Papers by Miguel A. Lopez-Toledano
Stem Cells, 2011
Neural precursor cells (NPCs) are activated in central nervous system injury. However, despite be... more Neural precursor cells (NPCs) are activated in central nervous system injury. However, despite being multipotential, their progeny differentiates into astrocytes rather than neurons in situ. We have investigated the role of epidermal growth factor receptor (EGFR) in the generation of non-neurogenic conditions. Cultured mouse subventricular zone NPCs exposed to differentiating conditions for 4 days generated approximately 50% astrocytes and 30% neuroblasts. Inhibition of EGFR with 4-(3-chloroanilino)-6,7-dimethoxyquinazoline significantly increased the number of neuroblasts and decreased that of astrocytes. The same effects were observed upon treatment with the metalloprotease inhibitor galardin, N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM 6001), which prevented endogenous transforming growth factor-α (TGF-α) release. These results suggested that metalloprotease-dependent EGFR-ligand shedding maintained EGFR activation and favored gliogenesis...
Journal of Clinical Lipidology, 2017
prevalence of plasma EPA ,150ug/ml and EPA/AA ,0.4 and ,0.75. Methods: The cohort included 3,547 ... more prevalence of plasma EPA ,150ug/ml and EPA/AA ,0.4 and ,0.75. Methods: The cohort included 3,547 patients who met NLA treatment goals for LDL-C and non-HDL-C and who otherwise qualified as ''very high risk'' for ASCVD. EPA and AA were measured using Boston Heart Diagnostics Fatty Acid BalanceÔ Test. Baseline lipid panels and prevalence of plasma EPA and EPA/AA were evaluated. Results: Mean EPA was 31.6 mg/mL and 98.9% of patients had EPA ,150 mg/ml. Mean EPA/AA was 0.13, 98.8% of patients had EPA/AA ,0.75, and 95.2% had EPA/AA ,0.4. Conclusions: This study shows for the first time that very high risk patients at NLA recommended treatment guidelines for LDL-C and non-HDL-C have markedly low plasma EPA and EPA/AA compared to the Japanese population. Applying JELIS cutoffs, almost 99% of patients had insufficient plasma EPA or EPA/AA, which suggests they are at increased CV risk representing a source of residual risk. Less than 96% of patients had EPA/AA ,0.4, which suggests they may benefit from EPA treatment.
Copyright © 2011 Farzaneh Modarresi et al. This is an open access article distributed under the C... more Copyright © 2011 Farzaneh Modarresi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Alzheimer’s disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Aβ) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript for β-secretase-1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1-antisense transcript (BACE1-AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1-A...
Experimental Eye Research, 2019
This article presents the relationship of machining parameters containing pulse-on time (T on), p... more This article presents the relationship of machining parameters containing pulse-on time (T on), pulseoff time (T off), peak current (IP) and servo voltage (SV) on surface integrity characteristics, including white layer thickness (WLT), heat-affected zone (HAZ) and surface crack density (SCD) and also on material removal rate (MRR), after wire electric discharge machining of Ti-6Al-4V. Taguchi's method was utilized to design the experiments, and response surface methodology (RSM) was employed for developing the empirical models. Results indicated that T on and IP played a significant role on surface integrity characteristics. In addition, the microstructure of selected machined samples was analysed using a field emission scanning electron microscope (FESEM) and energy-dispersive X-ray (EDX) analysis. Accuracy of models was examined using residual analysis and confirmation runs. Finally, multi-response optimization of process parameters was obtained using desirability approach. Results can be used to improve the quality of the machined workpiece significantly to fulfil the requirements of the various industries. The novelty of this research is mainly investigation and multi-response optimization of all the surface integrity characteristics at the same time.
Here we demonstrate that natural antisense transcripts (NATs), which are abundant in mammalian ge... more Here we demonstrate that natural antisense transcripts (NATs), which are abundant in mammalian genomes, can function as repressors of specific genomic loci and that their removal or inhibition by AntagoNAT oligonucleotides leads to transient and reversible upregulation of sense gene expression. As one example, we show that Brain-Derived Neurotrophic Factor (BDNF) is under the control of a conserved noncoding antisense RNA transcript, BDNF-AS, both in vitro and in vivo. BDNF-AS tonically represses BDNF sense RNA transcription by altering chromatin structure at the BDNF locus, which in turn reduces endogenous BDNF protein and function. By providing additional and analogous examples of endogenous mRNA upregulation, we suggest that antisense RNA mediated transcriptional suppression is a common phenomenon. In sum, we demonstrate a novel pharmacological strategy by which endogenous gene expression can be upregulated in a locus-specific manner.
Complementary Therapies in Medicine, 2020
Sickle cell disease (SCD) is a hematologic disorder with complex pathophysiology that includes ch... more Sickle cell disease (SCD) is a hematologic disorder with complex pathophysiology that includes chronic hemolysis, vaso-occlusion and inflammation. Increased leukocyte-erythrocyte-endothelial interactions, due to upregulated expression of adhesion molecules and activated endothelium, are thought to play a primary role in initiation and progression of SCD vaso-occlusive crisis and end-organ damage. Several new pathophysiology-based therapeutic options for SCD are being developed, chiefly targeting the inflammatory pathways. Omega-3 fatty acids are polyunsaturated fatty acids that are known to have effects on diverse physiological processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the principal biologically active omega-3 fatty acids. The therapeutic effects of DHA and EPA on chronic inflammatory disorders and cardiovascular diseases are well recognized. The therapeutic effects of omega-3 fatty acids are attributed to their anti-inflammatory and anti-thrombotic eicosanoids, and the novel class of EPA and DHA derived lipid mediators: resolvins, protectins and maresins. Blood cell membranes of patients with SCD have abnormal fatty acids composition characterized by high ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (high omega-6/omega-3 ratio). In addition, experimental and clinical studies provide evidence that treatment with DHA does confer improvement in rheological properties of sickle RBC, inflammation and hemolysis. The clinical studies have shown improvements in VOC rate, markers of inflammation, adhesion, and hemolysis. In toto, the results of studies on the therapeutic effects of omega-3 fatty acids in SCD provide good body of evidence that omega-3 fatty acids could be a safe and effective treatment for SCD.
Journal of Clinical Lipidology, 2017
The absorption of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) om... more The absorption of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) omega-3-acid ethyl esters (EEs) is influenced by food. There is a need for a formulation of EE that is less impacted by food effect. SC401 is a novel Advanced Lipid Technologies-based formulation of EPA-EE and DHA-EE. In the presence of an aqueous medium, Advanced Lipid Technologies forms stable micelles in situ independent of bile salt secretion. This effect is hypothesized to improve EPA-EE and DHA-EE bioavailability while it helps mitigate the food effect associated with their consumption. The aim of the article was to assess the effect of food on the bioavailability of DHA and EPA after a single oral dose of 1530 mg omega-3 fatty acids EE (SC401) in 24 healthy subjects under fasted and low-fat (9% of total calories from fat) and high-fat (50% of total calories from fat) meal conditions. This was a randomized, open-label, single-dose, 3-period, 3-way crossover study. Blood samples for pharmacokinetic analyses were taken at predose and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12 and 24 hours postdose. To assess the safety of the intervention, active monitoring of adverse events, physical examinations, vital signs, clinical laboratory assessments (chemistry, hematology, and urinalysis), and 12-lead electrocardiograms were conducted. SC401 showed high bioavailability of both EPA and DHA in fasted, low-fat meal, and high-fat meal conditions. No differences were found in SC401 DHA AUC0-t (t = 24 hours) among the 3 conditions (91.69% high-fat/fasted, 97.12% low-fat/fasted, and 105.92% low-fat/high-fat; P > .05 in all cases). In contrast, SC401 EPA AUC0-t was affected by food intake (179.06% high-fat/fasted, P < .0001; 150.05% low-fat/fasted, P < .0001) and the amount of fat taken with SC401 (83.80% low-fat/high-fat; P = .0009). SC401 was safe and well tolerated. A single dose of SC401 resulted in high levels of EPA and DHA total lipids in plasma in fasting and fed conditions. SC401 overcame the food effect for DHA and partially ameliorated it for EPA. SC401 represents a convenient option for treatment of severe hypertriglyceridemia, especially for patients under a restricted intake of dietary fat.
Clinical therapeutics, Jan 9, 2017
The US Food and Drug Administration has approved several highly purified ω-3 fatty acid prescript... more The US Food and Drug Administration has approved several highly purified ω-3 fatty acid prescription drugs for the treatment of severe hypertriglyceridemia. These differ in the amounts and forms of docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). This study compared the bioavailability of SC401 (1530 mg EPA-ethyl esters [EEs] and DHA-EEs plus Advanced Lipid Technologies(⁎) [ALT(†)], a proprietary lipid-delivery platform to improve absorption), with. Lovaza(‡) (3600 mg ω-3, primarily EPA-EEs and DHA-EEs) under low-fat feeding conditions. This was a Phase I, randomized, open-label, single-dose, 2-way crossover study in healthy participants housed from day -3 to day 2 in each treatment period. Blood samples for pharmacokinetic measurements were collected before and after dosing, and safety profile and tolerability were assessed. In unadjusted analyses, SC401 had 5% lower Cmax and approximately the same AUC0-last of EPA + DHA total lipids compared with Lovaza. When adjuste...
Journal of Neuropathology & Experimental Neurology, 2004
The human neurofilament medium (hNFM) subunit is one of the 3 neurofilament (NF) polypeptides, wh... more The human neurofilament medium (hNFM) subunit is one of the 3 neurofilament (NF) polypeptides, which are the most abundant intermediate filament (IF) proteins in post-mitotic neurons. The formation of neurofilamentous aggregates is a pathological hallmark of many neurodegenerative diseases, including the Lewy bodies found in Parkinson disease (PD). A Gly336Ser (G336S) variant in the rod domain of hNFM has recently been described in a patient with early-onset autosomaldominant PD. In this study, we have generated a mammalian expression vector encoding the variant hNFM cDNA and characterized its effects on the formation of heteropolymeric IFs in heterologous cell lines. We have also investigated the distribution of the (G336S) hNFM variant protein in neuronal CAD cells, as well as the effects of the variant on the distribution of other cellular organelles and proteins. Our results demonstrate that the G336S variant does not affect the formation of IF networks nor the distribution of the variant hNFM protein. Our data suggest that if the G336S variant is involved in the development of PD, it does not appear to be due to defects in the assembly and distribution of NFs.
Neurodegenerative Diseases, 1996
ENDOGENOUS AMINO ACID PROFILE DURING IN VITRO DIFFERENTIATION OF NEURAL STEM CELLS Eulalia Bazan,... more ENDOGENOUS AMINO ACID PROFILE DURING IN VITRO DIFFERENTIATION OF NEURAL STEM CELLS Eulalia Bazan, Miguel A. Lopez-Toledano, Maria A. Mena, Rafael Martin del Rio, Carlos L. Paino and Antonio S. Herranz Dpto ... 3), with the exception of glutamine (Gin)(Fig ...
Journal of Neuroscience, 2011
The generation, differentiation, and migration of newborn neurons are critical features of normal... more The generation, differentiation, and migration of newborn neurons are critical features of normal brain development that are subject to both extracellular and intracellular regulation. However, the means of such control are only partially understood. Here, we show that expression of RTP801/REDD1, an inhibitor of mTOR (mammalian target of rapamycin) activation, is regulated during neuronal differentiation and that RTP801 functions to influence the timing of both neurogenesis and neuron migration. RTP801 levels are high in embryonic cortical neuroprogenitors, diminished in newborn neurons, and low in mature neurons. Knockdown of RTP801 in vitro and in vivo accelerates cell cycle exit by neuroprogenitors and their differentiation into neurons. It also disrupts migration of rat newborn neurons to the cortical plate and results in the ectopic localization of mature neurons. On the other hand, RTP801 overexpression delays neuronal differentiation. These findings suggest that endogenous RTP801 plays an essential role in temporal control of cortical development and in cortical patterning.
Stem Cells and Development, 2008
Mesenchymal stem cell (MSC)-mediated tissue regeneration is a promising strategy to treat several... more Mesenchymal stem cell (MSC)-mediated tissue regeneration is a promising strategy to treat several neurodegenerative diseases and traumatic injuries of the central nervous system. Bone marrow MSCs have great potential as therapeutic agents, since they are easy to isolate and expand and are capable of producing various cell types, including neural cells. Recently we developed a highly effi cient methodology to produce neural stem-like and neural precursor-like cells from mice bone marrow-derived MSCs that eventually differentiate into neuronaland glial-like cells in vitro. The aim of this study is to further elucidate neural expression profi le of neurally induced mesenchymal stem cells (NI-MSCs) and their ability to retain neural differentiation potential when grafted into the intact spinal cord of rats. To this end, we further characterized in vitro and in vivo properties of NI-MSCs by immunocytochemistry, Western blot, ELISA, and immunohistochemistry. Immunocytochemical data demonstrated that NI-MSCs express several mature neural markers such as B3T, GFAP MAP-2, NF-200, and NeuN, which were confi rmed through Western blot. ELISA data showed that NI-MSCs release nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In vivo studies demonstrated that grafted NI-MSCs survived after transplantation into intact spinal cord and produced cells that expressed neural markers. All these data suggest that neurally modifi ed MSCs, induced by recently developed methodology, could be a potential source of cells to replace damaged neurons and glia in injured spinal cord, and/or to promote cell survival and axonal growth of host tissue.
Journal of Clinical Lipidology, 2017
Prostaglandins, Leukotrienes and Essential Fatty Acids
Prostaglandins, Leukotrienes and Essential Fatty Acids
Sickle cell disease (SCD) is one of the most common inherited blood disorder among African Americ... more Sickle cell disease (SCD) is one of the most common inherited blood disorder among African Americans affecting 70,000-100,000 individuals in the United States. It is characterized by abnormal hemoglobin (HbS) which develops into severe hemolytic anemia and vaso-occlusive crisis. Therefore, patients with SCD suffer from a chronic state of inflammation, which is responsible for multiple organ damage, ischemic attacks, and premature death. Another major hallmark of SCD patients is the abnormally low levels of omega-3 fatty acids, especially docosahexaenoic acid (DHA) in their red blood cell membranes. Treatment with DHA can reduce red blood cell adhesion and enhance cerebral blood flow, thus, our main goal is to investigate the effect of SC411, which is a novel, highly purified DHA ethyl ester formulation with a proprietary delivery platform in SCD. Utilizing a transgenic mouse model of SCD (HbSS-Townes) and recurrent hypoxic challenges (10%O2, 0.5% CO2 and balance N2 for 3 h) to mimic ischemic-like conditions, our data suggest that SC411 can elevate blood DHA and eicosapentaenoic acid (EPA) levels after 8 weeks of treatment. SC411 can also decrease arachidonic acid (AA) and sickling of red blood cells. In addition, SC411-treated SCD mice showed presented with cerebral blood flow, alleviated neuroinflammation, and revived working memory which ultimately enhanced overall survival. In summary, this study suggests that treatment with SC411 improves cellular and functional outcomes in SCD mice. This finding may provide novel therapeutic opportunities in the treatment against ischemic injury elicited by SCD.
Journal of Alzheimer's Disease
APP overexpressing mice have been widely used in the study of Alzheimer's disease (AD), focusing ... more APP overexpressing mice have been widely used in the study of Alzheimer's disease (AD), focusing mainly at older ages, with higher accumulation of amyloid-β peptide (Aβ). A decrease in hippocampal adult neurogenesis has been described in these models and proposed to be a consequence of Aβ accumulation. Only one study demonstrates increased neurogenesis in the hippocampus of APP-overexpressing J20 mice, and suggests it is a compensatory effect due to a subtle Aβ-induced damage. We have previously reported that a specific aggregation of Aβ has neurogenic potential on neural stem cells (NSC) in vitro. In order to clarify the contradicting data reported in vivo, we investigated NSC proliferation and neuronal differentiation in the hippocampi of J20 mice at a broader range of ages. Using immunohistochemistry, we show increased proliferation and neuronal differentiation in the hippocampi of 3 month-old J20 mice that reverted when animals became older. The increase in neurogenesis correlated with detectable levels of oligomeric Aβ, measured by ELISA and western blot. We suggest that oligomeric Aβ directly induces neurogenesis in vivo as has been demonstrated in vitro. Understanding the mechanisms underlying these changes could lead to treatments to control the neuronal differentiation of endogenous precursors through the progress of AD.
The Journal of Nutritional Biochemistry, 2015
Food-derived peptides, such as β-casomorphin BCM7, have potential to cross the gastrointestinal t... more Food-derived peptides, such as β-casomorphin BCM7, have potential to cross the gastrointestinal tract and blood-brain barrier and are associated with neurological disorders and neurodevelopmental disorders. We previously established a novel mechanism through which BCM7 affects the antioxidant levels in neuronal cells leading to inflammatory consequences. In the current study, we elucidated the effects of casein-derived peptides on neuronal development by using the neurogenesis of neural stem cells (NSCs) as an experimental model. First, the transient changes in intracellular thiol metabolites during NSC differentiation (neurogenesis) were investigated. Next, the neurogenic effects of food-derived opioid peptides were measured, along with changes in intracellular thiol metabolites, redox status and global DNA methylation levels. We observed that the neurogenesis of NSCs was promoted by human BCM7 to a greater extent, followed by A2-derived BCM9 in contrast to bovine BCM7, which induced increased astrocyte formation. The effect was most apparent when human BCM7 was administered for 1 day starting on 3 days postplating, consistent with immunocytochemistry. Furthermore, neurogenic changes regulated by bovine BCM7 and morphine were associated with an increase in the glutathione/glutathione disulfide ratio and a decrease in the S-adenosylmethionine/S-adenosylhomocysteine ratio, indicative of changes in the redox and the methylation states. Finally, bovine BCM7 and morphine decreased DNA methylation in differentiating NSCs. In conclusion, these results suggest that food-derived opioid peptides and morphine regulated neurogenesis and differentiation of NSCs through changes in the redox state and epigenetic regulation.
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Papers by Miguel A. Lopez-Toledano