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Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease 总被引:2,自引:0,他引:2
Huntington's Disease (HD) is characterized primarily by neuropathological changes in the striatum, including loss of medium-spiny neurons, nuclear inclusions of the huntingtin protein, gliosis, and abnormally high iron levels. Information about how these conditions interact, or about the temporal order in which they appear, is lacking. This study investigated if, and when, iron-related changes occur in the R6/2 transgenic mouse model of HD and compared the results with those from HD patients. Relative to wild-type mice, R6/2 mice had increased immunostaining for ferritin, an iron storage protein, in the striatum beginning at 2-4 weeks postnatal and in cortex and hippocampus starting at 5-7 weeks. The ferritin staining was found primarily in microglia, and became more pronounced as the mice matured. Ferritin-labeled microglia in R6/2 mice appeared dystrophic in that they had thick, twisted processes with cytoplasmic breaks; some of these cells also contained the mutant huntingtin protein. Brains from HD patients (Vonsattel grades 0-4) also had increased numbers of ferritin-containing microglia, some of which were dystrophic. The cells were positive for Perl's stain, indicating that they contained abnormally high levels of iron. These results provide the first evidence that perturbations to iron metabolism in HD are predominately associated with microglia and occur early enough to be important contributors to HD progression. 相似文献
2.
Linda Orkin Lewin Mamta Singh Betzi L Bateman Bligh Pamela Glover 《BMC medical education》2009,9(1):33
Background
Standardizing the experiences of medical students in a community preceptorship where clinical sites vary by geography and discipline can be challenging. Computer-assisted learning is prevalent in medical education and can help standardize experiences, but often is not used to its fullest advantage. A blended learning curriculum combining web-based modules with face-to-face learning can ensure students obtain core curricular principles. 相似文献3.
Betzi S Restouin A Opi S Arold ST Parrot I Guerlesquin F Morelli X Collette Y 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(49):19256-19261
Protein-protein recognition is the cornerstone of multiple cellular and pathological functions. Therefore, protein-protein interaction inhibition (2P2I) is endowed with great therapeutic potential despite the initial belief that 2P2I was refractory to small-molecule intervention. Improved knowledge of complex molecular binding surfaces has recently stimulated renewed interest for 2P2I, especially after identification of "hot spots" and first inhibitory compounds. However, the combination of target complexity and lack of starting compound has thwarted experimental results and created intellectual barriers. Here we combined virtual and experimental screening when no previously known inhibitors can be used as starting point in a structure-based research program that targets an SH3 binding surface of the HIV type I Nef protein. High-throughput docking and application of a pharmacophoric filter on one hand and search for analogy on the other hand identified drug-like compounds that were further confirmed to bind Nef in the micromolar range (isothermal titration calorimetry), to target the Nef SH3 binding surface (NMR experiments), and to efficiently compete for Nef-SH3 interactions (cell-based assay, GST pull-down). Initial identification of these compounds by virtual screening was validated by screening of the very same library of compounds in the cell-based assay, demonstrating that a significant enrichment factor was attained by the in silico screening. To our knowledge, our results identify the first set of drug-like compounds that functionally target the HIV-1 Nef SH3 binding surface and provide the basis for a powerful discovery process that should help to speed up 2P2I strategies and open avenues for new class of antiviral molecules. 相似文献
4.
Mirella Guarnizo-Poma Diego Urrunaga-Pastor Cory Montero-Suyo Herbert Lazaro-Alcantara Socorro Paico-Palacios Betzi Pantoja-Torres Vicente A. Benites-Zapata 《Diabetes & Metabolic Syndrome: Clinical Research & Reviews》2018,12(6):943-948
Aims
To determine the association between serum levels of vitamin B12 and metabolic syndrome (MetS) in a population of euthyroid adults.Materials and methods
We carried out an analytical cross-sectional study in euthyroid adults of both sexes, who attended the outpatient service of a private clinic in Lima-Peru during the 2012–2016 period. Participants were divided into tertiles (low, intermediate and high) according to their serum vitamin B12 values. MetS was defined when three or more metabolic criteria were met by the participants. We elaborated crude and adjusted Poisson regression models to evaluate the association between the serum vitamin B12 tertiles and the presence of MetS. The reported association measure was the prevalence ratio (PR) with their respective 95% confidence intervals (95%CI).Results
We analyzed 346 participants, the average age was 38.3?±?10.8 (SD) years, 117 (33.8%) were males, the serum vitamin B12 median was 364.1 (IQR: 274.2–473.4) pmol/L and the prevalence of MetS was 30.1% (n?=?104). In the crude Poisson regression model, we found an association between the serum vitamin B12 tertiles and the presence of MetS, with marginal significance. The association gained statistical significance in the adjusted model by potential confounders; and compared with the low serum vitamin B12 tertile, the prevalence of MetS was 36% lower (aPR?=?0.64; 95%CI: 0.43–0.96) among the high tertile group.Conclusion
Euthyroid participants with elevated levels of serum vitamin B12 showed a lower prevalence of MetS compared to those who had low levels of this marker. 相似文献5.
Diego Urrunaga-Pastor Mirella Guarnizo-Poma Enrique Moncada-Mapelli Luis G. Aguirre Herbert Lazaro-Alcantara Socorro Paico-Palacios Betzi Pantoja-Torres Vicente A. Benites-Zapata 《Diabetes & Metabolic Syndrome: Clinical Research & Reviews》2018,12(2):155-161
Aims
To determine the association between free triiodothyronine (FT3), free thyroxine (FT4) and free-triiodothyronine-to-free-thyroxine ratio (FT3/FT4) levels and Metabolic Syndrome (MetS).Materials and methods
We carried out an analytical cross-sectional study in euthyroid adults of both sexes, who attended the outpatient service of a private clinic in Lima-Peru during the 2014–2016 period. Participants were divided into tertiles (low, intermediate and high) according to their FT3, FT4, and FT3/FT4 ratio values. MetS was defined when three or more metabolic criteria were met by the participants. ROC curves were constructed, and Youden’s Index were used to identify the optimal cut-points of each thyroid marker. We elaborated crude/adjusted Poisson regression models to evaluate the association between the thyroid markers and the presence of MetS. The reported association measure was the prevalence ratio (PR) with their respective 95% confidence intervals (95% CI).Results
We analyzed 245 participants, the average age was 38.5?±?10.3?years, 29.8% were males, and the prevalence of MetS was 31%. In the adjusted Poisson regression models, the prevalence of MetS was higher among the high FT3 tertile compared to the low tertile (aPR?=?2.01; 95% CI: 1.22–3.34). The prevalence of MetS was higher among the intermediate FT3/FT4 ratio tertile and the high FT3/FT4 ratio tertile compared to the low tertile, (aPR?=?1.78; 95% CI: 1.02–3.10) and (aPR?=?2.80; 95% CI: 1.67–4.72); respectively. The highest areas under the curve (AUC) were found for FT3 and FT3/FT4 ratio with areas of 0.654 (95% CI: 0.58–0.73) and 0.649 (95% CI: 0.57–0.72); respectively.Conclusion
Elevated levels of FT3 and FT3/FT4 ratio were associated with MetS in a euthyroid population. 相似文献6.
Betzi Pantoja-Torres Carlos J. Toro-Huamanchumo Diego Urrunaga-Pastor Mirella Guarnizo-Poma Herbert Lazaro-Alcantara Socorro Paico-Palacios Vitalia del Carmen Ranilla-Seguin Vicente A. Benites-Zapata 《Diabetes & Metabolic Syndrome: Clinical Research & Reviews》2019,13(1):382-388
AimTo evaluate the association between high triglyceride/HDL-cholesterol (TG/HDL-C) ratio and insulin resistance (IR) or hyperinsulinemia after oral glucose tolerance test (OGTT) in normal-weight healthy adults.MethodsWe carried out an analytical cross-sectional study in euthyroid non-diabetic adults, who attended the outpatient service of a private clinic in Lima-Peru from 2012 to 2016. Participants were divided in two groups according to the presence or absence of high TG/HDL-C ratio, IR or hyperinsulinemia after OGTT. TG/HDL-C ratio values ≥ 3 were considered as high. IR was defined as a Homeostasis Model Assessment (HOMA-IR) value ≥ 2.28 and hyperinsulinemia after OGTT as a serum insulin value ≥ 80μU/mL after 120 min of 75-g glucose intake. We elaborated crude and adjusted Poisson generalized linear models to evaluate the association between high TG/HDL-C ratio and IR or hyperinsulinemia after OGTT and reported the prevalence ratio (PR) with their respective 95% confidence intervals (95%CI).ResultsWe analyzed the data of 118 individuals. Prevalence of high TG/HDL-C ratio was 17.8% (n = 21) while the prevalence of IR and hyperinsulinemia after OGTT was 24.6% (n = 29) and 17.0% (n = 20), respectively. TG/HDL-C-ratio values were positively correlated with HOMA-IR (r = 0.498; p < 0.01) and serum insulin after OGTT (r = 0.326; p < 0.001). In the adjusted model, high TG/HDL-C ratio was associated with both IR (aPR = 3.16; 95%CI: 1.80–5.77) and hyperinsulinemia after OGTT (aPR = 2.36; 95%CI: 1.20–4.63).ConclusionsHigh TG/HDL-C ratio was associated with both IR markers used in our study, appearing to be a clinically useful tool to assess IR in euthyroid normal-weight adults without type 2 diabetes mellitus. 相似文献
7.
Jeremy ArieyBonnet Kendall Carrasco Marion Le Grand Laurent Hoffer Stphane Betzi Mikael Feracci Philipp Tsvetkov Francois Devred Yves Collette Xavier Morelli Pedro Ballester Eddy Pasquier 《Molecular oncology》2020,14(12):3083
The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already‐approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro (IC50 values ranging from 288 nm to 2.1 µm). Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly upregulated at the gene level in glioblastoma as compared to normal brain tissue (fold change > 1.5; P < 0.0001). Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2, and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose‐dependent manner, with a high potency against MAPK14 (IC50 = 104 ± 46 nm). Its direct binding to MAPK14 was further validated in vitro, and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases.
Abbreviations
- BRET
- bioluminescence resonance energy transfer
- GBM
- glioblastoma
- GTeX
- Genotype‐Tissue Expression
- IC50
- half‐maximal inhibitory concentration
- ITC
- isothermal titration calorimetry
- MBZ
- mebendazole
- nanoDSF
- nanoscale differential scanning fluorimetry
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- RT
- room temperature
- siRNA
- small interfering RNA
- TCGA
- The Cancer Genome Atlas
- TSA
- thermal shift assay
8.
Mirella Guarnizo-Poma Socorro Paico-Palacios Betzi Pantoja-Torres Herbert Lazaro-Alcantara Diego Urrunaga-Pastor Vicente A. Benites-Zapata 《Diabetes & Metabolic Syndrome: Clinical Research & Reviews》2018,12(4):531-535
Aims
To determine the association between the thyroid hormones(FT3, FT4 and TSH) and the lipid profile markers(HDL-c, LDL-c and triglycerides) values in middle-aged women with no metabolic disorders and recurrent chronic symptomatology.Materials and Methods
We carried out an analytical cross-sectional study in euthyroid women with recurrent chronic symptoms of at least six months with no apparent diagnosis who attended the endocrinological gynaecology outpatient service of a private clinic in Lima-Peru during 2012–2014. Participants who met the eligibility criteria were evaluated according to their thyroid hormones(FT3, FT4 and TSH) and lipid profile markers(HDL-c, LDL-c and triglycerides) values. We elaborated univariate/multivariate linear regression models to evaluate the association between the thyroid markers and the lipid profile levels. The reported association measure was the beta coefficient(β) with its respective p-value.Results
We analyzed 211 participants, the average age was 44.9?±?14.0(SD) years, the FT3 and FT4 mean levels were 3.2?±?0.4?pg/mL and 1.2?±?0.2?ng/dL respectively, while the TSH median was 2.8(IQR:1.9–4.0) μU/mL. The mean or median levels of LDL-c, HDL-c and triglycerides were of 137.5?±?37.9?mg/dL, 54.0?±?15.0?mg/dL and 118.5(IQR:79.5–169.5) mg/dL respectively. In the multivariate linear regression model between the FT3 and LDL-c levels, we found that for each increase in a FT3 unit, the LDL-c values decreased on average 30.85?mg/dL(p?<?0.01). We found no statistically significant associations in the other multivariate models of linear regression, among the other thyroid hormones and lipid markers.Conclusion
We found an inverse association between the FT3 and LDL-c values in women with chronic gynaecological symptoms. 相似文献
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