota in IgAN was affected by host genetics, which is a new strategy for future pathogenesis and intervention studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSystems.00819-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901477PMC
January 2021

Nanovesicles released by OKT3 hybridoma express fully active antibodies.

J Enzyme Inhib Med Chem 2021 Dec;36(1):175-182

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Recent findings have shown that nanovesicles preparations from either primary immune cells culture supernatants or plasma contain immunoglobulins, suggesting that a natural way of antibody production may be through exosome release. To verify this hypothesis, we used the OKT3 hybridoma clone, which produces a murine IgG2a monoclonal antibody used to reduce rejection in patients undergoing organ transplantation. We showed exosome-associated immunoglobulins in hybridoma supernatants, by Western blot, nanoscale flow cytometry and immunocapture-based ELISA. The OKT3-exo was also being able to trigger cytokines production in both CD4 and CD8 T cells. These results show that nanovesicles contain immunoglobulin and could be used for immunotherapy. These data could lead to a new approach to improve the effectiveness of therapeutic antibodies by exploiting their natural property to be expressed on nanovesicle membrane, that probably render them more stable and as a consequence more capable to interact with their specific ligand in the best way.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2020.1852401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801098PMC
December 2021

Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people.

Thorax 2021 07 5;76(7):714-722. Epub 2021 Jan 5.

The Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

Background: The association between current tobacco smoking, the risk of developing symptomatic COVID-19 and the severity of illness is an important information gap.

Methods: UK users of the Zoe COVID-19 Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, and were asked to log their condition daily. Participants who reported that they did not feel physically normal were then asked by the app to complete a series of questions, including 14 potential COVID-19 symptoms and about hospital attendance. The main study outcome was the development of 'classic' symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness and their association with current smoking. The number of concurrent COVID-19 symptoms was used as a proxy for severity and the pattern of association between symptoms was also compared between smokers and non-smokers.

Results: Between 24 March 2020 and 23 April 2020, data were available on 2 401 982 participants, mean (SD) age 43.6 (15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834 437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to report symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR (95% CI) 1.14 (1.10 to 1.18); >5 symptoms 1.29 (1.26 to 1.31); >10 symptoms 1.50 (1.42 to 1.58). The pattern of association between reported symptoms did not vary between smokers and non-smokers.

Interpretation: These data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2020-216422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789201PMC
July 2021

HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication.

Int J Mol Sci 2020 Dec 30;22(1). Epub 2020 Dec 30.

National HIV/AIDS Research Center, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161 Rome, Italy.

Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling-docking calculations identify a low-energy Tat-αvβ3 integrin complex in which Tat makes contacts with both the αv and β3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22010317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796023PMC
December 2020

A reference map of potential determinants for the human serum metabolome.

Nature 2020 12 11;588(7836):135-140. Epub 2020 Nov 11.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment. The origins of specific compounds are known, including metabolites that are highly heritable, or those that are influenced by the gut microbiome, by lifestyle choices such as smoking, or by diet. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts that were not available to us when we trained the algorithms. We used feature attribution analysis to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2896-2DOI Listing
December 2020

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

National Center for Research and Preclinical and Clinical Evaluation of Drugs, Istituto Superiore di Sanità, 00161 Rome, Italy.

An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583077PMC
September 2020

Looking for Sunshine: Genetic Predisposition to Sun Seeking in 265,000 Individuals of European Ancestry.

J Invest Dermatol 2021 Apr 10;141(4):779-786. Epub 2020 Sep 10.

Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, United Kingdom. Electronic address:

Despite growing public awareness of the adverse consequences of excessive sun exposure, modifying sun-seeking behavior is challenging because it appears to be driven by addictive mechanisms. This can have effects on health because sun exposure, although beneficial, when prolonged and repeated shows a causal relationship with skin cancer risk. Using data from 2,500 United Kingdom twins, we observed sun seeking to be significantly heritable (h2 ≥ 58%). In a GWAS meta-analysis of sun-seeking behavior in 261,915 subjects of European ancestry, we identified five GWAS-significant loci previously associated with addiction, behavioral and personality traits, cognitive function, and educational attainment and enriched for CNS gene expression: MIR2113 (P = 2.08 × 10), FAM76B/MTMR2/CEP57 (P = 3.70 × 10), CADM2 (P = 9.36 × 10), TMEM182 (P = 1.64 × 10), and PLCL1/LINC01923/SATB2 (P = 3.93 × 10). These findings imply that the behavior concerning UV exposure is complicated by a genetic predisposition shared with neuropsychological traits. This should be taken into consideration when designing awareness campaigns and may help improve people's attitudes toward sun exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2020.08.014DOI Listing
April 2021

Evolution and new frontiers of histology in bio-medical research.

Microsc Res Tech 2021 Feb 11;84(2):217-237. Epub 2020 Sep 11.

Biomedical and Neuromotor Sciences, Alma Mater University Bologna, Bologna, Italy.

Histology refers to the study of the morphology of cells within their natural tissue environment. As a bio-medical discipline, it dates back to the development of first microscopes which allowed to override the physical visual limitation of the human eye. Since the first observations, it was understood that cell shape predicts function and, therefore, shape alterations can identify and explain dysfunction and diseases. The advancements in morphological investigation techniques have allowed to extend our understanding of the shape-function relationships close to the molecular level of organization of tissues, as well as to derive reliable data not only from fixed, and hence static, biological samples but also living cells and tissues and even for extended time periods. These modern approaches, which encompass quantitative microscopy, precision microscopy, and dynamic microscopy, represent the new frontier of morphology. This article summarizes how the microscopy techniques have evolved to properly face the challenges of biomedical sciences, thus transforming histology from a merely qualitative discipline, which played an ancillary role to traditional "major" sciences such as anatomy, to a modern experimental science capable of driving knowledge progress in biology and medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jemt.23579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103384PMC
February 2021

During host cell traversal and cell-to-cell passage, Toxoplasma gondii sporozoites inhabit the parasitophorous vacuole and posteriorly release dense granule protein-associated membranous trails.

Int J Parasitol 2020 11 31;50(13):1099-1115. Epub 2020 Aug 31.

Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Electronic address:

Toxoplasma gondii has a worldwide distribution and infects virtually all warm-blooded animals, including humans. Ingestion of the environmentally resistant oocyst stage, excreted only in the feces of cats, is central to transmission of this apicomplexan parasite. There is vast literature on the host and T. gondii tachyzoite (proliferative stage of the parasite) but little is known of the host-parasite interaction and conversion of the free-living stage (sporozoite inside the oocyst) to the parasitic stage. Here, we present events that follow invasion of host cells with T. gondii sporozoites by using immunofluorescence (IF) and transmission electron microscopy (TEM). Several human type cell cultures were infected with T. gondii sporozoites of the two genotypes (Type II, ME49 and Type III, VEG) most prevalent worldwide. For the first known time, using anti-rhoptry neck protein 4 (RON4) antibodies, the moving junction was visualized in sporozoites during the invasion process and shortly after its completion. Surprisingly, IF and TEM evaluation revealed that intracellular sporozoites release, at their posterior end, long membranous tails, herein named sporozoite-specific trails (SSTs). Differential permeabilization and IF experiments showed that the SSTs are associated with several dense granule proteins (GRAs) and that their membranous component is of parasite origin. Furthermore, TEM observations demonstrated that SST-associated sporozoites are delimited by a typical parasitophorous vacuole, which is retained during parasite exit from the host cell and during cell-to-cell passage. Our data strongly suggest that host cell traversal by T. gondii sporozoites relies on a novel force-producing mechanism, based on the massive extrusion at the parasite posterior pole of GRA-associated membranous material derived from the same pool of membranes forming the intravacuolar network.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpara.2020.06.012DOI Listing
November 2020

ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition.

medRxiv 2020 Aug 14. Epub 2020 Aug 14.

COVID-19 severity has varied widely, with demographic and cardio-metabolic factors increasing risk of severe reactions to SARS-CoV-2 infection, but the underlying mechanisms for this remain uncertain. We investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 ( ), which has been shown to act as a receptor for SARS-CoV-2 cellular entry. In a meta-analysis of three independent studies including up to 1,471 participants, lower adipose tissue expression was associated with adverse cardio-metabolic health indices including type 2 diabetes (T2D) and obesity status, higher serum fasting insulin and BMI, and lower serum HDL levels (P<5.32x10 ). expression levels were also associated with estimated proportions of cell types in adipose tissue; lower expression was associated with a lower proportion of microvascular endothelial cells (P=4.25x10 ) and higher macrophage proportion (P=2.74x10 ), suggesting a link to inflammation. Despite an estimated heritability of 32%, we did not identify any proximal or distal genetic variants (eQTLs) associated with adipose tissue expression. Our results demonstrate that at-risk individuals have lower background levels in this highly relevant tissue. Further studies will be required to establish how this may contribute to increased COVID-19 severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.08.11.20171108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430606PMC
August 2020

Genetics plays a role in nevi distribution in women.

Melanoma Manag 2020 Mar 17;7(1):MMT35. Epub 2020 Mar 17.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/mmt-2019-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212503PMC
March 2020

Real-time tracking of self-reported symptoms to predict potential COVID-19.

Nat Med 2020 07 11;26(7):1037-1040. Epub 2020 May 11.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

A total of 2,618,862 participants reported their potential symptoms of COVID-19 on a smartphone-based app. Among the 18,401 who had undergone a SARS-CoV-2 test, the proportion of participants who reported loss of smell and taste was higher in those with a positive test result (4,668 of 7,178 individuals; 65.03%) than in those with a negative test result (2,436 of 11,223 participants; 21.71%) (odds ratio = 6.74; 95% confidence interval = 6.31-7.21). A model combining symptoms to predict probable infection was applied to the data from all app users who reported symptoms (805,753) and predicted that 140,312 (17.42%) participants are likely to have COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-0916-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751267PMC
July 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors.

Front Oncol 2019 22;9:1245. Epub 2019 Nov 22.

Myeloproliferative Neoplasm Research Consortium, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883719PMC
November 2019

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH.

J Enzyme Inhib Med Chem 2020 Dec;35(1):280-288

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Acidity, hypoxia and increased release of exosomes are severe phenotypes of tumours. The regulation of pH in tumours involves the interaction of several proteins, including the carbonic anhydrases which catalyze the formation of bicarbonate and protons from carbon dioxide and water. Among CA isoforms, CA IX is over-expressed in a large number of solid tumours, conferring to cancer cells a survival advantage in hypoxic and acidic microenvironment, but there isn't evidence that CA IX expression could have a real clinical impact. Therefore, in this study for the first time the expression and activity of CA IX have been investigated in the plasmatic exosomes obtained from patients with prostate carcinoma (PCa). For this purpose, the study was performed through different methodological approaches, such as NTA, western blot analysis, enzyme activity assay, Nanoscale flow cytometry, ELISA, confocal microscopy. The results showed that PCa exosomes significantly overexpressed CA IX levels and related activity as compared to healthy donors. Furthermore, CA IX expression and activity were correlated to the exosome intraluminal pH, demonstrating for the first time that PCa exosomes are acidic. Our data suggest the possible use of the exosomal CA IX expression and activity as a biomarker of cancer progression in PCa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2019.1697249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896418PMC
December 2020

Interplay between the human gut microbiome and host metabolism.

Nat Commun 2019 10 3;10(1):4505. Epub 2019 Oct 3.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

The human gut is inhabited by a complex and metabolically active microbial ecosystem. While many studies focused on the effect of individual microbial taxa on human health, their overall metabolic potential has been under-explored. Using whole-metagenome shotgun sequencing data in 1,004 twins, we first observed that unrelated subjects share, on average, almost double the number of metabolic pathways (82%) than species (43%). Then, using 673 blood and 713 faecal metabolites, we found metabolic pathways to be associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species showed less than 3,000 associations. Finally, we estimated that the microbiome was involved in a dialogue between 71% of faecal, and 15% of blood, metabolites. This study underlines the importance of studying the microbial metabolic potential rather than focusing purely on taxonomy to find therapeutic and diagnostic targets, and provides a unique resource describing the interplay between the microbiome and the systemic and faecal metabolic environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12476-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776654PMC
October 2019

TwinsUK: The UK Adult Twin Registry Update.

Twin Res Hum Genet 2019 12 17;22(6):523-529. Epub 2019 Sep 17.

The Department of Twin Research, King's College London, St Thomas' Hospital, London, UK.

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King's College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several 'omic' technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the 'TwinsUK' resource with the scientific community - interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/thg.2019.65DOI Listing
December 2019

A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells.

J Exp Clin Cancer Res 2019 Aug 22;38(1):373. Epub 2019 Aug 22.

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials.

Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy.

Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent.

Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-019-1383-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706930PMC
August 2019

Body site-specific genetic effects influence naevus count distribution in women.

Pigment Cell Melanoma Res 2020 03 25;33(2):326-333. Epub 2019 Aug 25.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

Body site is highly relevant for melanoma: it affects prognosis and varies according to the patient's sex. The distribution of naevi, a major risk factor for melanoma, at different body sites also varies according to sex in childhood. Using naevus counts at different body sites in 492 unrelated adults from both sexes, we observed that women have an increased number of naevi on the lower limbs compared to men (p = 8.5 × 10 ), showing that a high naevus count on this site persists from childhood throughout life. Then, using data from 3,232 twins, we observed, in women, the lowest naevus count heritability on the trunk (26%), and the highest on the lower limbs (69%). Finally, we showed that, in 2,864 women, six genomic loci previously associated with both naevus count and melanoma risk (IRF4, DOCK8, MTAP, 9q31.2, KITLG and PLA2G6) have an effect on naevus count that is body site-specific, but whose effect sizes are predominantly stronger on the lower limbs. Sex-specific genetic influence on naevus count at different sites may explain differences in site-specific melanoma incidence as well as prognosis between sexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pcmr.12820DOI Listing
March 2020

Adenosine A receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes.

Sci Rep 2019 07 5;9(1):9782. Epub 2019 Jul 5.

Research Coordination and Support Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.

Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A receptors (AR) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease. Since NPC1 disease is characterized by dysmyelination and maturational arrest of oligodendrocyte progenitors (OPs), in this study, we investigated whether AR stimulation could promote oligodendrocyte differentiation and myelin formation, thus overcoming these important neurological abnormalities. We developed a NPC1 pharmacological model, in which primary cultures of OPs are exposed to a cholesterol transport inhibitor to induce a NPC1-like phenotype characterized by several typical features such as (i) cholesterol accumulation, (ii) altered mitochondrial morphology and membrane potential, (iii) defect of autophagy and (iv) maturation arrest. The AR agonist CGS21680 normalized all NPC1-like features. The ability of CGS21680 of rescuing OP from maturational arrest and promoting their differentiation to mature OL, suggests that AR stimulation might be exploited to correct dysmyelination in NPC1, further supporting their therapeutic potential in the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46268-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611770PMC
July 2019