lysosomal storage diseases/obesity

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Exacerbating and reversing lysosomal storage diseases: from yeast to humans.

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Lysosomal storage diseases (LSDs) arise from monogenic deficiencies in lysosomal proteins and pathways and are characterized by a tissue-wide accumulation of a vast variety of macromolecules, normally specific to each genetic lesion. Strategies for treatment of LSDs commonly depend on reduction of

Safety of fluoxetine in the treatment of obesity.

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Observations related to the safety of fluoxetine in the treatment of obese patients are reviewed. The adverse event profile in obese patients, though differing slightly from that seen in depressed patients, was similar in that events observed were generally mild and well tolerated. Other than rash,

Discovery and development of 5-HT(₂C) receptor agonists for obesity: is there light at the end of the tunnel?

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Ever since the observation of late-onset obesity during the phenotypic characterization of the 5-HT(₂C) knock-out mouse, the serotonin 5-HT(₂C) receptor has been a drug target for obesity. Small-molecule agonists have repeatedly been shown to reduce food intake and body weight in rodent models of

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition.

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Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated.

Screening of Drug-Induced Steatosis and Phospholipidosis using Lipid Droplet-Selective Two-Photon Probes

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Lipid droplets (LDs) are organelles that play a major role in regulating the storage of neutral lipids. Dysregulation of LDs is associated with metabolic disorders, such as fatty liver diseases, obesity, diabetes, and atherosclerosis. We have de-veloped LD-selective small-molecule fluorescence

Renal phospholipidosis and impaired magnesium handling in high-fat-diet-fed mice.

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Hypomagnesemia (blood Mg²⁺ concentration <0.7 mM) is a common electrolyte disorder in patients with type 2 diabetes (T2D), but the etiology remains largely unknown. In patients with T2D, reduced blood Mg²⁺ levels are associated with an increased decline in renal function,

Severe lysosomal storage disease of liver in del(1)(p36): a new presentation.

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1p36 deletion is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. The deletion is of variable size. It usually involves less than 10 Mb in the 1pter-1p36.23 interval. Variability of the phenotype is partially related to the extent of the deletion. Some

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908.

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Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives.

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Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272

Role of membranes in disease.

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The membranes of mammalian cells are composed of an ordered array of lipids and proteins, the latter containing carbohydrate residues directed towards the exterior and important in the interaction of cells with each other and with external proteins. This external (plasma) membrane and other more

Lysosomal dysfunction results in altered energy balance.

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The mucopolysaccharidosis (MPS) type VII mouse was originally described as the adipose storage deficiency mouse because of its extreme lean phenotype of unknown etiology. Here, we show that adipose storage deficiency and lower leptin levels are common to five different lysosomal storage diseases

The Emerging Role of Cardiovascular Magnetic Resonance Imaging in the Evaluation of Metabolic Cardiomyopathies.

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The aim of this review is to discuss the role of Cardiovascular Magnetic Resonance (CMR) in the diagnosis, risk stratification, and follow-up of metabolic cardiomyopathies. The classification of myocardial diseases, proposed by WHO/ISFC task force, distinguished specific cardiomyopathies, caused by

Annexins as organizers of cholesterol- and sphingomyelin-enriched membrane microdomains in Niemann-Pick type C disease.

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Growing evidence suggests that membrane microdomains enriched in cholesterol and sphingomyelin are sites for numerous cellular processes, including signaling, vesicular transport, interaction with pathogens, and viral infection, etc. Recently some members of the annexin family of conserved calcium

Lipid homeostasis in macrophages - implications for atherosclerosis.

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In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of

Endosomal-lysosomal dysfunction in metabolic diseases and Alzheimer's disease

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The endosomal-lysosomal pathways and related autophagic processes are responsible for proteostasis, involving complexes between lysosomes and autophagosomes. Lysosomes are a key component of homeostasis, involved in cell signaling, metabolism, and quality control, and they experience functional

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