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Molecular mechanisms and treatment strategies for Dupuytren’s disease  [cached]
David B O’Gorman,Linda Vi,Bing Siang Gan
Therapeutics and Clinical Risk Management , 2010,
Abstract: David B O’Gorman1,2,3,4, Linda Vi1,2,5, Bing Siang Gan1,2,3,5,61Cell and Molecular Biology Laboratory, 2The Hand and Upper Limb Centre, St. Joseph’s Health Care London, Schulich School of Medicine and Dentistry, 3Departments of Surgery, 4Biochemistry, 5Physiology and Pharmacology, 6Medical Biophysics, The University of Western Ontario, London, OT, CanadaAbstract: Dupuytren’s disease (DD) is a common disease of the hand and is characterized by thickening of the palmar fascia and formation of tight collagenous disease cords. At present, the disease is incurable and the molecular pathophysiology of DD is unknown. Surgery remains the most commonly used treatment for DD, but this requires extensive postoperative therapy and is associated with high rates of recurrence. Over the past decades, more indepth exploration of the molecular basis of DD has raised the hopes of developing new treatment modalities. This paper reviews the clinical presentation and molecular pathophysiology of this disease, as well as current and emerging treatment. It also explores the implications of new findings in the laboratory for future treatment.Keywords: Dupuytren’s contracture, Dupuytren’s disease, fibrosis
Current Strategies of Therapy in Alzheimer’s Disease
A. Martocchia and P. Falaschi
The Open Neuropsychopharmacology Journal , 2008, DOI: 10.2174/1876523800801010019]
Abstract: The molecular mechanisms involved in the plaques and tangles pathogenesis in Alzheimer’s disease (AD) discloses new potential targets for therapies that could modify the clinical course. In the last years, the neurotransmission defect (cholinergic hypothesis) has been extensively investigated. Cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and N-methyl-D-aspartate receptor antagonist (memantine) are approved agents that can delay the cognitive deterioration. Recent evidence in the literature suggests innovative strategies of treatment in AD, acting at the level of the amyloid cascade that is related to the neuronal defects and the neurotransmission disturbances. Confirmatory data are necessary and they will arise from the clinical trials with these potential disease-modifying drugs.
Molecular Mechanisms of Survival Strategies in Extreme Conditions  [PDF]
Salvatore Magazù,Federica Migliardo,Miguel A. Gonzalez,Claudia Mondelli,Stewart F. Parker,Beata G. Vertessy
Life , 2012, DOI: 10.3390/life2040364
Abstract: Today, one of the major challenges in biophysics is to disclose the molecular mechanisms underlying biological processes. In such a frame, the understanding of the survival strategies in extreme conditions received a lot of attention both from the scientific and applicative points of view. Since nature provides precious suggestions to be applied for improving the quality of life, extremophiles are considered as useful model-systems. The main goal of this review is to present an overview of some systems, with a particular emphasis on trehalose playing a key role in several extremophile organisms. The attention is focused on the relation among the structural and dynamic properties of biomolecules and bioprotective mechanisms, as investigated by complementary spectroscopic techniques at low- and high-temperature values.
A window on disease pathogenesis and potential therapeutic strategies: molecular imaging for arthritis
Luke L Gompels, Ewa M Paleolog
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3197
Abstract: The objectives of molecular imaging are the visualization, characterization and quantification of molecular and cellular processes non-invasively within intact living organisms. This can help evaluate physiological and pathophysiological processes, facilitate diagnosis and monitor the effects of therapy. At the preclinical stage novel molecular imaging techniques can facilitate the development of new therapies and understanding of novel mechanisms of action of biologically targeted agents.Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, primarily characterised by inflamed synovial tissue in multiple joints leading to localised destruction of bone. Despite significant advances in conventional imaging strategies, such as the use of power doppler ultrasound scans and magnetic resonance imaging (MRI), the early diagnosis and monitoring of inflammatory conditions such as RA remains challenging. Current imaging reflects irreversible pathological and anatomical change as opposed to perturbations in specific molecular pathways. Pathological change visualized on X-ray imaging may not be seen until many months after disease onset [1]. Osteoarthritis (OA) is characterised by joint pain, inactivity-related stiffness, impaired social role and reduced quality of life, which may be associated with radiographic abnormalities. It is the most prevalent joint disease and a major cause of disability [2-4]. While in some ways similar to RA, it is recognised that cartilage loss may occur for several years before even minor changes can be detected on plain radiographs in OA [5]. Molecular in vivo imaging in animal models of disease is also important in increasing our understanding of disease pathogenesis and in developing methods of monitoring disease activity in vivo. Robust disease monitoring will also allow for better appraisal of potential therapeutics. Ultimately, the aim is to translate molecular imaging techniques into functional systems for imaging of human di
Molecular mechanisms of steatosis in nonalcoholic fatty liver disease
Pettinelli,P.; Obregón,A. M.; Videla,L. A.;
Nutrición Hospitalaria , 2011,
Abstract: nonalcoholic fatty liver disease (nafld) is the most important cause of chronic liver disease and is considered the hepatic manifestation of the metabolic syndrome associated with diabetes mellitus type 2. the prevalence of nafld in the general population reaches 15-20%. it is also estimated that nonalcoholic steatohepatitis (nash) affects 3% of the population. nafld refers to a wide spectrum of liver damage, which ranges from simple steatosis or intracellular triglyceride accumulation, to inflammation (nash), fibrosis and cirrhosis. the mechanisms involved in the accumulation of triglycerides in the liver and subsequent hepatocellular damage are multifactorial and are not completely understood. however, metabolic changes such as insulin resistance (ir) are developed, being a common factor in the retention of fatty acids (fa) within the hepatocytes with oxidation and production of free radicals at the mitochondrial level, which are capable of causing lipid peroxidation, cytokine production, and necrosis. in addition, there are alterations in the hepatic bioavailability of long chain n-3 polyunsaturated fatty acids, conditions that alter the expression of a series of transcriptional factors involved in lipolytic and lipogenic processes in the liver. a greater knowledge of the etiopathogenic mechanisms of nafld is fundamental for the development of future effective therapeutic strategies. the pathophysiological fundamentals of liver steatosis are analyzed in this study.
Alcohol-induced liver disease: From molecular damage to treatment
Fernández Checa,José C; Bellentani,Stefano; Tiribelli,Claudio;
Revista médica de Chile , 2002, DOI: 10.4067/S0034-98872002000600013
Abstract: although the interaction between alcohol and the liver has been the subject of intensive investigation since many years, several uncertainties remain to be solved. good examples of what we need to learn are: the real number of patients with alcohol-induced liver disease (aild), the dose of alcohol "safe" for the liver, the genetic predisposition to the damage or, on the other side of the coin, protecting from the damage. rather recently, however, part of these questions started to be clarified, thus permitting a better definition of the role of each of these factors in aild. in parallel to the clinical approach to aild, the unveiling of the molecular and biochemical mechanisms involved in aild has progressed and proved to be important in both a better understanding of the disease and, more important, in a more rational treatment of these disorders. this review will focus on what we currently know of aild in clinical, biochemical and molecular terms and what we need to address in the future (rev med chile 2002; 130: 681-690).
Molecular determinants of selective dopaminergic vulnerability in Parkinson’s disease: an update  [PDF]
Lars Brichta
Frontiers in Neuroanatomy , 2014, DOI: 10.3389/fnana.2014.00152
Abstract: Numerous disorders of the central nervous system are attributed to the selective death of distinct neuronal cell populations. Interestingly, in many of these conditions, a specific subset of neurons is extremely prone to degeneration while other, very similar neurons are less affected or even spared for many years. In Parkinson’s disease (PD), the motor manifestations are primarily linked to the selective, progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). In contrast, the very similar DA neurons in the ventral tegmental area (VTA) demonstrate a much lower degree of degeneration. Elucidating the molecular mechanisms underlying the phenomenon of differential DA vulnerability in PD has proven extremely challenging. Moreover, an increasing number of studies demonstrate that considerable molecular and electrophysiologic heterogeneity exists among the DA neurons within the SNpc as well as those within the VTA, adding yet another layer of complexity to the selective DA vulnerability observed in PD. The discovery of key pathways that regulate this differential susceptibility of DA neurons to degeneration holds great potential for the discovery of novel drug targets and the development of promising neuroprotective treatment strategies. This review provides an update on the molecular basis of the differential vulnerability of midbrain DA neurons in PD and highlights the most recent developments in this field.
Molecular Mechanisms of Resistance to Tumour Anti-Angiogenic Strategies  [PDF]
Renaud Grépin,Gilles Pagès
Journal of Oncology , 2010, DOI: 10.1155/2010/835680
Abstract: Tumour angiogenesis, described by Folkman in the early seventies, is an essential, complex, and dynamic process necessary for the growth of all solid tumours. Among the angiogenic factors secreted by the tumour cells, the Vascular Endothelial Growth Factor (VEGF) is one of the most important. Most types of human cancer cells express elevated levels of this proangiogenic factor and its receptors. New molecules, called anti-angiogenic, are developed to impair VEGF pathway and tumour vasculature. Despite important results, the clinical benefits of anti-VEGF therapy are relatively modest and usually measured in weeks or months. Why following anti-angiogenic therapy do some patients respond transiently and then why does tumour grow again and disease progress and which compensatory mechanisms could explain the anti-angiogenic treatment failure? 1. Introduction Tumour angiogenesis, as described by Folkman in the early seventies and confirmed today [1], is an essential, complex, and dynamic process necessary for the growth of all solid tumours. It stipulates that a tumour cannot grow through a defined volume if it is not vascularized. The cores of solid tumours rapidly undergo hypoxic with low oxygen levels and nutrients deficiency. Tumour cells counteract this process by producing angiogenic factors responsible for growth and migration of quiescent endothelial cells of proximal blood vessels. The consequence is the creation of a new vascular network to supply the tumour with oxygen, nutrients, growth factors, proteolytic enzymes, tumours cells, and dissemination in host [2, 3]. Tumour angiogenesis and hypoxia are considered as hallmarks of solid tumours [4, 5]. Among the angiogenic factors secreted by tumour cells, the Vascular Endothelial Growth Factor (VEGF) is one of the most important. Different stimuli are responsible of its production. Among them hypoxia was one of the first described. During the angiogenic switch, the frail existing balance between pro- and anti-angiogenic factors is broken in favour of proangiogenic factors [6]. Most types of human cancer cells express elevated levels of VEGF. They also express VEGF receptors at their surface including VEGF-R1,2,3, VEGF-R3 participating to lymphangiogenesis [7–11]. All these results have allowed the development of therapeutic tools targeting VEGF (Bevacizumab) [12] or their receptors (Tyrosine kinase inhibitors) [13]. 2. Examples of Antiangiogenic Treatments Commonly Used in Metastatic Cancers For example, Bevacizumab (Avastin, Roche), a humanized neutralizing monoclonal antibody against VEGF, is the
Current and emerging drugs for the treatment of inflammatory bowel disease  [cached]
Triantafillidis JK,Merikas E,Georgopoulos F
Drug Design, Development and Therapy , 2011,
Abstract: John K Triantafillidis, Emmanuel Merikas, Filippos GeorgopoulosDepartment of Gastroenterology, Center for Inflammatory Bowel Disease, “Saint Panteleimon” General Hospital, Nicea, GreeceAbstract: During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn’s disease and ulcerative colitis.Keywords: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, treatment, biologic agents, immunosuppressives, mesalazine, antibiotics
Future strategies in treatment of parkinson’s disease  [PDF]
KH Janbaz,MI Qadir,F Younas,SA Malik
Journal of College of Medical Sciences-Nepal , 2011, DOI: 10.3126/jcmsn.v7i2.6687
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder. COMT inhibitors, MOA-B inhibitors, Levodopa, Levodopa in combination with Dopa Decarboxylase (DDC) inhibitors, Entacapone, Tolcapone, Pramipexole, Ropinirole, Zonisamide, Cholinesterase inhibitors such as rivastigmine, galantamine and donepezil are used for treatment of Parkinson’s disease. Gene therapy of cellular and brain circuit pathways for the treatment of PD is under trials. Recently nuclear transfer embryonic stem cells or induced pluripotent stem derived cells can be used. The presence of Lewy bodies, reduced dopamine transporter and tyrosine hydroxylase expression within transplanted cells indicated that grafted cells are pathological. Adult and fetal neural stem cells are self-renewable.
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