Physiological Functions Of Body Research Articles

English

DNA-synthesis, DNA-repair, and DNA imprinting processes require efficient conversion of homocysteine to methionine. This methylation is catalyzed by methylentetrahydrofolate reductase through reduction of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate. Normal DNA synthesis is considered critical for physiological functions of body. The enzyme is coded by the gene with the symbol MTHFR on chromosome 1 location p36.3 in humans. At least 24 mutations in the MTHFR gene have been identified in people with homocystinuria. There is DNA sequence variants (genetic polymorphisms) associated with this gene. Two of the most investigated are C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms (SNP). Mutations at C677T and A1298C which confer amino acid substitution Ala222Val and Glu429Ala respectively with a considerable reduced activity. This polymorphism and mild hyperhomocysteinemia are associated with neural tube defects in offspring, arterial and venous thrombosis, and cardiovascular disease. 677TT individuals are at a decreased risk for certain leukemia and colon cancer. The MTHFR gene could be one of the factors of overall schizophrenia risk. In silico analysis now has added important and wide range applications to proteomics from structure modeling to its functional levels. Several algorithms have been suggested from many authors to bring an accurate modeling at its best but ultimately every protein has its own variant features to be treated by the same algorithm. Studies in proteomics through computational techniques need complements between critical requirement for a protein and features available in an algorithm. Comparative modeling is now bridging the gap between available sequences and structures modeled with accuracy. Effective refinement techniques made it capable of driving models toward native structure. Structure of MTHFR can assist the study of involvement of this enzyme in the disorders and can provide better level of understanding about structural aspects of it. We have modeled wild type and mutated type MTHFR using comparative modeling and structure validation has given appreciable values. This work can further account for the structure based drug design community in the search of MTHFR inhibitors. Keywords - MTHFR, Comparative modeling, PDB, Mutation, Toxicity

Neuroendocrine biomarkers, allostatic load, and the challenge of measurement: A commentary on Gersten

In this commentary, we discuss Gersten's findings particularly in relation to the challenge of accurately measuring stress, neuroendocrine markers and allostatic load. Allostatic load is a timely, potentially useful tool to measure the degree in which the body's physiological function is outside of optimal range. As with most biomarkers early on in development, there are sound opportunities to advance methods that will help understand the etiology of allostatic load and allow it to become more accurately measured. We present a biomarker development framework that should aid in furthering measurement of allostatic load, emphasizing the importance of biomarker measurement accuracy, standardization of methods, and relevance to clinically meaningful outcomes.

Melatonin

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.

Mitogen Activated Protein (MAP) Kinases: Development of ATP and Non- ATP Dependent Inhibitors

Extracellular signals regulate most of the body's physiological functions through the MAP kinase signaling pathways. These MAP kinase signaling pathways are normally under tight regulation such that activation and inactivation occurs only when needed. However, aberrant regulation observed with naturally occurring mutations in specific signaling proteins often results in constitutive activation of the MAP kinases and is involved in several pathophysiological conditions, such as cancer, neurodegeneration, and inflammation. As such, much effort has been expended to develop inhibitory molecules of the MAP kinase signaling pathways. Several compounds have been identified that inhibit MAP kinase signaling by targeting receptors or other proteins upstream of the MAP kinases. The development of specific inhibitors of the MAP kinases themselves has been less successful and only a few compounds, which interfere with ATP binding, have been identified. A common problem with kinase inhibitors that compete with ATP binding is their lack of specificity. Thus, alternative approaches to inhibit MAP kinase function are being sought. The MAP kinase proteins contain docking domains that direct the interactions with a variety of substrate proteins. Using the 3-dimensional structure of MAP kinases and computer modeling, molecules that target specific docking domains and selectively disrupt substrate interactions are being developed. This non-ATP interfering approach may allow the selective inhibition of MAP kinase substrates involved in disease processes while preserving MAP kinase functions associated with normal cells.

Association of IgA‐anti‐Fab autoantibodies with disease stage in head‐and‐neck cancer

Patients with head-and-neck cancer commonly have immune defects. It was reported that these patients have raised serum IgA levels. We investigated whether IgA-anti-Fab autoantibodies, which occur in association with immune dysfunction, are present in patients with head-and-neck cancer. Sera of 101 patients with squamous-cell carcinoma (SCCHN) and 8 patients with adenoid cystic carcinoma (ACCHN) of the head and neck were tested in ELISA for IgA-anti-Fab autoantibody activity. IgA-anti-Fab serum activity was significantly higher in both SCCHN and ACCHN patients than in healthy controls. In patients with SCCHN, an association between disease stage and IgA-anti-Fab activity was established. Stage-IV patients had significantly higher IgA-anti-Fab than stage-I patients or healthy controls. Stage-II and stage-III patients had intermediate levels. Extremely high IgA-anti-Fab activity was observed in 7 patients who died within 6 months following testing, suggesting a relationship of autoimmunity with terminal disintegration of physiological body functions. IgA-anti-Fab autoantibodies may explain the occurrence of immune defects in patients with head-and-neck cancer.