Non-metabolic Diseases Research Articles

Bile Acids as Novel Pharmacological Agents: the Interplay between Gene Polymorphisms, Epigenetic Factors and Drug Response

The field of bile acid research has become tremendously active. Bile acids have been shown to act as signaling molecules that are involved in many metabolic processes, but their role in carcinogenesis is also emerging. The aim of this review was to summarize the present knowledge in the innovative field of bile acids pharmacology, to reveal the novel mechanisms of their action, particularly focusing on clinically relevant aspects, and to evaluate the role of both genetic and epigenetic variation in genes encoding bile acid-activated receptors in determining the therapy outcome. Most effects of bile acids are mediated by both nuclear and G protein-coupled receptors. Three natural bile acids have already been registered for the use in humans, but various semi-synthetic bile acid analogues with improved pharmacokinetic and pharmacodynamic properties have been developed, which opens up new avenues in pharmacotherapy. Many efforts have been made to evaluate the impact of nuclear receptors on inter-individual variation in responses to drugs, since nuclear receptors are significant mediators between environmental stimuli and pharmacokinetics. Genetic variation of bile acid-activated receptors is associated with both benign and malignant diseases, in terms of disease risk and severity, but also with pharmacokinetics and therapy outcome. Furthermore, the activity of these receptors may be masked or amplified by epigenetic modifications. Both genetic and epigenetic factors may alter complex and intricate network of bile acid signaling pathways, contributing to the development of several metabolic and non-metabolic diseases and altered activities of drug-metabolizing enzymes and transporters. These polymorphisms and epigenetic modifications may also impact the effectiveness and pharmacokinetics of bile acid analogues, which must be taken into account during the development of these compounds as novel therapeutic agents.

Obesity, insulin resistance and comorbidities? Mechanisms of association.

Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities.

Pentose Phosphate Pathway in Disease and Therapy

Pentose phosphate (PP) pathway, which is ubiquitously present in all living organisms, is one of the major metabolic pathways associated with glucose metabolism. The most important functions of this pathway includes the generation of reducing equivalents in the form of NADPH for reductive biosynthesis, and production of ribose sugars for the biosynthesis of nucleotides, amino acids, and other macromolecules required by all living cells. Under normal conditions of growth, PP pathway is important for cell cycle progression, myelin formation, and the maintenance of the structure and function of brain, liver, cortex and other organs. Under diseased conditions, such as in cases of many metabolic, neurological or malignant diseases, pathological mechanisms augment due to defects in the PP pathway genes. Adoption of alternative metabolic pathways by cells that are metabolically abnormal, or malignant cells that are resistant to chemotherapeutic drugs often plays important roles in disease progression and severity. Accordingly, the PP pathway has been suggested to play critical roles in protecting cancer or abnormal cells by providing reduced environment, to protect cells from oxidative damage and generating structural components for nucleic acids biosynthesis. Novel drugs that targets one or more components of the PP pathway could potentially serve to overcome challenges associated with currently available therapeutic options for many metabolic and non-metabolic diseases. However, careful designing of drugs is critical that takes into the accounts of cell’s broader genomic, proteomic and metabolic contexts under consideration, in order to avoid undesirable side-effects. In this review, we discuss the role of PP pathway under normal and abnormal physiological conditions and the potential of the PP pathway as a target for new drug development to treat metabolic and non-metabolic diseases.

Histological and electron micr oscopy findings in fabry disease cardiomyopathy: a case report

<h3>Aim</h3> To understand the features and role of histological and electron microscopy findings in a cardiac biopsy from patients with suspected Fabry disease. <h3>Methods</h3> Report of a recent case and review of current literature on the histological and ultrastructural findings in Fabry disease cardiomyopathy. <h3>Results</h3> Perinuclear vacuolisation of cardiac myocytes was seen on light microscopy and dense concentric lamellar bodies or my-elin figures were present on electron microscopy. <h3>Discussion</h3> The light microscopy findings are non-specific and can be seen in a range of metabolic and non-metabolic diseases. The diagnosis of Fabry disease must be complemented by electron microscopy, biochemical findings and ultimately genetic studies.

Metabolic Syndrome, Its Components and Risk of Age-Related Cataract Extraction: A Case-Control Study in Italy

We sought to explore the relationship between age-related cataract extraction and the metabolic syndrome or its various components separately and in various combinations in an Italian case-control study. A total of 761 cases and 1,522 controls in hospital for acute, non-neoplastic, non-ophthalmologic, non-metabolic diseases were interviewed between 1991 and 2003. Odds ratios (ORs), and their 95% confidence intervals (CIs), were computed from multiple logistic regression models, conditioned on sex, age, and study center and adjusted for education and smoking. The ORs were 1.41 for a history of central obesity, 1.42 for hypertension, 1.25 for hyperlipidemia, and 1.16 for diabetes. Patients with the metabolic syndrome (defined as the simultaneous presence of central obesity and at least two other factors among hypertension, hyperlipidemia, diabetes) had an increased risk of cataract, with an OR of 2.01 (95% CI: 1.43-2.83). The ORs were 1.75 for the presence of any of two components and 2.50 for three to four components, with a linear trend in risk. This study indicates that the metabolic syndrome, its components, and their combination are associated with an increased risk of cataract extraction in this Italian population.

Nonmetabolic Causes of Triphasic Waves: A Reappraisal

Two more patients with triphasic waves (TW) on their EEGs in the absence of metabolic disturbances are described. One patient had coma associated with cerebellar hematoma, the other had mild dementia associated with idiopathic calcifications of the basal ganglia and normal auditory brainstem responses, subcortical and cortical somatosensory evoked potentials. Neurologic examination failed to show asterixis in both patients. The literature on nonmetabolic causes of TW was also reviewed, and the clinical and anatomic reports of 10 patients have been analyzed: 7 patients had focal brainstem-diencephalic lesions (craniopharyngioma: 2 patients; thalamic gliomas: 3 patients; pontine stroke: 2 patients), and 3 patients suffered from diffuse subcortical or multifocal encephalopathies (Binswanger's encephalopathy: 1 patient; cerebral carcinomatosis: 1 patient; multifocal cerebral lymphoma: 1 patient). From the clinical point of view, patients with nonmetabolic diseases causing TW presented either disturbance of higher cerebral functions with no asterixis or sudden onset of coma. It is concluded that TW may result from focal brainstem/diencephalic lesions or from diffuse subcortical or multifocal encephalopathies in the absence of concomitant metabolic abnormalities. Nonmetabolic causes of TW should be suspected in patients presenting with neurologic disturbances not associated with asterixis.