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Hypertension and cardiovascular disorders: The biological effects of nitric oxide (NO) are in large part mediated by S-nitrosylation of peptides and proteins to produce bioactive S-nitrosothiols (SNOs).44-46 The observation of abnormal SNO levels in numerous pathophysiological states45 suggests that dysregulation of SNO homeostasis may contribute to disease pathogenesis. For example, the hypotension of human sepsis is accompanied by increases in circulating levels of vasodilatory SNOs.46 Gandley et al47 has shown that the buffering function of SNO-albumin is impaired in preeclamptic patients, where the thiol of albumin acts as a sink for NO and thus, raises blood pressure. Gandley et al extend this paradigm by proposing that a defect in SNO turnover contributes to the hypertension of preeclampsia. In the blood, S-nitrosoalbumin (SNO-albumin) and Snitrosohemoglobin (SNO-Hb) constitute the major conduits for circulating NO bioactivity. Although both SNOs may influence blood pressure, they operate within distinct signaling circuits. SNO-Hb can be viewed as a principal regulator of SNO homeostasis, adaptively modulating NO chemistry to control NO bioactivity. In contrast, it appears that rather than transducing a specific signal, albumin operates as a buffer to maintain NO homeostasis.48 S-nitrosylation of albumin occurs at Cys-34 via reactions—with NO or nitrosothiols—that are favored by design: specifically, both hydrophobic pockets in albumin (NO/O2 coupling) and bound copper (NO/metal redox coupling) may serve to generate nitrosylating species.49-51 Gandley et al47 make the case that the buffering function of SNO-albumin is impaired in preeclamptic patients, where the thiol of albumin acts as a sink for NO and thus, raises blood pressure. Redistribution of NO, from the tissues into the hydrophobic core of the protein, subserves S-nitrosylation and lowers the steadystate level of vasodilatory NO within the vascular smooth muscle.50 Accumulating evidence strongly suggests a role of SNOalbumin in mitigating cardiovascular risk. In women with preeclampsia, homocysteine and cysteine levels, which are lowered in normotensive pregnancy, were comparable to levels in nonpregnant women, whereas glutathione levels were lower. Those results suggest that in women with preeclampsia, glutathione use is higher or its synthesis is disturbed. Therefore, glutathione might affect pathophysiology of preeclampsia.52 Zhang et al53 demonstrate regulation by a mitochondria-specific thioredoxin, which reduces oxidative stress and increases NO bioavailability, thus preserving vascular endothelial cell function and preventing atherosclerosis development. It has been shown that LDL oxidation by L-cysteine and Cu2/ requires superoxide bu t not hydrogen peroxide or hydroxyl radical. The reaction may involve the metal ion-dependent formation of L-cystine radical anion which is oxidized by oxygen yielding superoxide and the disulfide. LDL modified by L-cysteine and smooth muscle cells exhibited similar physical and biological properties, indicating that thiol-dependent superoxide generation may be the oxidative mechanism in both the systems. Thiols also promote superoxide independent lipid peroxidation but human macrophages fail to rapidly degrade these oxidized LDLs.54 In Kidney Diseases Presence of oxidative stress in renal failure is well proved and the several studies have shown decreased levels of thiol status in chronic renal failure (CRF).55-57 Increased presence of ROS generated in these patients are believed to consume the available thiol groups. Studies have also shown negative correlation of serum creatinine with the protein thiols,57 indicating increased protein SH consumption with increase in severity of renal failure.58 Albumin provides the bulk of the total serum thiols 56,59 and loss of albumin in the urine of CRF patients, logically, should increase thiol groups in urine. Contrary to this, a study has shown significantly low levels of urinary protein thiols.59 The authors have also shown significant decrease in serum albumin and protein-bound thiol groups in CRF patients. These findings suggest that the albumin excreted in the urine is deficient in thiol groups. The decrease in protein thiols in the urine of CRF patients could be because of increased oxidation of albumin-bound thiol groups in the serum.56,59 Excretion of such albumin, deficient in the reduced form of thiol groups, in the urine decreased the levels of protein bound thiols in urine. There occurs a significant decrease in urinary thiols in patients with proteinuria and it varies with the amount of protein excreted in urine.60 There was also a significant decrease in plasma protein thiol levels in pediatric nephrotic syndrome.61 primary glomerular diseases62, moderate to severe chronic kidney disease63, end stage renal disease64, systemic lupus erythematosus (SLE) with and without nephritis65. It was seen that when the sodium consumption was increased, the serum protein thiols were found to be decreased.66 Gastro Intestinal Diseases: Oxidative stress gets exacerbated by pro-oxidants such as various drugs including alcohol. Ingested alcohol besides producing striking metabolic imbalances in the liver, also leads to the formation of reactive oxygen species (ROS). The levels of serum protein thiols were found to be decreased in alcohol abusers.67,68 Synthesis of glutathione and cysteine mainly occurs in hepatocytes, whereas most other tissues are supplied with these thiols via sinusoidal efflux into the blood. Since canalicular efflux also occurs, thiols may be present in human bile. However, thiol composition of human gallbladder bile is largely unknown, which makes it difficult to speculate on the exact function of thiols in bile.69 Variation in non protein thiol levels was found in human gall bladder bile of patients with most of the thiols in their oxidized forms84 which may indicate the presence of considerable chemical or oxidative stress.70 Also, inflammatory and oxidative events have remarkable importance in bladder cancer. Patients with bladder cancer were found to have significantly lower levels of total thiols and protein bound thiol groups, the levels were much lower in invasive type.71 Therefore, thiols are present in considerable amounts in human gallbladder bile of patients with various gastrointestinal disorders, with most of the thiols in their oxidised forms, which may indicate the presence of considerable chemical or oxidative stress in the patients. Previous studies have also suggested that Helicobacter pylori (H. pylori) infection may play an important role in the process of atherosclerosis. Serum -SH levels were significantly lower in H. pylori positive group than H. pylori negative group. Diabetes mellitus and other disease conditions: Free radical mediated oxidative stress has been implicated in the pathogenesis of diabetes mellitus (DM) and its complications.73 Serum protein thiols have been found to be decreased in both types of diabetes mellitus. These decreases were partially explained by metabolic-, inflammatory- and iron alterations.74 Serum protein thiols have been found to be decreased in patients with complications of type 2 diabetes mellitus.75 There have been s on decreased plasma thiol levels in diabetic patients recently.76 Significant decrease in P-SH levels in diabetic hemodialysis (DHD) patients compared with the level in healthy participants and DM patients. While there was no significant difference in the whole blood GSH levels between the DM patients and controls, It was significantly higher in DHD patients in comparison to the DM patients. The low PSH level in DHD patients, but not in DM patients, suggests that dialysis is responsible for this decrease.77 A significant increase in free iron in Fe/3 state with a decrease in protein thiols has been shown in diabetic cases under poor glycemic control.78 The finding that thiols as facile targets of glycation and low molecular mass thiols as potent glycation inhibitors, may aid the design of therapeutic agents for the treatment of the complications of diabetes.79 Elevated glucose levels can induce oxidative stress in gestational diabetes (GDM) mothers. This may be due to the increased oxidative stress prevalent in GDM.80-83 A significant increase in the erythrocytic GSH and protein thiols in GDM maternal blood when compared to controls have been observed. Cord blood levels of protein thiols were also significantly increased in GDM84 This may be in response to the milieu of increased oxidative stress in case of GDM cord blood and oxidative stress in the fetus induced by GDM.83 Human amylin (hA) is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type-2 diabetes mellitus. There is growing evidence that hA toxicity towards islet b-cells is responsible for their gradual loss of function in type-2 diabetes mellitus. Preventing hA-mediated cytotoxicity has been proposed as a route to halt the progression of this disease, although this has not yet been demonstrated in vivo. The thiol antioxidants, N-acetyl-L-cysteine (NAC), GSH and dithiothreitol, which not only react with ROS, but also modulate the cellular redox potential by increasing intracellular levels of GSH and ⁄ or by acting as thiol reducing agents, afford almost complete protection and inhibit the progression of hA-evoked apoptosis. These results indicate that, in addition to the induction of oxidative stress, hA appears to mediate cytotoxicity through signalling pathways that are sensitive to the actions of thiol antioxidants.85 Other disorders: A significant fall in plasma protein thiols have also been observed after the assisted reproduction procedures like intrauterine insemination, indicating increased oxidative stress after the procedure.86 Oxidative stress has been implicated in the degeneration of dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD) patients. An important biochemical feature of presymptomatic PD is a significant depletion of the thiol antioxidant glutathione (GSH) in these neurons resulting in oxidative stress, mitochondrial dysfunction, and ultimately cell death.87 In schizophrenic patients, the amount of homocysteine in plasma was higher compared and the level of GSH, C-SH and CG-SH was decreased. This indicates that ROS and RNS may stimulate oxidative/nitrative modifications of plasma proteins in schizophrenic patients.88,89 In apoptosis, generation of oxidative stress, leads to perturbation of protein thiols.90()，英语论文题目，英语毕业论文 |
