Mining the Biomarker Potential of the Urine Peptidome: From Amino Acids Properties to Proteases

Native biofluid peptides offer important information about diseases, holding promise as biomarkers. Particularly, the non-invasive nature of urine sampling, and its high peptide concentration, make urine peptidomics a useful strategy to study the pathogenesis of renal conditions. Moreover, the high number of detectable peptides as well as their specificity set the ground for the expansion of urine peptidomics to the identification of surrogate biomarkers for extra-renal diseases. Peptidomics further allows the prediction of proteases (degradomics), frequently dysregulated in disease, providing a complimentary source of information on disease pathogenesis and biomarkers. Then, what does urine peptidomics tell us so far? In this paper, we appraise the value of urine peptidomics in biomarker research through a comprehensive analysis of all datasets available to date. We have mined > 50 papers, addressing > 30 different conditions, comprising > 4700 unique peptides. Bioinformatic tools were used to reanalyze peptide profiles aiming at identifying disease fingerprints, to uncover hidden disease-specific peptides physicochemical properties and to predict the most active proteases associated with their generation. The molecular patterns found in this study may be further validated in the future as disease biomarker not only for kidney diseases but also for extra-renal conditions, as a step forward towards the implementation of a paradigm of predictive, preventive and personalized (3P) medicine.     

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.     

Interaction between the Renin–Angiotensin System and Enteric Neurotransmission Contributes to Colonic Dysmotility in the TNBS-Induced Model of Colitis

Angiotensin II (Ang II) regulates colon contraction, acting not only directly on smooth muscle but also indirectly, interfering with myenteric neuromodulation mediated by the activation of AT₁ /AT₂ receptors. In this article, we aimed to explore which mediators and cells were involved in Ang II-mediated colonic contraction in the TNBS-induced rat model of colitis. The contractile responses to Ang II were evaluated in distinct regions of the colon of control animals or animals with colitis in the absence and presence of different antagonists/inhibitors. Endogenous levels of Ang II in the colon were assessed by ELISA and the number of AT₁/AT₂ receptors by qPCR. Ang II caused AT₁ receptor-mediated colonic contraction that was markedly decreased along the colons of TNBS-induced rats, consistent with reduced AT₁ mRNA expression. However, the effect mediated by Ang II is much more intricate, involving (in addition to smooth muscle cells and nerve terminals) ICC and EGC, which communicate by releasing ACh and NO in a complex mechanism that changes colitis, unveiling new therapeutic targets.     

RNA-Cleaving DNA Thresholder Controlled by Concentrations of miRNA Cancer Marker

Oligonucleotide gene therapy (OGT) agents suppress specific mRNAs in cells and thus reduce the expression of targeted genes. The ability to unambiguously distinguish cancer from healthy cells can solve the low selectivity problem of OGT agents. Cancer RNA markers are expressed in both healthy and cancer cells with a higher expression level in cancer cells. We have designed a DNA-based construct, named DNA thresholder (DTh) that cleaves targeted RNA only at high concentrations of cancer marker RNA and demonstrates low cleavage activity at low marker concentrations. The RNA-cleaving activity can be adjusted within one order of magnitude of the cancer marker RNA concentration by simply redesigning DTh. Importantly, DTh recognizes cancer marker RNA, while cleaving targeted RNA; this offers a possibility to suppress vital genes exclusively in cancer cells, thus triggering their death. DTh is a prototype of computation-inspired molecular device for controlling gene expression and cancer treatment.     

Anthropometric measurements among four Asian countries in designing sitting and standing workstations

An anthropometric database for sitting and standing dimensions for Malaysian operators was developed based on the measurements from 146 male and 168 female participants (18–45 years old). The anthropometric data were subsequently compared to those from three selected Asian countries, focussing on the sitting and standing posture dimensions. Thirty-six anthropometric dimensions were selected for comparison based on common availability among the four countries. The results indicated that the Indonesians were the tallest (male: 172 cm, female: 159 cm) among the four countries, whereas the Filipinos were the shortest for both male and female (male: 167 cm, female: 153.9 cm). Filipinos and Malaysian data were almost similar and appear to have the smallest values for eye height (male: 155 cm, female: 143 cm) and elbow height (male: 104 cm, female: 96 cm). The knowledge of variations in the population is useful in designing sound workstations and facilities for the betterment of the industrial environment.     

Properties of multilayered sandwich panels with an agglomerated cork core for interior applications in buildings

Four types of sandwich panels with multilayered designs were produced using wood veneer of Aleppo pine as face and inner sheets, and cork agglomerate as core, intended for use in construction as panelling or partition walls in interior applications. These multilayered sandwich panels were characterized regarding static hardness and dimensional stability when facing changes in relative humidity and when subjected to a deformation. The panels showed a considerable increase in dimensional stability and shear strength with the increase of the number of layers. The results suggest that the correct design choice, for example number of inner wood sheets and thickness of cork core layers, allows these sandwich panels to be used as non-structural construction elements such as partition walls.     

Food safety knowledge, attitudes, and behaviors among Puerto Rican caretakers living in Hartford, Connecticut

Household food safety education is needed to minimize the risk of exposure to foodborne pathogens. The Latino population in the United States is growing at a fast rate and has become the largest minority group in this country. However, little research has been done to identify the food safety behavioral risks faced by Puerto Ricans. Ten in-depth household observations and a quantitative survey on food safety knowledge, attitudes, and behaviors (n = 100) were conducted to understand food-handling techniques among Puerto Rican caretakers of young children. This was followed by two focus groups (n = 12) to further characterize food safety knowledge, attitudes, and behaviors and the proper media channels for the delivery of food safety education. Even though 97% of survey participants reported washing their hands with soap and water before preparing foods, only 1 of the 10 participants in the household observations actually did it. About 60% of the household participants washed the cutting boards with soap and water compared with 89% of survey participants who claimed to do it. In the survey, 5% reported to know the meaning of cross-contamination, and 71% (n = 80) to use the same cutting board for meats and vegetables. Overall, 96% of survey participants did not use a thermometer to check if meats were cooked properly and only 10% defrosted their meats in the refrigerator. Statistically significant relationships (P < 0.05) were found between speaking English and knowing the meaning of cross-contamination and how to use a meat thermometer. Employed individuals and those with higher education were also more likely to be familiar with the term pasteurization. These results fully justify the delivery of culturally appropriate food safety education in this community.     

Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.