The Quest for Renal Disease Proteomic Signatures: Where Should We Look?

Renal diseases are prevalent and important. However, despite significant strides in medicine, clinical nephrology still relies on nonspecific and inadequate markers such as serum creatinine and total urine protein for monitoring and diagnosis of renal disease. In case of glomerular renal diseases, biopsy is often necessary to establish the diagnosis. With new developments in proteomics technology, numerous studies have emerged, searching for better markers of kidney disease diagnosis and/or prognosis. Blood, urine, and renal biopsy tissue have been explored as potential sources of biomarkers. Some interesting individual or multiparametric biomarkers have been found; however, none have yet been validated or entered clinical practice. This review focuses on some studies of biomarkers of glomerular renal diseases, as well as addresses the question of which sample type(s) might be most promising in preliminary discovery phases of candidate proteins.     

Neuroprotective Effect of Natural Products Against Alzheimer’s Disease

Nature has gifted mankind with a plethora of flora-bearing fruits, vegetables and nuts. The diverse array of bioactive nutrients present in these natural products plays a pivotal role in prevention and cure of various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease and other neuronal dysfunctions. Accumulated evidence suggests that naturally occurring phyto-compounds, such as polyphenolic antioxidants found in fruits, vegetables, herbs and nuts, may potentially hinder neurodegeneration, and improve memory and cognitive function. Nuts such as walnut have also demonstrated neuroprotective effect against AD. The molecular mechanisms behind the curative effects rely mainly on the action of phytonutrients on distinct signalling pathways associated with protein folding and neuroinflammation. The neuroprotective effects of various naturally occurring compounds in AD is evaluating in this review.     

Quantitative Proteomic Analysis of Human Substantia Nigra in Alzheimer’s Disease, Huntington’s Disease and Multiple Sclerosis

The substantia nigra plays important roles in the brain function and is critical in the development of many diseases, particularly Parkinson??s disease. Pathological changes of the substantia nigra have also been reported in other neurodegenerative diseases. Using a quantitative proteomic approach, we investigated protein expressions in the substantia nigra of Alzheimer??s disease, Huntington??s disease, and Multiple sclerosis. The expression level of one hundred and four proteins that were identified in at least three samples of each group were compared with the control group, with nineteen, twenty-two and thirteen proteins differentially expressed in Alzheimer??s diseases, Huntington??s disease and Multiple sclerosis respectively. The result indicates that the substantia nigra also undergoes functional adaption or damage in these diseases.     

Environmental Occurrence of the Whipple’s Disease Bacterium (Tropheryma whippelii)

Whipple’s disease is a systemic disorder in which a gram-positive rod-shaped bacterium is constantly present in infected tissues. After numerous unsuccessful attempts to culture this bacterium, it was eventually characterized by 16S rRNA gene analysis to be a member of the actinomycetes. The name Tropheryma whippelii was proposed. Until now, the bacterium has only been found in infected human tissues, but there is no evidence for human-to-human transmission. Here we report the detection of DNA specific for the Whipple’s disease bacterium in 25 of 38 wastewater samples from five different sewage treatment plants in the area of Heidelberg, Germany. These findings provide the first evidence that T. whippelii occurs in the environment, within a polymicrobial community. This is in accordance with the phylogenetic relationship of this bacterium as well as with known epidemiological aspects of Whipple’s disease. Our data argue for an environmental source for infection with the Whipple’s disease bacterium.Whipple’s disease, which was first described in 1907 as intestinal lipodystrophy (18), is a multisystem disorder characterized by the presence of gram-positive, rod-shaped bacteria in infected human tissues (2). Numerous attempts to culture the bacterium associated with Whipple’s disease have failed (2), and eventually its phylogenetic position within the actinomycetes was established by 16S rRNA gene analysis (11, 19). The name Tropheryma whippelii was proposed (11).The clinical presentation of Whipple’s disease is heterogeneous. Frequently, patients suffer for years from arthralgias, chronic diarrhea, and weight loss, and less often from dementia or cardiac insufficiency. If untreated, the disease is usually fatal, but with appropriate antibiotic therapy the prognosis is favorable (2). However, the pathogenesis of Whipple’s disease appears to involve more than just an infection with T. whippelii. Immunological abnormalities are presumed to play a necessary role as predisposing factors (2, 7, 8), a view which is strengthened by the detection of T. whippelii in association with AIDS (5).Two outstanding questions in the epidemiology of Whipple’s disease are the bacterium’s natural habitat and the route of infection. Until now, T. whippelii has never been found outside of infected human hosts, and although an oral route of infection has often been suspected (10), it has not been proven. There is no evidence for human-to-human transmission.A reassessment of its phylogeny revealed a close relationship of the Whipple’s disease bacterium to typical environmental bacteria, such as the cellulomonads and the rare group B peptidoglycan organisms (6). This would support the hypothesis that T. whippelii may be a soil or water inhabitant. This may also explain the difficulties involved with its culture, as an estimated 80 to 99% of bacteria occurring in such natural environments are not culturable on artificial media (14, 17) and uncultured members of the actinomycete line of descent have been found in different environments and geographical locations (12). Soil and water bacteria tend to concentrate in sewage to form communities in which a large variety of different species are found. Therefore, the search for the Whipple’s disease bacterium was concentrated at sewage treatment plants.From September 1995 to July 1996, a total of 38 effluent samples from the sedimentation ponds of five different sewage treatment plants were examined by PCR for the presence of the Whipple’s disease bacterium. The sewage treatment plants are located within a distance of 5 to 25 km from Heidelberg, Germany (Fig. ​(Fig.1).1). Effluent was sampled in 1,000-ml single-use plastic flasks and filtered as described previously (4) in portions of 25 ml through cellulose acetate prefilters (25-mm diameter, 5-μm pore size; Sartorius, Göttingen, Germany). It was then passed through polyvinylidene fluoride filters (25-mm diameter, 0.45-μm pore size; Millipore, Bedford, Mass.). The DNA from the 0.45-μm-pore-size filters was extracted with the EnviroAmp Legionella sample preparation kit (Perkin-Elmer, Norwalk, Conn.), with the addition of 0.2% bovine serum albumin to the water in the final extraction step. Distilled water for negative controls was sampled in the same flasks and treated in the same way as the sewage. Open in a separate windowFIG. 1Map of the area around Heidelberg, Germany, displaying the rivers Rhine (Rhein) and Neckar, the relevant townships (shaded areas with names in capital letters), and the five sewage treatment plants (dots) from which samples were taken. The inset in the figure shows the localization of the area within Germany.PCR amplification and detection were performed as described in detail elsewhere (15). Primers whip1 (5′-AGAGATACGCCCCCCGCAA) and whip2 (5′-ATTCGCTCCACCTTGCGA), which amplify a fragment of 267 bp from the 16S rRNA gene of the bacterium, were used. In addition to hybridization with oligonucleotide whip3 (5′-TGGTACAGAGGGTTGCAATA), a second hybridization in a separate reaction was performed with oligonucleotide whip4 (5′-GTAATGGCGGGGACTCACAG). The specificities of primers whip1 and whip2 and of probe whip3 have been tested previously (15), and testing of probe whip4 with the same set of 37 control bacteria gave the same results as those reported for whip3 (15).Of the 38 sewage samples tested, 25 were found to be positive by PCR and hybridization with both oligonucleotides (Table ​(Table1).1). Positive samples were found at each of the five sewage treatment plants. Most of the positive PCR products displayed relatively weak bands at the expected size of 267 bp. They also contained some extraneous bands, which were not of the expected size, probably due to the large amount of DNA from other organisms present in sewage. On hybridization, however, the PCR products displayed distinct bands, which were consistent between the two oligonucleotides (Fig. ​(Fig.2).2).

TABLE 1

Results of PCR for the Whipple’s disease bacterium from sewage samples

Metabolomics and In-Silico Analysis Reveal Critical Energy Deregulations in Animal Models of Parkinson’s Disease

Parkinson’s disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a complex I blocker. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level.     

Rate of Primary Refractory Disease in B and T-Cell Non-Hodgkin’s Lymphoma: Correlation with Long-Term Survival

Background

Primary refractory disease is a main challenge in the management of non-Hodgkin’s Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients.

Methods

Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months.

Results

Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001).

Conclusion

Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.     

Icariin: A Potential Neuroprotective Agent in Alzheimer’s Disease and Parkinson’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

     

An Exploratory Study of Domestic Violence: Perpetrators’ Reports of Violence Against Animals

The goal of the current exploratory study was to examine associations between animal cruelty (AC), intimate partner violence (IPV), and antisocial personality disorder (ASPD) among incarcerated adult males. Forty-two men incarcerated in a state prison participated in the study; all participants were incarcerated for IPV and/or admitted to committing IPV in a past relationship. They completed measures on childhood animal cruelty (CAC), lifetime prevalence of AC, and IPV. It was hypothesized that men with ASPD diagnoses would report greater exposure to, and perpetration of, AC, as well as more severe IPV behaviors. It was also expected that lifetime exposure to, and perpetration of, AC would be associated with greater animal abuse in the context of IPV. Lastly, it was hypothesized that participants who reported exposure to, and perpetration of, AC would also report higher rates of IPV behaviors. Rates of animal cruelty were high in this sample. Approximately 36% of participants endorsed CAC, 81% reported animal cruelty perpetration in their lifetime, 85.7% reported being exposed to animal cruelty during their lifetime, 38% endorsed using threats against animals during a relationship conflict, and 52% reported abusing and/or killing a pet during a relationship conflict. CAC was significantly related to increased use of psychological abuse and sexual coercion in the context of intimate relationships. ASPD was not related to animal cruelty in the context of IPV. CAC was significantly associated with both threats to, and actual perpetration of, animal abuse during relationship conflicts. The limitations and implications of our findings are discussed in relation to future research.     

Proteomic approach to studying parkinson’s disease

Parkinson’s disease is a common age-related neurodegenerative disease characterized pathologically by a loss of dopaminergic neurons in the substantia nigra with resultant depletion of striatal dopamine and presence of Lewy bodies in the remaining neurons. The Lewy body contains numerous functional and structural proteins, including α-synuclein and ubiquitin; aggregation of α-synuclein is thought to be important in Lewy body formation as well as neurodegeneration, although the detailed mechanisms remain to be defined. Increasing evidence has suggested that mitochondrial dysfunction, increased oxidative stress, and dysfunction of the ubiquitin-proteasome system may be involved in α-synuclein aggregation, Lewy body formation, and neurodegeneration. However, how these processes are related to each other is not fully understood, given that there are Parkinsonian animal models as well as human diseases with significant nigral neurodegeneration regardless of whether Lewy bodies form or not. This review summarizes the current related research fields and proposes a proteomic approach to investigate the mechanisms that may dictate α-synuclein aggregation, Lewy body formation, and neurodegeneration.     

Natural Antioxidants Protect Neurons in Alzheimer’s Disease and Parkinson’s Disease

“Modern” medicine and pharmacology require an effective medical drug with a single compound for a specific disease. This seams very scientific but usually has unavoidable side effects. For example, the chemical therapy to cancer can totally damage the immunological ability of the patient leading to death early than non-treatment. On the other hand, natural antioxidant drugs not only can cure the disease but also can enhance the immunological ability of the patient leading to healthier though they usually have several compounds or a mixture. For the degenerative disease such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), natural antioxidant drugs are suitable drugs, because the pathogenesis of these diseases is complex with many targets and pathways. These effects are more evidence when the clinic trial is for long term treatment. The author reviews the studies on the protecting effects of natural antioxidants on neurons in neurodegenerative diseases, especially summarized the results about protective effect of green tea polyphenols on neurons against apoptosis of cellular and animal PD models, and of genestine and nicotine on neurons against Aβ—induced apoptosis of hippocampal neuronal and transgenic mouse AD models. Special issue in honor of Dr. Akitane Mori.     

Alzheimer’s Disease: Analyzing the Missing Heritability

Alzheimer’s disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to analyze >2 million SNPs for 10,922 individuals from the Alzheimer’s Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer’s Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer’s disease.     

Battling Alzheimer’s Disease: Targeting SUMOylation-Mediated Pathways

SUMO (small ubiquitin-like modifier) conjugation is a critically important control process in all eukaryotic cells, because it acts as a biochemical switch and regulates the function of hundreds of proteins in many different pathways. Although the diverse functional consequences and molecular targets of SUMOylation remain largely unknown, SUMOylation is becoming increasingly implicated in the pathophysiology of Alzheimer’s disease (AD). Apart from the central SUMO-modified disease-associated proteins, such as amyloid precursor protein, amyloid β, and tau, SUMOylation also regulates several other processes underlying AD. These are involved in inflammation, mitochondrial dynamics, synaptic transmission and plasticity, as well as in protective responses to cell stress. Herein, we review current reports on the involvement of SUMOylation in AD, and present an overview of potential SUMO targets and pathways underlying AD pathogenesis.     

Dopaminergic Axons: Key Recitalists in Parkinson’s Disease

Neurochemical Research - Parkinson's disease (PD) is associated with dopamine depletion in the striatum owing to the selective and progressive loss of the nigrostriatal dopaminergic neurons,...     

Alzheimer’s Disease and Cholesterol: The Fat Connection

Since the discovery of the significance of the cholesterol-carrying apolipoprotein E and cholesterolaemia as major risk factors for Alzheimer's Disease (AD) there has been a mounting interest in the role of this lipid as a possible pathogenic agent. In this review we analyse the current evidence linking cholesterol metabolism and regulation in the CNS with the known mechanisms underlying the development of Alzheimer's Disease. Cholesterol is known to affect amyloid-beta generation and toxicity, although it must be considered that the results studies using the statin class of drugs to lower plasma cholesterol may be affected by other effects associated with these drugs. Finally, we report some of our results pointing at the interplay between neurons and astrocytes and NADPH oxidase activation as a new candidate mechanism linking cholesterol and AD pathology.     

Daytime Sleepiness in Parkinson’s Disease: A Reappraisal

Background

Excessive daytime sleepiness is a frequent complaint in Parkinson’s disease (PD); however the frequency and risk factors for objective sleepiness remain mostly unknown. We investigated both the frequency and determinants of self-reported and objective daytime sleepiness in patients with Parkinson’s disease (PD) using a wide range of potential predictors.

Methods

One hundred and thirty four consecutive patients with PD, without selection bias for sleep complaint, underwent a semi-structured clinical interview and a one night polysomnography followed by a multiple sleep latency test (MSLT). Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behaviour disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness.

Results

Of 134 patients with PD, 46.3% had subjective and only 13.4% had objective sleepiness with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness, and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behaviour disorder and nighttime sleep evaluation.

Conclusion

We found a high frequency of self-reported EDS in PD, a finding which is however not confirmed by the gold standard neurophysiological evaluation. Current treatment options for EDS in PD are very limited; it thus remains to be determined whether decreasing pain and BMI in association with the treatment of sleep apnea syndrome would decrease significantly daytime sleepiness in PD.