Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling.

Mitochondrial dysfunction is becoming one of the most emerging pathological process in the etiology of neurological disorders. Other common etiologies of the neurological disorders are aging and oxidative stress. Neurodegenerative disorders for instance Huntington's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Epilepsy, Schizophrenia, Multiple sclerosis, Neuropathic pain and Alzheimer's disease involves mitochondrial dysfunction and is regarded as the core of their pathological processes. Most central pathological feature of the neurodegenerative diseases is apoptosis which is regulated by mitochondria. Altered signaling of the apoptotic mechanisms are involved in neurodegeneration. Abnormal levels of these molecular apoptotic proteins promotes the pathogenesis of neurological disorders. Mitochondria are also implicated in the production of reactive oxygen species (ROS). Raised ROS levels initiates the cascade leading to the non-apoptotic death of cells. ROS produced in cells acts as signaling molecules, but when produced in abundance will result in cellular consequences to deoxyribonucleic acid, proteins and lipids, decreased effectiveness of cellular mechanisms, initiation of inflammatory pathways, excitotoxicity, protein agglomeration and apoptosis. Protecting mitochondrial function has been identified as the most effective therapeutic approach to attenuate the pathogenesis of neurodegenerative diseases. This review aims to provide an insight into the mitochondrial dysfunction in the pathogenesis of neurological disorders, alteration in signaling cascades of apoptosis in mitochondrial dysfunction and the therapeutic strategies (both natural and synthetic drugs) targeting these mitochondrial apoptotic pathways and oxidative stress that holds great promise.

Nutritional status in short daily hemodialysis versus conventional hemodialysis patients in China.

PURPOSE: Malnutrition is the main determinant of mortality and morbidity in maintenance hemodialysis patients. In many countries except for China, it has been reported that short daily hemodialysis (SDHD) could improve nutritional status. We will report here the nutritional results obtained in the SDHD therapy period compared with conventional hemodialysis (cHD) therapy period in Chinese patients. METHODS: This study compared 29 SDHD patients (SDHD group), each patient served as his own control, with 30 cHD patients (cHD group) serving as the parallel controls. The hematologic parameters, anthropometric measurements, modified quantitative subjective global assessment (MQSGA) score, weekly standard Kt/V (std Kt/V) and average daily intake of protein were measured at baseline (SDHD0 or cHD0 period), at 3 months (SDHD1 or cHD1 period) and at 6 months (SDHD2 or cHD2 period). RESULTS: The average daily intake of protein, dry weight, body mass index, mid-arm circumference, mid-arm muscle circumference, serum albumin, prealbumin, cholesterol, hemoglobin, weekly std Kt/V values at SDHD2 were higher than the corresponding values at SDHD0 (p < 0.05, p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.001 and p < 0.001, respectively). Meanwhile, the average daily intake of protein, serum albumin, prealbumin, cholesterol, hemoglobin, weekly std Kt/V values at SDHD2 were higher than the corresponding values at cHD2 (p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.001 and p < 0.001, respectively), whereas the MQSGA score at SDHD2 was lower than the score at SDHD0 and cHD0 (p < 0.05, respectively). CONCLUSIONS: SDHD may improve the nutritional status compared with cHD in Chinese patients undergoing maintenance hemodialysis.

Advanced glycation end­products affect the cytoskeletal structure of rat glomerular endothelial cells via the Ras­related C3 botulinum toxin substrate 1 signaling pathway.

The present study aimed to determine the molecular mechanisms leading to the production of advanced glycation end­products (AGEs) and their effect on the morphology and function of rat glomerular capillary endothelial cells (GECs). Primary rat GECs were treated with AGE­modified human serum albumin (AGE­HSA) and divided into groups according to AGE concentration and treatment time. The structure and distribution of cytoskeletal protein F­actin and the cortical actin binding protein, cortactin, were analyzed using immunofluorescence and confocal microscopy. As the Ras­related C3 botulinum toxin substrate 1 (Rac1) signaling pathway was previously identified to be involved in mediating the contraction of endothelial actin­myosin activity, Rac1 was examined subsequent to treatment of the cells with the Rac1 agonist 2'­O­methyladenosine­3',5'­cyclic monophosphate (O­Me­cAMP) for 1 h using a pull­down assay. Cell permeability was determined by the leakage rate of a fluorescein isothiocyanate fluorescent marker protein. AGE­HSA treatment resulted in alterations in the structure and distribution of F­actin and cortactin in a dose­ and time­dependent manner, while no effect was observed with HSA alone. The effect of AGE on the cytoskeleton was inhibited by the addition of O­Me­cAMP. AGE­HSA significantly reduced the level of Rac1 activity (P<0.05); however, no effect was observed on total protein levels. Furthermore, AGE­HSA treatment led to a significant increase in the permeability of endothelial cells (P<0.01), which was inhibited by O­Me­cAMP (P<0.01). The Rac1 signaling pathway is thus suggested to serve an important function in mediating AGE­induced alterations in GEC morphology and function.

Peritoneal dialysis catheter placement in the right lower quadrant is associated with a lower risk of catheter tip migration: a retrospective single-center study.

PURPOSE: The aim of this study was to investigate the effect of a modified technique for peritoneal dialysis catheter placement in the right lower quadrant with respect to catheter tip migration. METHODS: This retrospective study included 237 patients with end-stage renal disease who underwent implantation of a two-cuff straight-end swan-neck catheter for peritoneal dialysis. Ninety-eight patients received conventional catheter placement in the left quadrant (beside the umbilicus 12-13 cm above the pubic symphysis) with catheter exit site on the left, and 139 patients received modified catheter placement in the right lower quadrant (beside the umbilicus 6-7 cm above the pubic symphysis) with catheter exit site on the right. Dialysate inflow time, dialysate outflow time, ultrafiltration volume, infection, hemorrhage, intestinal obstruction, and catheter tip migration were recorded. RESULTS: There were no significant differences in dialysate inflow time, dialysate outflow time, ultrafiltration volume, infection, hemorrhage, or intestinal obstruction between the conventional and modified groups. Catheter tip migration occurred in 19 (19.3%) of the 98 patients in the conventional group, and in 5 (3.6%) of the 139 patients in the modified group. The frequency of occurrence of catheter tip migration was significantly less in the modified group compared with the conventional group (p < 0.01). In addition, repositioning of the catheter occurred in all five patients with catheter tip migration in the modified group after conservative treatment, whereas 12 patients required surgical repositioning of the catheter in the conventional group. CONCLUSIONS: The modified technique is superior to the conventional technique in reducing catheter tip migration. This technique can be widely performed in the clinic.

The role of short daily hemodialysis in the control of hyperphosphatemia, secondary hyperparathyroidism and anemia.

BACKGROUND: Hyperphosphatemia, secondary hyperparathyroidism (SHPT) and anemia are common secondary complications in hemodialysis patients with end-stage renal disease (ESRD). Compared with conventional hemodialysis (CHD), short daily hemodialysis (sDHD) has been found to be more effective in patients with ESRD. The objective of this study was to determine whether sDHD could improve hyperphosphatemia, SHPT and anemia in patients with ESRD. METHODS: Twenty-seven patients (11 women and 16 men, 46.8 ± 13.4 years old) were switched from CHD to sDHD. All hematologic parameters were measured prior to the switch (baseline), at 3 months after the switch (sDHD(1)) and at 6 months after the switch (sDHD(2)). RESULTS: The serum phosphate decreased from 2.54 ± 0.32 mmol/L at baseline to 2.15 ± 0.36 mmol/L (p < 0.001) at sDHD(1) and 1.97 ± 0.33 mmol/L (p < 0.001) at sDHD(2). Calcium-phosphate product decreased from 5.18 ± 1.24 mmol(2)/L(2) at baseline to 4.20 ± 0.71 mmol(2)/L(2) (p < 0.001) at sDHD(1) and 4.02 ± 0.83 mmol(2)/L(2) (p < 0.001) at sDHD(2). The serum PTH levels decreased from 223.9 ± 124.7 pmol/L at baseline to 196.3 ± 101.3 pmol/L (p < 0.05) at sDHD(2). The hemoglobin concentration increased significantly from CHD to sDHD. However, the requirement for erythropoietin (EPO) dose decreased from 6847.8 ± 1057.3 u/week at baseline to 5869.6 ± 1094.6 u/week (p < 0.05) at sDHD(2). CONCLUSIONS: sDHD may decrease serum phosphate, calcium-phosphate product and PTH, increase hemoglobin levels and decrease exogenous EPO dose requirements compared with CHD in hemodialysis patients.