Effects of Citric Acid and l-Carnitine on Physical Fatigue

We examined the effects of citric acid and l-carnitine administration on physical fatigue. In a double-blind, placebo-controlled, 3-way crossover study, 18 healthy volunteers were randomized to oral citric acid (2,700 mg/day), l-carnitine (1,000 mg/day), or placebo for 8 days. The fatigue-inducing physical task consisted of workload trials on a cycle ergometer at fixed workloads for 2 h on 2 occasions. Before the physical load, salivary chromogranin A, measured as a physiological stress marker, was lower in the group given citric acid than in the group given placebo. Also, after the physical load, the subjective feeling of fatigue assessed with a visual analogue scale was lower in the citric acid group than in the placebo group. In contrast, l-carnitine had no effect on chromogranin A or subjective fatigue. These results suggest that citric acid reduces physiological stress and attenuates physical fatigue, whereas l-carnitine does not

Diagnosing metabolic acidosis in chronic kidney disease: importance of blood pH and serum anion gap

Metabolic acidosis is one of the most common complications of chronic kidney disease (CKD). It is associated with the progression of CKD, and many other functional impairments. Until recently, only serum bicarbonate levels have been used to evaluate acid-base changes in patients with reduced kidney function. However, recent emerging evidence suggests that nephrologists should reevaluate the clinical approach for diagnosing metabolic acidosis in patients with CKD based on two perspectives; pH and anion gap. Biochemistry and physiology textbooks clearly indicate that blood pH is the most important acid-base parameter for cellular function. Therefore, it is important to determine if the prognostic impact of hypobicarbonatemia varies according to pH level. A recent cohort study of CKD patients showed that venous pH modified the association between a low bicarbonate level and the progression of CKD. Furthermore, acidosis with a high anion gap has recently been recognized as an important prognostic factor, because veverimer, a nonabsorbable hydrochloride-binding polymer, has been shown to improve kidney function and decrease the anion gap. Acidosis with high anion gap frequently develops in later stages of CKD. Therefore, the anion gap is a time-varying factor and renal function (estimated glomerular filtration rate) is a time-dependent confounder for the anion gap and renal outcomes. Recent analyses using marginal structural models showed that acidosis with a high anion gap was associated with a high risk of CKD. Based on these observations, reconsideration of the clinical approach to diagnosing and treating metabolic acidosis in CKD may be warranted

Identification of oxidative stress-regulated genes in rat aortic smooth muscle cells by suppression subtractive hybridization

AbstractA suppression subtractive hybridization technique was used to identify reactive oxygen species (ROS)-regulated genes in rat vascular smooth muscle cells. Three genes out of 89 clones, identified as fibronectin, p105 coactivator and ECA39, showed increased expression after treatment with H2O2. The mRNA expressions of these three genes were induced in a time- and dose-dependent manner, independent of protein kinase C activation. Immunohistochemical staining showed that the p105 coactivator expression was markedly induced in the neointima of balloon-injured rat carotid arteries. These results suggest that ROS may play an important role in the development of atherosclerosis by regulating the gene expressions we identified in this study

Elevated C-reactive protein associates with early-stage carotid atherosclerosis in young subjects with type 1 diabetes

WSTĘP. Celem badania była ocena wpływu procesu zapalnego o małym nasileniu na wczesną fazę rozwoju zaawansowanej miażdżycy tętnic szyjnych u młodych chorych na cukrzycę typu 1. MATERIAŁ I METODY. U 55 chorych na cukrzycę typu 1 (22 mężczyzn i 33 kobiety, w wieku 22,1 &plusmn; 3,6 lat (&plusmn; SD), z cukrzycą trwającą 14,2 &plusmn; 5,7 lat) oraz u 75 osób bez cukrzycy z tej samej grupy wiekowej (28 mężczyzn i 47 kobiet) wykonano pomiar średniej i maksymalnej grubości kompleksu błony wewnętrznej i środkowej (IMT, intima-media thickness) w tętnicy szyjnej przy użyciu ultrasonograficznej prezentacji B. Stężenie białka C-reaktywnego dużej czułości (hs-CRP, high-sensitive C-reactive protein) oznaczano za pomocą immunonefelometru z zastosowaniem lateksu. WYNIKI. U chorych na cukrzycę typu 1 stężenie hs-CRP (mediana 0,35, zakres 0,05&#8211;1,47 mg/l u chorych na cukrzycę; mediana 0,14, zakres 0,05&#8211;1,44 mg/l u osób bez cukrzycy; p = 0,001) oraz średnia i maksymalna IMT (średnia IMT 0,76 &plusmn; 0,09 vs. 0,72 &plusmn; 0,04 mm, p = 0,003; maksymalna IMT 0,84 &plusmn; 0,11 vs. 0,77 &plusmn; 0,06, p < 0,0001) były wyraźnie większe niż u osób bez cukrzycy. Stężenie hs-CRP wykazywało wyraźną zależność ze średnią i maksymalną IMT u chorych na cukrzycę typu 1 oraz z maksymalną IMT u osób bez cukrzycy. Analiza metodą regresji wielowymiarowej przeprowadzona łącznie dla grupy chorych na cukrzycę oraz osób bez cukrzycy wykazała, że stężenie hs-CRP niezależnie koreluje ze średnią oraz maksymalną IMT (odpowiednio: p = 0,002 i p = 0,023), jak również z rozkurczowym ciśnieniem tętniczym, płcią i czasem trwania cukrzycy. WNIOSKI. Dane uzyskane w badaniu wskazują, że u młodych chorych na cukrzycę typu 1 stężenie hs- -CRP jest podwyższone, co może mieć związek z wczesną fazą rozwoju zaawansowanej miażdżycy tętnic szyjnych.INTRODUCTION. To evaluate whether low-grade inflammation contributes to early-stage advanced carotid atherosclerosis in young subjects with type 1 diabetes. MATERIAL AND METHODS. The mean and maximum (max) intima-media thicknesses (IMT) of the carotid artery were assessed using ultrasound B-mode imaging in 55 patients with type 1 diabetes (22 men and 33 women, aged 22.1 &#177; 3.6 years (&#177; SD), duration of diabetes 14.2 &#177; 5.7 years) and 75 age-matched healthy nondiabetic subjects (28 men and 47 women). High-sensitive C-reactive protein (hs-CRP) levels were measured with a latex-enhanced immunonephelometer. RESULTS. The patients with type 1 diabetes had significantly higher hs-CRP levels (median 0.35, range 0.05&#8211;1.47 mg/l vs. median 0.14, range 0.05&#8211;1.44 mg/l; P = 0.001) as well as significantly higher mean IMT and max IMT than the nondiabetic subjects (mean IMT 0.76 &#177; 0.09 vs. 0.72 &#177; 0.04 mm, P = 0.003; max IMT 0.84 &#177; 0.11 vs. 0.77 &#177; 0.06 mm, P < 0.0001). Hs-CRP levels were significantly correlated with the mean and max IMT of patients with type 1 diabetes and with the max IMT of nondiabetic patients. Multivariate regression analyses for both diabetic and nondiabetic subjects as a single group showed that hs-CRP levels are independently correlated with the mean IMT and max IMT levels (P = 0.002 and P = = 0.023, respectively) as well as with diastolic blood pressure, sex, and duration of diabetes. CONCLUSIONS. Our data indicate that hs-CRP levels are elevated in young patients with type 1 diabetes, possibly corresponding with early-stage advanced carotid atherosclerosis

Hypotonic swelling-induced activation of PKN1 mediates cell survival in cardiac myocytes

Hypotonic cell swelling in the myocardium is induced by pathological conditions, including ischemia-reperfusion, and affects the activities of ion transporters/channels and gene expression. However, the signaling mechanism activated by hypotonic stress (HS) is not fully understood in cardiac myocytes. A specialized protein kinase cascade, consisting of Pkc1 and MAPKs, is activated by HS in yeast. Here, we demonstrate that protein kinase N1 (PKN1), a serine/threonine protein kinase and a homolog of Pkc1, is activated by HS (67% osmolarity) within 5 min and reaches peak activity at 60 min in cardiac myocytes. Activation of PKN1 by HS was accompanied by Thr774 phosphorylation and concomitant activation of PDK1, a potential upstream regulator of PKN1. HS also activated RhoA, thereby increasing interactions between PKN1 and RhoA. PP1 (10−5 M), a selective Src family tyrosine kinase inhibitor, significantly suppressed HS-induced activation of RhoA and PKN1. Constitutively active PKN1 significantly increased the transcriptional activity of Elk1-GAL4, an effect that was inhibited by dominant negative MEK. Overexpression of PKN1 significantly increased ERK phosphorylation, whereas downregulation of PKN1 inhibited HS-induced ERK phosphorylation. Downregulation of PKN1 and inhibition of ERK by U-0126 both significantly inhibited the survival of cardiac myocytes in the presence of HS. These results suggest that a signaling cascade, consisting of Src, RhoA, PKN1, and ERK, is activated by HS, thereby promoting cardiac myocyte survival

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation