Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimer's disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.
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PMID:Calpain inhibition: a therapeutic strategy targeting multiple disease states. 1647 52

Several lines of evidence indicate that the nonenzymatic oxidative modification of proteins and the subsequent accumulation of the modified proteins have been found in cells during aging and oxidative stress and in various pathological states, including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. Our previous work suggested the existence of molecular mimicry between antibodies raised against hydroxy-2-nonenal (HNE)-modified protein and anti-DNA autoantibodies, a serologic hallmark of systemic lupus erythematosus (SLE). In the present study, we investigated the possible involvement of HNE-modified proteins as the endogenous source of the anti-DNA antibodies. Accumulation of the antigen recognized by the antibody against the HNE-modified protein was observed in the nucleus of almost all of the epidermal cells from patients with autoimmune diseases, including SLE. The SLE patients also showed significantly higher serum levels of the anti-HNE titer than healthy individuals. To determine if a specific anti-DNA response could be initiated by the HNE-derived epitopes, we immunized BALB/c mice with the HNE-modified protein and observed a progressive increase in the anti-DNA response. Moreover, we generated the monoclonal antibodies, showing recognition specificity toward DNA, and found that they can bind to two structurally distinct antigens (i.e. the native DNA and protein-bound 4-oxo-2-nonenal). The findings in this study provide evidence to suspect an etiologic role for lipid peroxidation in autoimmune diseases.
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PMID:Protein-bound 4-hydroxy-2-nonenal: an endogenous triggering antigen of antI-DNA response. 1758 42

Several lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the modified proteins have been found in cells during aging, oxidative stress, and in various pathological states including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. The important agents that give rise to the modification of a protein may be represented by reactive aldehydic intermediates, such as ketoaldehydes, 2-alkenals and 4-hydroxy-2-alkenals. These reactive aldehydes are considered important mediators of cell damage due to their ability to covalently modify biomolecules, which can disrupt important cellular functions and can cause mutations. Furthermore, the adduction of aldehydes to apolipoprotein B in low-density lipoproteins (LDL) has been strongly implicated in the mechanism by which LDL is converted to an atherogenic form that is taken up by macrophages, leading to the formation of foam cells. During the search for an endogenous inducer of cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses, 4-hydroxy-2-noennal (HNE), one of the most representative lipid peroxidation product, has been identified as the potential inducer of COX-2. In addition, the following study on the molecular mechanism of the COX-2 induction by HNE has unequivocally established that a serum component, which is eventually identified to be denatured LDL, is essential for COX-2 induction. Here I review current understanding of the mechanisms by which HNE in cooperation with the serum component activates gene expression of COX-2.
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PMID:A lipid-derived endogenous inducer of COX-2: a bridge between inflammation and oxidative stress. 1848 67

Caveolae are specialized lipid rafts that form flask-shaped invaginations of the plasma membrane. They are involved in cell signalling and transport and have been shown critically regulate vascular reactivity and blood pressure. The organization and functions of caveolae are mediated by coat proteins (caveolins) and support or adapter proteins (cavins). The caveolins, caveolin-1, -2, and -3, form the structural backbone of caveolae. These proteins are also highly integrated into caveolae function and have their own activity independent of caveolae. The cavins, cavins 1-4, are involved in regulation of caveolae and modulate the function of caveolins by promoting the membrane remodelling and trafficking of caveolin-derived structures. The relationships between these different proteins are complex and intersect with many aspects of cell function. Caveolae have also been implicated in chronic inflammatory conditions and other pathologies including atherosclerosis, inflammatory bowel disease, muscular dystrophy, and generalized dyslipidaemia. The pathogenic role of the caveolins is an emerging area, however, the roles of cavins in disease is just beginning to be explored. This review will examine the relationship between caveolins and cavins and explore the role of caveolae in inflammatory signalling mechanisms.
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PMID:Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. 2020 78

The cathepsins are a family of lysosomal cysteine proteases that are abundant in living cells and play important roles in intracellular proteolysis. Cathepsins are necessary for cell survival, and disruption of regulation of the activity of these enzymes causes serious diseases including allergy, atherosclerosis, muscular dystrophy, Alzheimer's disease and cancer. Therefore, the design of inhibitors for cathepsins is important in development of therapeutic agents. This review will focus on the features of the tertiary structure and substrate-binding specificity of cathepsins B, L, S and K, based on X-ray crystal structures of their complexes with inhibitors. To illustrate an approach to drug design, an example of structure-based design of a cathepsin B-specific inhibitor is described.
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PMID:Development of cathepsin inhibitors and structure-based design of cathepsin B-specific inhibitor. 2033 81

Marine microalgae constitute a natural source of a variety of drugs for pharmaceutical, food and cosmetic applications-which encompass carotenoids, among others. A growing body of experimental evidence has confirmed that these compounds can play important roles in prevention (and even treatment) of human diseases and health conditions, e.g., cancer, cardiovascular problems, atherosclerosis, rheumatoid arthritis, muscular dystrophy, cataracts and some neurological disorders. The underlying features that may account for such favorable biological activities are their intrinsic antioxidant, anti-inflammatory and antitumoral features. In this invited review, the most important issues regarding synthesis of carotenoids by microalgae are described and discussed-from both physiological and processing points of view. Current gaps of knowledge, as well as technological opportunities in the near future relating to this growing field of interest, are also put forward in a critical manner.
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PMID:Microalgae as sources of carotenoids. 2173 54

Cellular responses to mechanical forces are crucial in embryonic development and adult physiology, and are involved in numerous diseases, including atherosclerosis, hypertension, osteoporosis, muscular dystrophy, myopathies and cancer. These responses are mediated by load-bearing subcellular structures, such as the plasma membrane, cell-adhesion complexes and the cytoskeleton. Recent work has demonstrated that these structures are dynamic, undergoing assembly, disassembly and movement, even when ostensibly stable. An emerging insight is that transduction of forces into biochemical signals occurs within the context of these processes. This framework helps to explain how forces of varying strengths or dynamic characteristics regulate distinct signalling pathways.
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PMID:Dynamic molecular processes mediate cellular mechanotransduction. 2177 77

Adeno-associated virus (AAV) is the most promising gene delivery vehicle for muscle-directed gene therapy. AAV's natural tropism to muscle cells, long-term persistent transgene expression, multiple serotypes, as well as its minimal immune response have made AAV vectors well suited for muscle-directed gene therapy. AAV vector-mediated gene delivery to augment muscle structural proteins, such as dystrophin and sarcoglycans, offers great hope for muscular dystrophy patients. In addition, muscle can be used as a therapeutic platform for AAV vectors to express nonmuscle secretory/regulatory pathway proteins for diabetes, atherosclerosis, hemophilia, cancer, etc. AAV vector can be delivered into both skeletal muscle and cardiac muscle by means of local, regional, and systemic administrations. Successful animal studies have led to several noteworthy clinical trials involving muscle-directed gene therapy. In this chapter, we describe the basic methodology that is currently utilized in the area of AAV-mediated muscle-directed gene therapy. These methods include vector delivery route, vector dosage, detection of transgene expression by immunostaining and western blot, determination of vector copy numbers and quantification of mRNA expression, as well as potential immune responses involved in AAV delivery. Technical details and tips leading to successful experimentation are also discussed.
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PMID:Gene therapy in skeletal muscle mediated by adeno-associated virus vectors. 2203 28

Caveolae and their coat proteins, caveolins (Cav), are cave-like invaginations found in the plasma membrane of a variety of cells. These unique vesicles and their coat proteins, Cavs, have diverse effects on endothelial function, nitric oxide synthesis regulation, signal transduction, cholesterol metabolism, and apoptosis. Animal studies in Cav knockout mice demonstrate the vital role of these structural proteins on endothelial and vascular function. Genetic studies have proposed that beside neoplasia, Cavs may play a role in the development of atherosclerosis, cardiomyopathy, long QT syndrome, pulmonary fibrosis, and muscular dystrophy. The role of Cav expression in atherosclerotic disease is poorly understood and remains controversial. Interestingly, there is emerging evidence between low Cav-1 levels and the vulnerable plaque, which could potentially identify Cav-1 as a novel plaque biomarker. Cavs, through intricate biochemical pathways involving endothelial nitric oxide synthase and mitogen-activated protein kinase, are known to affect the cardiovascular system at multiple levels. In the present review, we aim to highlight the nature and types of caveolae, caveolar signaling mechanisms and regulation, and the pathophysiology of Cavs as it pertains to the cardiovascular system. Ongoing research is needed to clarify the diagnostic and prognostic role of these novel proteins and to determine how the effects of Cavs can translate into clinical medicine.
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PMID:Myocardial tissue caveolae. 2588 May 16

A growing body of evidence suggests that mechanical signals emanating from the cell's microenvironment are fundamental regulators of cell behaviour. Moreover, at the macroscopic scale, the influence of forces, such as the forces generated by blood flow, muscle contraction, gravity and overall tissue rigidity (for example, inside of a tumour lump), is central to our understanding of physiology and disease pathogenesis. Still, how mechanical cues are sensed and transduced at the molecular level to regulate gene expression has long remained enigmatic. The identification of the transcription factors YAP and TAZ as mechanotransducers started to fill this gap. YAP and TAZ read a broad range of mechanical cues, from shear stress to cell shape and extracellular matrix rigidity, and translate them into cell-specific transcriptional programmes. YAP and TAZ mechanotransduction is critical for driving stem cell behaviour and regeneration, and it sheds new light on the mechanisms by which aberrant cell mechanics is instrumental for the onset of multiple diseases, such as atherosclerosis, fibrosis, pulmonary hypertension, inflammation, muscular dystrophy and cancer.
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PMID:Mechanobiology of YAP and TAZ in physiology and disease. 2895 64


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