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Biomedical subjects

Anh Le

Publications and source records attributed to Anh Le.

10 recordsLinked to original sources
PubMed2025

Longitudinal multi-omics in alpha-synuclein Drosophila model discriminates disease- from age-associated pathologies in Parkinson's disease.

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies.

Journal Article↗
PubMed2005

JLP associates with kinesin light chain 1 through a novel leucine zipper-like domain.

Scaffolding proteins exist in eukaryotes to properly assemble signaling proteins into specific multimeric functional complexes. JLP is a novel leucine zipper protein belonging to a family of scaffolding proteins that assemble JNK signaling modules. JLP is a proline-rich protein that contains two leucine zipper domains and a highly conserved C-terminal domain. We have identified kinesin light chain 1 (KLC1) as a binding partner for the second leucine zipper domain of JLP using yeast two-hybrid screening. The interaction domain of KLC1 was mapped to its tetratripeptide repeat, which contains a novel leucine zipper-like domain that is crucial for the interaction with JLP. Mutations of Leu-280, Leu-287, Val-294, and Leu-301 within this domain of KLC1 disrupted its ability to associate with JLP. Immunofluorescence studies showed that JLP and KLC1 co-localized in the cytoplasm and that the localization of JLP was dependent on its second leucine zipper. Ectopic expression of a dominant negative form of KLC1 resulted in the mislocalization of endogenous JLP. Moreover, the association between JLP and KLC1 occurred in vivo and was important in the formation of ternary complex with JNK1. These results identify a novel protein-protein interaction between KLC1 and JLP that involves leucine zipper-like domains and support the role of motor proteins in the spatial regulation of signaling modules.

Adaptor Proteins, Signal Transducing↗
PubMed2005

The influence of lipoproteins on whole-blood viscosity at multiple shear rates.

Whole-blood viscosity appears to be an independent predictor of stroke, carotid intima-media thickening, and carotid atherosclerosis. The purpose of this study was to examine for relationships between whole-blood viscosity and blood lipids in young healthy subjects over a range of shear rates. Twenty-seven healthy men and women aged 10 to 25 years having a range of low-density lipoprotein (LDL) cholesterol values 88 to 258 mg/dL and body mass index z scores -1.18 to 2.64 SDs were studied. Whole-blood viscosity at shear rates from 1 to 1000 per second was measured using an automated capillary viscometer. Blood lipids were measured using standard techniques. Triglyceride-rich lipoproteins were isolated by ultracentrifugation at density of <1.020 g/mL, and a high ratio of cholesterol to triglyceride was used as an indicator of lipoprotein remnants. Whole-blood viscosity at shear rates of 100 to 1000 per second showed significant negative correlations with apolipoprotein A-1, but not with high-density lipoprotein cholesterol. Whole-blood viscosity at a shear rate of 1000 per second correlated with LDL cholesterol and inversely with LDL size. On stepwise multivariate analysis, apolipoprotein A-1 accounted for 14.7% of the variation in whole-blood viscosity at a shear rate of 150 per second. This study points to the importance of high-density lipoprotein particle number on whole-blood viscosity at physiological shear rates. The physiological significance of the relationships between whole-blood viscosity and LDL cholesterol and LDL particle size at a very high shear rate remains to be determined.

Adolescent↗
PubMed2005

Assessment of morphological and immunohistological alterations in long-term keloid skin explants.

One of the major impediments in keloid research is the lack of a keloid animal model that can mimic human keloid. This imposes investigative constraints on studying cellular interactions and biochemical processes that normally occur in vivo. Our main objective is to establish an in vitro model for maintaining long-term viable keloid dermal explants as a tool for investigating the pathogenesis of keloid scar formation. Explants of adult keloid scars were cultured in vitro by embedding them in enriched collagen gel matrix and maintaining them for up to 6 weeks, whereupon changes in tissue morphology and cellular differentiation were examined. The effects of medium enrichment, air versus liquid submersion, and different substrates on the explants were examined. Our results indicated that keloid explants embedded in a collagen gel matrix were morphologically better preserved than explants placed on a plastic substrate. Explants with epidermis at the air-liquid interface had better morphology than collagen-submerged explants, and there were no differences between serum-free and serum-supplemented explant cultures. Immunohistochemical and apoptotic analyses were performed to assess cellular viability and differentiation. In situ hybridization confirmed that keloid fibroblasts had sustained collagen type I gene expression throughout the 6 weeks in culture, thus validating the integrity of a long-term keloid culture system. In conclusion, the collagen-embedded skin explant system demonstrates that keloid tissues could be maintained for up to 6 weeks for long-term in vitro studies.

Cell Differentiation↗
PubMed2004

Autoimmune lymphoproliferative syndrome: a cause of chronic splenomegaly, lymphadenopathy, and cytopenias in children-report on diagnosis and management of five patients.

Autoimmune lymphoproliferative syndrome (ALPS) usually manifests in early childhood with splenomegaly, lymphadenopathy, and cytopenias. In most patients, it results from mutations in genes that regulate lymphocyte apoptosis via the Fas pathway. Here, we report five children with ALPS. All five children had splenomegaly, cytopenias, and hypertriglyceridemia at presentation; four had lymphadenopathy. Mutations in the Fas receptor gene were demonstrated in three children. Clinical picture is variable: in only one child manifestations are severe enough to require immunosuppressive therapy. Diagnosis of ALPS can be challenging and increased awareness of the disease can result in more directed diagnostic approaches as well as earlier initiation of treatment.

Autoimmune Diseases↗
PubMed2004

Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma.

Understanding the development and progression of oral cancer is critical in the quest for successful therapeutic intervention. The hypoxic microenvironment present in human oral tumor in vivo may actively influence tumor growth and neovascularization. This study correlates expression of both VEGF and HIF-1alpha in normal keratinocytes and oral cancer cell lines and determine whether hypoxia played a role in VEGF and HIF-1alpha regulation. Three human oral cancer cell lines and three normal keratinocytes were exposed to both normoxia and hypoxia culture conditions. Northern and Western blot analysis were used to assess VEGF and HIF-1alpha expression in the different culture conditions. ELISA assays were performed to measure VEGF production in the different cell lines tested. Hypoxia upregulated VEGF and HIF-1alpha expression on both normal and oral cancer cell lines, with a statistically significant difference between normal and oral cancer cell lines. Pattern of hypoxia-induced VEGF mRNA level tightly followed the HIF-1alpha mRNA expression in the cell lines tested. These results suggest that hypoxia regulates both VEGF and HIF-1alpha expression in head and neck carcinoma cell lines, thus establishing a biochemical pathway between tumor hypoxia and neoangiogenesis in these aggressive neoplasms.

Blotting, Northern↗
PubMed2003

Thermodynamic study of two different chewing-gum bases by inverse gas chromatography.

This work describes the physico-chemical characterisation of two different chewing gum bases and the interactions with the incorporated flavour molecules using inverse gas chromatography as a specific technique. Ethyl butyrate, limonene, 1-octanol and cis-2-hexenal were injected to calculate the partition coefficients, the activity coefficients and the Henry's constants at infinite dilution and 298 K. The partition coefficients, activity coefficients and Henry's constants showed a difference between the two gum bases, but the excess molar heat of mixing (deltaHm) showed an incompatibility for the flavour compounds in both gum bases. Finally, the determination of the solubility parameter of the gum bases by two methods showed that the two gum bases have similar solubility parameters at 298 K.

Chemical Phenomena↗
PubMed2003

Inhibition of NF-kappaB by hydroquinone sensitizes human bone marrow progenitor cells to TNF-alpha-induced apoptosis.

Suppression of hematopoiesis is an important mechanism governing blood cell formation. Factors such as tumor necrosis factor alpha (TNF-alpha) inhibit proliferation and colony-forming activity of bone marrow cells and activate nuclear factor kappa B (NF-kappaB) in multiple cell types. Activated NF-kappaB is required for many cells to escape apoptosis, including hematopoietic progenitor cells (HPC). The benzene metabolite hydroquinone (HQ) alters cytokine response and induces cell death in HPC, and inhibits NF-kappaB activation in T and B cells. Therefore, we studied the potential role of HQ-induced NF-kappaB inhibition in a hematopoietic cell line (TF-1) and primary HPC in rendering these cells susceptible to TNF-alpha-induced apoptosis. We demonstrate in both cell types that TNF-alpha activates NF-kappaB, and HQ exposure inhibits activation of NF-kappaB by TNF-alpha in a dose dependent manner. We further investigated the ability of HQ to potentiate TNF-alpha-induced apoptosis in these cells, and found that HQ sensitized the cells to the pro-apoptotic effect of TNF-alpha. These results suggest that NF-kappaB plays a key role in HPC survival, and that HQ-induced inhibition of NF-kappaB leaves these cells susceptible to cytokine-induced apoptosis. These effects may play a role in the suppression of hematopoiesis seen in some benzene exposed individuals.

Apoptosis↗
PubMed2003

Increased plasminogen activator inhibitor-1 in keloid fibroblasts may account for their elevated collagen accumulation in fibrin gel cultures.

Proteolytic degradation of the provisional fibrin matrix and subsequent substitution by fibroblast-produced collagen are essential features of injury repair. Immunohistochemical studies revealed that although dermal fibroblasts of normal scars and keloids expressed both urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1), keloid fibroblasts had a much higher PAI-1 expression. In long-term three-dimensional fibrin gel cultures (the in vitro fibroplasia model), normal fibroblasts expressed moderate and modulated activity levels of uPA and PAI-1. In contrast, keloid fibroblasts expressed a persistently high level of PAI-1 and a low level of uPA. The high PAI-1 activity of keloid fibroblasts correlated with their elevated collagen accumulation in fibrin gel cultures. Substituting collagen for fibrin in the gel matrix resulted in increased uPA activity and reduced collagen accumulation of keloid fibroblasts. Furthermore, decreasing PAI-1 activity of keloid fibroblasts in fibrin gel cultures with anti-PAI-1-neutralizing antibodies also resulted in a reduction in collagen accumulation by keloid fibroblasts. Cumulatively, these results suggest that PAI-1 overexpression is a consistent feature of keloid fibroblasts both in vitro and in vivo, and PAI-1 may play a causative role in elevated collagen accumulation of keloid fibroblasts.

Adolescent↗