Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.

Background Nicotinamide N -methyltransferase (NNMT) is overexpressed in various human tumors and involved in the development and progression of several carcinomas. In breast cancer, NNMT was found to be overexpressed in several cell lines. However, the clinical relevance of NNMT in breast cancer is not yet clear. Methods NNMT expression in breast carcinoma was examined by immunohistochemistry, and then, its relationship with patient clinicopathological characteristics was analyzed. The effects of NNMT on chemoresistance in breast cancer cells were assessed by cell viability, colony formation, and apoptosis assay. The NNMT, SIRT1, p53, and acetyl-p53 proteins, which are involved in NNMT-related chemoresistance, were examined by Western blotting. The SIRT1 mRNA was examined by real-time PCR, and its activity was measured by using the SIRT1 deacetylase fluorometric reagent kit. Results NNMT expression was significantly higher (53.9%) in breast carcinoma than in paracancerous tissues (10.0%) and breast hyperplasia (13.3%). A high level of NNMT expression correlated with poor survival and chemotherapy response in breast cancer patients who received chemotherapy. Ectopic overexpression of NNMT significantly inhibited the apoptotic cell death and suppression of colony formation induced by adriamycin and paclitaxel. Mechanistic studies revealed that NNMT overexpression increased SIRT1 expression and promoted its activity. Either inhibition of SIRT1 by EX527 or knockdown of SIRT1 by siRNA could reverse NNMT-mediated resistance to adriamycin and paclitaxel, which suggests that SIRT1 plays a critical role in NNMT-related chemoresistance in breast cancer. Conclusions The results of this study demonstrate a novel correlation between the NNMT expression level and patient survival, suggesting that NNMT has the potential to become a new prognostic biomarker to predict the treatment outcomes of the clinical chemotherapy in breast cancer. Moreover, targeting NNMT or downstream SIRT1 may represent a new therapeutic approach to improve the efficacy of breast cancer chemotherapy. Electronic supplementary material The online version of this article (10.1186/s13058-019-1150-z) contains supplementary material, which is available to authorized users.

The lack of blood–brain barrier (BBB) penetrating ability has hindered the delivery of many therapeutic agents for tauopathy treatment. In this study, we report the synthesis of a circular bifunctional aptamer to enhance the in vivo BBB penetration for better tauopathy therapy. The circular aptamer consists of one reported transferrin receptor (TfR) aptamer to facilitate TfR-aptamer recognition-induced transcytosis across BBB endothelial cells, and one Tau protein aptamer that we recently selected to inhibit Tau phosphorylation and other tauopathy-related pathological events in the brain. This novel circular Tau–TfR bifunctional aptamer displays significantly improved plasma stability and brain exposure, as well as the ability to disrupt tauopathy and improve traumatic brain injury (TBI)-induced cognitive/memory deficits in vivo, providing important proof-of-principle evidence that circular Tau–TfR aptamer can be further developed into diagnostic and therapeutic candidates for tauopathies.

The present study aimed to examine the expression and function of the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA (miR)-146a/nuclear factor (NF)-κB axis in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). The mRNA levels of MALAT1 and miR-146a in AKI tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction analysis. The NF-κB pathway proteins and cell viability were assessed using western blot analysis and the MTT method, respectively. The secretion of inflammatory factors was determined using the ELISA method. The present study also examined effects of the abnormal expression of MALAT1 and miR-146a on cytokines and the NF-κB pathway. A potential binding region between MALAT1 and miR-146a was confirmed via RNA immunoprecipitation. The results revealed that the upregulation of MALAT1 reduced the expression of miR‑146a, and there was a negative linear correlation between MALAT1 and miR-146a in a RNA-induced silencing complex‑dependent manner. The expression levels of miR-146a were lower in the kidney injury specimens and NRK-52E cells, compared with those in the controls. MALAT1 knockdown and the overexpression of miR-146a reduced the production of phosphorylated inhibitor of NF-κB and np65 protein. miR‑146a was found to be transcriptionally induced by NF-κB, and miR-146a repressed the pro-inflammatory NF-κB pathway and downstream transcription factors. Taken together, these data indicated that the MALAT1/miR‑146a/NF-κB pathway exerted key functions in LPS-induced AKI, and provided novel insights into the mechanisms of this therapeutic candidate for the treatment of the disease.

AimsTo investigate whether uric acid (UA) is an independent predictor of cardiovascular (CV) and all-cause mortality in peritoneal dialysis (PD) patients after controlling for recognized CV risk factors.MethodsA total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic and laboratory data were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of CV and all-cause mortality with adjustments for recognized traditional and uremia-related CV factors.ResultsThere were no significant differences in baseline characteristics between patients with (n = 2193) and without (n = 71) UA measured. Each 1 mg/dL of increase in UA was associated with higher all-cause mortality with 1.05(1.00∼1.10) of HR and higher CV mortality with 1.12 (1.05∼1.20) of HR after adjusting for age, gender and center size. The highest gender-specific tertile of UA predicted higher all-cause mortality with 1.23(1.00∼1.52) of HR and higher CV mortality with 1.69 (1.21∼2.38) of HR after adjusting for age, gender and center size. The predictive value of UA was stronger in patients younger than 65 years without CV disease or diabetes at baseline. The prognostic value of UA as both continuous and categorical variable weakened or disappeared after further adjusted for uremia-related and traditional CV risk factors.ConclusionsThe prognostic value of UA in CV and all-cause mortality was weak in PD patients generally, which was confounded by uremia-related and traditional CV risk factors.

ObjectivesWe aimed to explore the impacts of individual and environmental socioeconomic status (SES) on the outcome of peritoneal dialysis (PD) in regions with significant SES disparity, through a retrospective multicenter cohort in China.MethodsOverall, 2,171 incident patients from seven PD centers were included. Individual SES was evaluated from yearly household income per person and education level. Environmental SES was represented by regional gross domestic product (GDP) per capita and medical resources. Undeveloped regions were defined as those with regional GDP lower than the median. All-cause and cardiovascular death and initial peritonitis were recorded as outcome events.ResultsPoorer PD patients or those who lived in undeveloped areas were younger and less-educated and bore a heavier burden of medical expenses. They had lower hemoglobin and serum albumin at baseline. Low income independently predicted the highest risks for all-cause or cardiovascular death and initial peritonitis compared with medium and high income. The interaction effect between individual education and regional GDP was determined. In undeveloped regions, patients with an elementary school education or lower were at significantly higher risk for all-cause death but not cardiovascular death or initial peritonitis compared with those who attended high school or had a higher diploma. Regional GDP was not associated with any outcome events.ConclusionLow personal income independently influenced all-cause and cardiovascular death, and initial peritonitis in PD patients. Education level predicted all-cause death only for patients in undeveloped regions. For PD patients in these high risk situations, integrated care before dialysis and well-constructed PD training programs might be helpful.

Alzheimer’s disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3–6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase of tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease of synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.

BackgroundCoronary artery calcification (CAC) is associated with cardiovascular mortality in end-stage renal disease (ESRD) patients. The present study aimed to identify modifiable risk factors for CAC progression in peritoneal dialysis (PD) patients.MethodsAdult patients who received regular PD for more than 6 months and underwent a series of coronary artery calcification score (CaCS) measurements by multislice spiral computed tomography (MSCT) with an interval of ≥ 6 months were included in this observational cohort study. The demographic characteristics and clinical data, including laboratory data and adequacy of PD, were collected. Curve estimation was used to fit the straight line and obtain the slope. Binary logistic regression was performed to identify the independent risk factors for CAC progression in the PD patients, and multivariate linear regression was conducted to identify factors associated with hyperphosphatemia.ResultsA total of 207 adult patients on PD (116 men, 56.0 %) with a mean age of 59.8 ± 15.9 years were recruited to this study, and 157 of them (75.8 %) received three or more CaCS assessments. The patients were divided into a slow group (n = 137) and a rapid group (n = 70) according to the linear regression slope or the average speed of development. The follow-up time was 33.0 ± 18.8 months. Multivariate logistic regression revealed that age and serum phosphate level were independent risk factors for CAC progression after adjustments. Multivariate linear regression revealed that hyperphosphatemia was associated with elevations in the transferrin and serum albumin levels and normalized protein catabolic rate (nPCR) and reductions in the hemoglobin level, residual Ccr, and PD Ccr.ConclusionsHyperphosphatemia is an independent risk factor for CAC progression, and the serum phosphate level may be associated with protein intake and PD adequacy. These results provide important information for the clinical management of ESRD patients.