29/Mar/2022

Nuclear receptors in renal health and disease

As a major social and economic burden for the healthcare system, kidney diseases contribute to the constant increase of worldwide deaths. A deeper understanding of the underlying mechanisms governing the etiology, development and progression of kidney diseases may help to identify potential therapeutic targets. As a superfamily of ligand-dependent transcription factors, nuclear receptors (NRs) are critical for the maintenance of normal renal function and their dysfunction is associated with a variety of kidney diseases. Increasing evidence suggests that ligands for NRs protect patients from renal ischemia/reperfusion (I/R) injury, drug-induced acute kidney injury (AKI), diabetic nephropathy (DN), renal fibrosis and kidney cancers. In the past decade, some breakthroughs have been made for the translation of NR ligands into clinical use. This review summarizes the current understanding of several important NRs in renal physiology and pathophysiology and discusses recent findings and applications of NR ligands in the management of kidney diseases.

Zhi-Lin Luan, Cong Zhang, Wen-Hua Min, Ying-Zhi Huang, You-Fei Guan, Xiao-Yan Zhang

Susana Ferreira

22/Mar/2022

Alzheimer’s disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus

BACKGROUND
Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored.

METHODS
In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3).

FINDINGS
We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, β- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments.

INTERPRETATION
We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact.

Jung-Hyun Lee, Christian Ostalecki, Timo Oberstein, Stefan Schierer, Elisabeth Zinser, Martin Eberhardt, et al.

Alzheimer’s disease

Joel Pedrosa

15/Mar/2022

THE (REAL) IMPACT OF RESEARCH ON THE PLANET

Although there is a general idea that the areas of Research are different, what is truly learned after years of research career is that, in fact, they are complementary. Despite the distinct characteristics they present, they all interconnect. For example, for several decades now, the field of Chemistry and Molecular Biology has been working side by side in the discovery of innovative treatments for numerous diseases that plague the human being. For example, in Molecular Biology many studies seek to find new ways to combat diseases such as cancer, which can be specifically focused on eliminating or at least preventing the rapid growth and spread that characterizes it. Considering this line of thought, a “symbiosis” was created with the area of Chemistry, where compounds that have characteristics that can act in these same pathways are (and were) developed and subsequently tested. In fact, many of the treatments that are commonly used in chemotherapy today resulted from this “symbiosis”. And this is just a small example of all the applications and efforts that researchers make daily with the same common goal: to promote and improve the sustainability of the lives of all beings on our planet. From studies of marine life and the impact of different components on their environment to the study of different pathways and mechanisms to control and eliminate the spread of cancer cells in humans, any researcher devotes their intelligence, resilience, and cunning to meeting this goal.

Joel Pedrosa

QA analyst, BIOLEGO

New Breathe – services

Susana Ferreira

08/Mar/2022

Integrative analysis from multi-center studies identities a consensus machine learning-derived lncRNA signature for stage II/III colorectal cancer

BACKGROUND
Long non-coding RNAs (lncRNAs) have recently emerged as essential biomarkers of cancer progression. However, studies are limited regarding lncRNAs correlated with recurrence and fluorouracil-based adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC).

METHODS
1640 stage II/III CRC patients were enrolled from 15 independent datasets and a clinical in-house cohort. 10 prevalent machine learning algorithms were collected and then combined into 76 combinations. 109 published transcriptome signatures were also retrieved. qRT-PCR assay was performed to verify our model.

FINDINGS
We comprehensively identified 27 stably recurrence-related lncRNAs from multi-center cohorts. According to these lncRNAs, a consensus machine learning-derived lncRNA signature (CMDLncS) that exhibited best power for predicting recurrence risk was determined from 76 kinds of algorithm combinations. A high CMDLncS indicated unfavorable recurrence and mortality rates. CMDLncS not only could work independently of common clinical traits (e.g., AJCC stage) and molecular features (e.g., microsatellite state, KRAS mutation), but also presented dramatically better performance than these variables. qRT-PCR results from 173 patients further verified our in-silico findings and assessed its feasible in different centers. Comparisons of CMDLncS with 109 published transcriptome signatures further demonstrated its predictive superiority. Additionally, patients with high CMDLncS benefited more from fluorouracil-based ACT and were characterized by activation of stromal and epithelial-mesenchymal transition, while patients with low CMDLncS suggested the sensitivity to bevacizumab and displayed enhanced immune activation.

INTERPRETATION
CMDLncS provides an attractive platform for identifying patient at high risk of recurrence and could optimize precision treatment to improve the clinical outcomes in stage II/III CRC.

FUNDING
This study was supported by the National Natural Science Foundation of China (81,972,663); Henan Province Young and Middle‐Aged Health Science and Technology Innovation Talent Project (YXKC2020037); and Henan Provincial Health Commission Joint Youth Project (SB201902014).

Zaoqu Liu, ChunGuang Guo, Qin Dang, Libo Wang, Long Liu, Siyuan Weng, et al.

Colorectal Cancer

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Nuclear receptors in renal health and disease

Nuclear receptors in renal health and disease

Alzheimer’s disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus

Alzheimer’s disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus