Cellular dysfunction

Little is known about the molecular mechanisms and complexity converting psychosocial stress into cellular dysfunction in the brain, endocrine, and immune systems. How ordinary and sustained maladapted psychosocial stressors, chronic stress, and an unhealthy lifestyle activate and exert an influence on the biochemistry of the neuro-endocrine-immune axes with implications for future health or disease, is an upcoming innovative research field due to the new and emerging fields of proteomics, metabonomics, and biochip technologies. 

Mutations change the sequence of DNA bases and may thus lead to cellular dysfunction or disease. 

Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general cellular function. Accordingly, the body has evolved a complex set of mechanisms by which calcium and phosphate homeostasis are carefully maintained (Figure 42-1). Approximately 98% of the 1-2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone, the principal reservoir for these minerals. These functions are dynamic, with constant remodeling of bone and ready exchange of bone mineral with that in the extracellular fluid. Bone also serves as the principal structural support for the body and provides the space for hematopoiesis. Thus, abnormalities in bone mineral homeostasis can lead not only to a wide variety of cellular dysfunctions (eg, tetany, coma, muscle weakness) but also to disturbances in structural support of the body (eg, osteoporosis with fractures) and loss of hematopoietic capacity (eg, infantile osteopetrosis). 

An excessive production of ROS induces the so-called oxidative stress and contributes to cellular dysfunctions and death. Oxidative stress is involved in aging process and contributes to the development of several diseases cataract, cardiovascular and degenerative diseases (Parkinson, Alzheimer), cancers, etc. [16]. 

R6. Reichlin, M., Cellular dysfunction induced by penetration of autoantibodies into living cells Cellular damage and dysfunction mediated by antibodies to dsDNA and ribosomal P proteins. J. Autoimmun. 11, 557-561 (1998). 

Bianchi L, Shen Z, Dennis AT, Priori SG, Napolitano C, Ronchetti E, Bryskin R, Schwartz PJ, Brown AM. Cellular dysfunction of LQT5-MinK mutants abnormalities of IKs, IKr and trafficking in long QT syndrome. Hum Mol Genet 1999 8(8) 1499-1507. 

In the early stages of reduced vitamin B12 absorption, the amount of vitamin B12 bound to TCII decreases rapidly (10-21 days) without any decrease in the total serum B12 level. The total vitamin B12 concentration begins to decline only when the saturation of TCII falls below 5%. Reduced saturation of TCII is thus one of the earliest indicators of reduced intake of vitamin B12 and is detectable in advance of clinical disease. This makes holo-TCII particularly valuable for use as a screening test in susceptible populations. Elevated serum and urine concentrations of homocysteine and MMA occur somewhat later and represent early evidence of cellular dysfunction that occurs when body (liver) stores have been greatly depleted. 

It is likely that one or more of these pathological events may promote cellular dysfunction or tissue damage in the LSDs (Table 3). At present, it is uncertain which of the processes that have been identified plays a dominant role. Certain mechanisms may also be cell-type-specific, but this remains to be clarified. 

In conclusion, the data demonstrated that synergistic mechanisms of cellular disruption caused by anticholinesterase agents led to cellular dysfunction and neurodegeneration. It has also been demonstrated that preventing CF-induced neuronal hyperactivity by pretreatment with MEM and atropine blocks pathways associated with oxidative damage in rat brain. The documented abihty of MEM therapy to reduce free radical generation and lipid peroxidation, prevent HEPs and attenuate the morphological injury provides further support for the role of ROS and RNS in anticholinesterase-induced seizures. 

Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hay war d SD, Moran TH, Montell C, Ross CA, Snyder SH, Sawa A (2005) p53 mediates cellular dysfunction and behavioral abnormalities in Huntington s disease. Neuron 47 1—3. 

After the initial binding to the anionic phospholipids of the PTC, the aminoglycoside molecule is quickly transferred to the transmembrane protein megalin and endocytosed [42, 43, 48-50, 52-59, 66-68, 72, 73]. Aminoglycosides enter the PTC on either the apical or basolateral plasma membrane via receptor-mediated endocytosis. and are ultimately sequestered in the same endosomal compartment [68]. In an experiment with LLC-PKl cells. Ford et al. demonstrated that aminoglycosides were internalized equally across the apical and basolateral membranes by receptor-mediated endocytosis. This was followed by colocalization within the lysosomal compartment and similar magnitudes of cellular dysfunction [68]. 

It seems likely that MBP exerts some efiects on epithelial function at much lower concentrations than those required to produce cellular dysfunction and detachment. Over a 24 h exposure period human nasal epithelium showed a 50% u[)-regulation of intercellular adhesion molecule-1 (ICAM-1) expression when exposed to concentrations of MBP within the range 0.1—0.2 ftgmP (Ayars et al., 1991). 

The underlying premise of toxicogenomics is that toxicity is associated with changes in the global gene expression. Since toxicity by itself is resultant due to some form of cellular dysfunction or cell death, it will either be preceded or followed by some level of... 

Wendt T, Tanji N, Guo J, Hudson BI, Bierhaus A, Ramasamy R> et al. Glucose, glycation, and RAGE implications for amplification of cellular dysfunction,... 

If chemical carcinogens or their electrophilic metabolites induce genetic changes which directly or in association with other cellular dysfunctions result in the malignant transformation of normal cells to potential tumor cells, then by the detection of mutagenic activity potential carcinogens could be identified. 

The length of the microtubule cylinder may measure upto 10,000 A, but the diameter is usually 180-250 A. The polymerisation of tubulins to microtubules takes place at 37°C in presence of Mg ions, endogenous cofactors such as GTP and microtubule-associated proteins (MAPs). The depolymerisation of microtubules occurs at temperatures lower than 37°C and in presence of Ca ions. The assembly and disassembly of microtubules proceeds in a nucleated fashion and is associated with a number of cellular functions. The formation of microtubules are required to control various cell activities such as cytoplasmic movement, cell division, cell shape and substrate and vesicle transport etc. Thus, interruption of the microtubulin assembly by a chemotherapeutic agent would result in several cellular dysfunctions leading to death of the parasites. Several drugs are known to bind with tubulin and block its polymerisation into microtubules. This results in gradual disappearance of microtubules from the cells. Consequently cytoplasmic movement and transport of nutrients are disturbed. These abnormal conditions cause death of the cell [59,60]. 

---