163 research outputs found

    Obesity Accelerates Leukocyte Telomere Length Shortening in Apparently Healthy Adults: A Meta-Analysis

    Get PDF
    Background: Shorter telomere length is associated with numerous comorbidities. Several studies have investigated the role of obesity in telomere shortening. In the current systematic review and meta-analysis, we summarized the results of studies that evaluated the association between obesity and telomere length. Methods: A systematic search from Scopus, PubMed, Embase, and ProQuest electronic databases up to 19 March 2021 without language restriction was performed and after data extraction and screening, 19 manuscripts were eligible to be included in the final meta-synthesis. Results: The highest category of telomere length was associated with an approximate 0.75 kg/m2 reduction in body mass index (BMI; WMD = −0.75 kg/m2; CI = −1.19, −0.31; p < 0.001; I2 = 99.4%). Moreover, overweight/obese individuals had 0.036 kbp shorter telomere length compared with non-overweight/obese adults (WMD = −0.036; CI = −0.05, −0.02; p = 0.030; I2 = 100%). According to the results of subgroupings, continent, age, and sample size could be possible sources of heterogeneity. Conclusion: From the results, it was clear that obesity was associated with shorter telomere length. Because of the observational design of included studies, the causality inference of results should be done with caution; thus, further longitudinal studies are warranted for better inference of causal association

    Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

    Get PDF
    Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases

    Aptamer-based multiplexed proteomic technology for biomarker discovery

    Get PDF
    Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

    Chemical and photophysiological impact of terrestrially-derived dissolved organic matter on nitrate uptake in the coastal western Arctic

    Get PDF
    The Arctic is warming at a rate nearly twice the global average, leading to thawing permafrost, increased coastal erosion, and enhanced delivery of riverine terrestrially-derived dissolved organic matter (tDOM) to coastal waters. This humic-rich tDOM has the ability to attenuate light required for photosynthesis and stimulate heterotrophic growth by supplying a source of labile organic carbon. Due to tDOM\u27s high carbon to nitrogen (C : N) ratio, additional nitrogen is required for microorganisms to utilize this excess carbon for growth, thus exacerbating competition between autotrophs and heterotrophs for limiting nutrients and potentially reducing primary production. The effect of Arctic tDOM additions on nitrate uptake by two microplankton size fractions in the coastal Chukchi Sea was quantified using 15 N tracer methods. To assess the biogeochemical vs. spectral impacts of tDOM, the uptake incubations were amended with either tDOM or light attenuating films that mimic light absorption by the tDOM. Nitrate uptake and primary production rates in the larger, predominantly phytoplankton, size fraction generally decreased with increasing tDOM additions. The change in light attenuation alone accounted for a similar to 50% reduction in nitrate uptake. Responses in the smaller size fraction varied seasonally with tDOM additions stimulating uptake in spring and suppressing it in summer. The largest variation in summer nitrate uptake can be explained by the shared effect of biogeochemistry and light attenuation. Therefore, large increases in tDOM delivery currently occurring and predicted to increase in the coastal Arctic, could reduce primary production, broadly impact nitrogen and carbon cycling, and affect higher trophic levels

    Hypoxia-inducible factor-2α regulates the expression of TRAIL receptor DR5 in renal cancer cells

    Get PDF
    To understand the role of hypoxia-inducible factor (HIF)-2α in regulating sensitivity of renal cancer cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, we transfected wild-type and mutant von Hippel Lindau (VHL) proteins into TRAIL-sensitive, VHL-negative A498 cells. We find that wild-type VHL, but not the VHL mutants S65W and C162F that do not degrade HIF proteins, cause TRAIL resistance. Knock down of the HIF-2α protein by RNA interference (short hairpin RNA) blocked TRAIL-induced apoptosis, decreased the level of TRAIL receptor (DR5) protein and inhibited the transcription of DR5 messenger RNA. By using luciferase constructs containing the upstream region of the DR5 promoter, we demonstrate that HIF-2α stimulates the transcription of the DR5 gene by activating the upstream region between −448 and −1188. Because HIF-2α is thought to exert its effect on gene transcription by interacting with the Max protein partner of Myc in the Myc/Max dimer, small interfering RNAs to Myc were used to lower the levels of this protein. In multiple renal cancer cell lines decreasing the levels of Myc blocked the ability of HIF-2α to stimulate DR5 transcription. PS-341 (VELCADE, bortezomib), a proteasome inhibitor used to treat human cancer, increases the levels of both HIF-2α and c-Myc and elevates the level of DR5 in renal cancer, sensitizing renal cancer cells to TRAIL therapy. Similarly, increasing HIF-2α in prostate and lung cancer cell lines increased the levels of DR5. Thus, in renal cancer cell lines expressing HIF-2α, this protein plays a role in regulating the levels of the TRAIL receptor DR5

    Small interfering RNA targeting mcl-1 enhances proteasome inhibitor-induced apoptosis in various solid malignant tumors

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Targeting the ubiquitin-proteasome pathway is a promising approach for anticancer strategies. Recently, we found Bik accumulation in cancer cell lines after they were treated with bortezomib. However, recent evidence indicates that proteasome inhibitors may also induce the accumulation of anti-apoptotic Bcl-2 family members. The current study was designed to analyze the levels of several anti-apoptotic members of Bcl-2 family in different human cancer cell lines after they were treated with proteasome inhibitors.</p> <p>Methods</p> <p>Different human cancer cell lines were treated with proteasome inhibitors. Western blot were used to investigate the expression of Mcl-1 and activation of mitochondrial apoptotic signaling. Cell viability was investigated using SRB assay, and induction of apoptosis was measured using flow cytometry.</p> <p>Results</p> <p>We found elevated Mcl-1 level in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human ovarian cancer cell line SKOV3; and human lung cancer cell line H1299, but not in human breast cancer cell line MCF7 after they were treated with bortezomib. This dramatic Mcl-1 accumulation was also observed when cells were treated with other two proteasome inhibitors, MG132 and calpain inhibitor I (ALLN). Moreover, our results showed Mcl-1 accumulation was caused by stabilization of the protein against degradation. Reducing Mcl-1 accumulation by Mcl-1 siRNA reduced Mcl-1 accumulation and enhanced proteasome inhibitor-induced cell death and apoptosis, as evidenced by the increased cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase.</p> <p>Conclusions</p> <p>Our results showed that it was not only Bik but also Mcl-1 accumulation during the treatment of proteasome inhibitors, and combining proteasome inhibitors with Mcl-1 siRNA would enhance the ultimate anticancer effect suggesting this combination might be a more effective strategy for cancer therapy.</p

    Tundra microbial community taxa and traits predict decomposition parameters of stable, old soil organic carbon.

    Get PDF
    The susceptibility of soil organic carbon (SOC) in tundra to microbial decomposition under warmer climate scenarios potentially threatens a massive positive feedback to climate change, but the underlying mechanisms of stable SOC decomposition remain elusive. Herein, Alaskan tundra soils from three depths (a fibric O horizon with litter and course roots, an O horizon with decomposing litter and roots, and a mineral-organic mix, laying just above the permafrost) were incubated. Resulting respiration data were assimilated into a 3-pool model to derive decomposition kinetic parameters for fast, slow, and passive SOC pools. Bacterial, archaeal, and fungal taxa and microbial functional genes were profiled throughout the 3-year incubation. Correlation analyses and a Random Forest approach revealed associations between model parameters and microbial community profiles, taxa, and traits. There were more associations between the microbial community data and the SOC decomposition parameters of slow and passive SOC pools than those of the fast SOC pool. Also, microbial community profiles were better predictors of model parameters in deeper soils, which had higher mineral contents and relatively greater quantities of old SOC than in surface soils. Overall, our analyses revealed the functional potential of microbial communities to decompose tundra SOC through a suite of specialized genes and taxa. These results portray divergent strategies by which microbial communities access SOC pools across varying depths, lending mechanistic insights into the vulnerability of what is considered stable SOC in tundra regions
    corecore