Cys34-cysteinylated human serum albumin is a sensitive plasma marker in oxidative stress-related chronic diseases

The degree of oxidized cysteine (Cys) 34 in human serum albumin (HSA), as determined by high performance liquid chromatography (HPLC), is correlated with oxidative stress related pathological conditions. In order to further characterize the oxidation of Cys34-HSA at the molecular level and to develop a suitable analytical method for a rapid and sensitive clinical laboratory analysis, the use of electrospray ionization time-of-flight mass spectrometer (ESI-TOFMS) was evaluated. A marked increase in the cysteinylation of Cys34 occurs in chronic liver and kidney diseases and diabetes mellitus. A significant positive correlation was observed between the Cys-Cys34-HSA fraction of plasma samples obtained from 229 patients, as determined by ESI-TOFMS, and the degree of oxidized Cys34-HSA determined by HPLC. The Cys-Cys34-HSA fraction was significantly increased with the progression of liver cirrhosis, and was reduced by branched chain amino acids (BCAA) treatment. The changes in the Cys-Cys34-HSA fraction were significantly correlated with the alternations of the plasma levels of advanced oxidized protein products, an oxidative stress marker for proteins. The binding ability of endogenous substances (bilirubin and tryptophan) and drugs (warfarin and diazepam) to HSA purified from chronic liver disease patients were significantly suppressed but significantly improved by BCAA supplementation. Interestingly, the changes in this physiological function of HSA in chronic liver disease were correlated with the Cys-Cys34-HSA fraction. In conclusion, ESI-TOFMS is a suitable high throughput method for the rapid and sensitive quantification of Cys-Cys34-HSA in a large number of samples for evaluating oxidative stress related chronic disease progression or in response to a treatment

Cognition in chronic kidney disease: a systematic review and meta-analysis

Background Cognitive impairment is common in people with chronic kidney disease (CKD) and associated with increased morbidity and mortality. Subtle changes can impact engagement with healthcare, comprehension, decision-making, and medication adherence. We aimed to systematically summarise evidence of cognitive changes in CKD. Methods We searched MEDLINE (March 2016) for cross-sectional, cohort or randomised studies that measured cognitive function in people with CKD (PROSPERO, registration number CRD42014015226). The CKD population included people with eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, in any research setting. We conducted a meta-analysis using random effects, expressed as standardised mean differences (SMD) with 95% confidence intervals (CI). Outcomes were performance in eight cognitive domains. Bias was assessed with the Newcastle-Ottawa Scale (NOS). Results We identified 44 studies reporting sufficient data for synthesis (51,575 participants). Mean NOS score for cohort studies was 5.8/9 and for cross-sectional 5.4/10. Studies were deficient in NOS outcome and selection due to poor methods reporting and in comparison group validity of demographics and chronic disease status. CKD patients (eGFR < 60 mL/min/1.73 m2) performed worse than control groups (eGFR ≥ 60 mL/min/1.73 m2) on Orientation & Attention (SMD –0.79, 95% CI, –1.44 to –0.13), Language (SMD –0.63, 95% CI, –0.85 to –0.41), Concept Formation & Reasoning (SMD –0.63, 95% CI, –1.07 to –0.18), Executive Function (SMD –0.53, 95% CI, –0.85 to –0.21), Memory (SMD –0.48, 95% CI, –0.79 to –0.18), and Global Cognition (SMD –0.48, 95% CI, –0.72 to –0.24). Construction & Motor Praxis and Perception were unaffected (SMD –0.29, 95% CI, –0.90 to 0.32; SMD –1.12, 95% CI, –4.35 to 2.12). Language scores dropped with eGFR (<45 mL/min/1.73 m2 SMD –0.86, 95% CI, –1.25 to –46; 30 mL/min/1.73 m2 SMD –1.56, 95% CI, –2.27 to –0.84). Differences in Orientation & Attention were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.62, 95% CI, –4.68 to –4.55). Concept Formation & Reasoning differences were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.27, 95% CI, –4.23 to –4.27). Differences in Executive Functions were greatest at eGFR < 30 mL/min/1.73 m2 (SMD –0.54, 95% CI, –1.00 to –0.08). Conclusions Cognitive changes occur early in CKD, and skills decline at different rates. Orientation & Attention and Language are particularly affected. The cognitive impact of CKD is likely to diminish patients’ capacity to engage with healthcare decisions. An individual’s cognitive trajectory may deviate from average

Association between asymptomatic hyperuricemia and new-onset chronic kidney disease in Japanese male workers: a long-term retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Hyperuricemia is prevalent in patients with chronic kidney disease (CKD). We explored the hypothesis that asymptmatic hyperuricemia may be associated with new-onset CKD.</p> <p>Methods</p> <p>The participants were all male factory workers in Kanagawa, Japan (n = 1,285). All were over 40 years of age and had undergone annual health examinations from 1990 to 2007. Individuals with a history of gouty attacks were excluded from the study. A retrospective cohort study was conducted by following the estimated glomerular filtration rate (eGFR) for each participant over a maximum period of 18 years. The endpoint was new-onset CKD defined as eGFR < 60 mL/min/1.73 m². The associations between new-onset CKD and the presence of hyperuricemia, low serum high-density lipoprotein cholesterol, hypertension, diabetes, and obesity were analyzed.</p> <p>Results</p> <p>The mean (± standard deviation) follow-up period was 95.2 (± 66.7) months, and new-onset CKD was observed in 100 participants (7.8%) during this follow-up. Cox proportional hazards model revealed that the hazard ratio of new-onset CKD due to hyperuricemia, low serum high-density lipoprotein cholesterol, hypertension and obesity were 3.99 (95% confidence interval: 2.59-6.15), 1.69 (1.00-2.86), 2.00 (1.29-3.11) and 1.35 (0.87-2.10), respectively. Concerning hyperuricemia, low serum high-density lipoprotein cholesterol, hypertension and obesity, the log-rank tests showed <it>P </it>values of < 0.01, 0.01, < 0.01 and < 0.01, respectively.</p> <p>Conclusion</p> <p>The results of this study suggest that asymptomatic hyperuricemia is a predictive factor for new-onset CKD for Japanese male workers.</p

Oxidative Stress and Inflammation in Renal Patients and Healthy Subjects

The first goal of this study was to measure the oxidative stress (OS) and relate it to lipoprotein variables in 35 renal patients before dialysis (CKD), 37 on hemodialysis (HD) and 63 healthy subjects. The method for OS was based on the ratio of cholesteryl esters (CE) containing C18/C16 fatty acids (R2) measured by gas chromatography (GC) which is a simple, direct, rapid and reliable procedure. The second goal was to investigate and identify a triacylglycerol peak on GC, referred to as TG48 (48 represents the sum of the three fatty acids carbon chain lengths) which was markedly increased in renal patients compared to healthy controls. We measured TG48 in patients and controls. Mass spectrometry (MS) and MS twice in tandem were used to analyze the fatty acid composition of TG48. MS showed that TG48 was abundant in saturated fatty acids (SFAs) that were known for their pro-inflammatory property. TG48 was significantly and inversely correlated with OS. Renal patients were characterized by higher OS and inflammation than healthy subjects. Inflammation correlated strongly with TG, VLDL-cholesterol, apolipoprotein (apo) C-III and apoC-III bound to apoB-containing lipoproteins, but not with either total cholesterol or LDL-cholesterol

PDZ domains and their binding partners: structure, specificity, and modification

PDZ domains are abundant protein interaction modules that often recognize short amino acid motifs at the C-termini of target proteins. They regulate multiple biological processes such as transport, ion channel signaling, and other signal transduction systems. This review discusses the structural characterization of PDZ domains and the use of recently emerging technologies such as proteomic arrays and peptide libraries to study the binding properties of PDZ-mediated interactions. Regulatory mechanisms responsible for PDZ-mediated interactions, such as phosphorylation in the PDZ ligands or PDZ domains, are also discussed. A better understanding of PDZ protein-protein interaction networks and regulatory mechanisms will improve our knowledge of many cellular and biological processes

Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni, Vidi, Vici!!

Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the “code of conduct” of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens