Changes in circulating extracellular vesicle cargo are associated with cognitive decline after major surgery: an observational case-control study.

Background: Postoperative neurocognitive decline is a frequent complication triggered by unclear signalling mechanisms. This observational case-control study investigated the effects of hip or knee replacement surgery on the composition of circulating extracellular vesicles (EVs), potential periphery-to-brain messengers, and their association with neurocognitive outcomes.

Methods: We mapped the microRNAome and proteome of plasma-derived EVs from 12 patients (six with good and six with poor neurocognitive outcomes at 3 months after surgery) at preoperative and postoperative timepoints (4, 8, 24, and 48 h).

Calcium-Regulating Hormonal System and HMGB1 in Cardiomyopathies.

Background: Calcium ions play a key role in the heart's functional activity. The steadystate levels of calcium are contingent on the calcium regulating hormonal system, impairment of which might result in the development of cardiac pathology. An important role in these processes is also attributed to the specific inflammatory mediator, HMGB1, one of the damage-associated molecular patterns (DAMPs) released by immune cells or cell damage.

Surgical Trauma in Mice Modifies the Content of Circulating Extracellular Vesicles.

Surgical interventions rapidly trigger a cascade of molecular, cellular, and neural signaling responses that ultimately reach remote organs, including the brain. Using a mouse model of orthopedic surgery, we have previously demonstrated hippocampal metabolic, structural, and functional changes associated with cognitive impairment. However, the nature of the underlying signals responsible for such periphery-to-brain communication remains hitherto elusive.

Rare genetic variability in human drug target genes modulates drug response and can guide precision medicine.

Interindividual variability in drug response constitutes a major concern in pharmacotherapy. While polymorphisms in genes involved in drug disposition have been extensively studied, drug target variability remains underappreciated. By mapping the genomic variability of all human drug target genes onto high-resolution crystal structures of drug target complexes, we identified 1094 variants localized within 6 Å of drug-binding pockets and directly affecting their geometry, topology, or physicochemical properties.

Whole blood gene expression signature in patients with obstructive sleep apnea and effect of continuous positive airway pressure treatment.

The molecular mechanisms of obstructive sleep apnea (OSA), in particular the gene expression patterns in whole blood of patients with OSA, can shed more light on the underlying pathophysiology of OSA and suggest potential biomarkers. In the current study, we have enrolled thirty patients with untreated moderate-severe OSA together with 20 BMI, age, and sex-matched controls and 15 normal-weight controls. RNA-sequencing of whole blood and home sleep apnea testing were performed in the untreated state and after three and twelve months of continuous positive airway pressure (CPAP) treatment.

Biomarkers for oxidative stress and organ injury during Transnasal Humidified Rapid-Insufflation Ventilatory Exchange compared to mechanical ventilation in adults undergoing microlaryngoscopy: A randomised controlled study.

Background: Apnoeic oxygenation using Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) during general anaesthesia prolongs the safe apnoeic period. However, there is a gap of knowledge how THRIVE-induced hyperoxia and hypercapnia impact vital organs. The primary aim of this randomised controlled trial was to characterise oxidative stress and, secondary, vital organ function biomarkers during THRIVE compared to mechanical ventilation (MV).

Can the calcium-regulating hormones counteract the detrimental impact of pro-inflammatory damage-associated molecular patterns in the development of heart failure?

Growing evidence suggests an important role of the inflammatory component in heart failure (HF). Recent developments in this field indicate an ambiguous role that innate immunity plays in immune-driven HF. Damaged or stressed cells, cardiomyocytes, in particular, emit damage-associated molecular patterns (DAMPs) including HMGB1, S100 A8/A9, HSP70, and other molecules, unfolding paracrine mechanisms that induce an innate immune response.

Association between cerebrospinal fluid biomarkers of neuronal injury or amyloidosis and cognitive decline after major surgery.

Background: Postoperative neurocognitive decline is a frequent complication in adult patients undergoing major surgery with increased risk for morbidity and mortality. The mechanisms behind cognitive decline after anaesthesia and surgery are not known. We studied the association between CSF and blood biomarkers of neuronal injury or brain amyloidosis and long-term changes in neurocognitive function.

The impact of damage-associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body.

New Findings: What is the central question of this study? Are carotid bodies (CBs) modulated by the damage-associated molecular patterns (DAMPs) and humoral factors of aseptic tissue injury? What are the main findings and their importance? DAMPs (HMGB1, S100 A8/A9) and blood plasma from rats subjected to tibia surgery, a model of aseptic injury, stimulate the release of neurotransmitters (ATP, dopamine) and TNF-α from ex vivo rat CBs. All-thiol HMGB1 mediates upregulation of immune-related biological pathways. These data suggest regulation of CB function by endogenous mediators of innate immunity.

Neuroinflammatory markers associate with cognitive decline after major surgery: Findings of an explorative study.

Objective: Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of ≥1.

Computational Methods for the Pharmacogenetic Interpretation of Next Generation Sequencing Data.

Up to half of all patients do not respond to pharmacological treatment as intended. A substantial fraction of these inter-individual differences is due to heritable factors and a growing number of associations between genetic variations and drug response phenotypes have been identified. Importantly, the rapid progress in Next Generation Sequencing technologies in recent years unveiled the true complexity of the genetic landscape in pharmacogenes with tens of thousands of rare genetic variants.

Hypoxia Regulates MicroRNA Expression in the Human Carotid Body.

How hypoxia regulates gene expression in the human carotid body (CB) remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the impact of important post-transcriptional regulators, such as non-coding RNAs, and in particular miRNAs is not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied.

An optimized prediction framework to assess the functional impact of pharmacogenetic variants.

Prediction of phenotypic consequences of mutations constitutes an important aspect of precision medicine. Current computational tools mostly rely on evolutionary conservation and have been calibrated on variants associated with disease, which poses conceptual problems for assessment of variants in poorly conserved pharmacogenes. Here, we evaluated the performance of 18 current functionality prediction methods leveraging experimental high-quality activity data from 337 variants in genes involved in drug metabolism and transport and found that these models only achieved probabilities of 0.

Calcium Signaling in Liver Injury and Regeneration.

The liver fulfills central roles in metabolic control and detoxification and, as such, is continuously exposed to a plethora of insults. Importantly, the liver has a unique ability to regenerate and can completely recoup from most acute, non-iterative insults. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease (NAFLD), long-term alcohol abuse and chronic use of certain medications, can cause persistent injury in which the regenerative capacity eventually becomes dysfunctional, resulting in hepatic scaring and cirrhosis.

Integrating rare genetic variants into pharmacogenetic drug response predictions.

Background: Variability in genes implicated in drug pharmacokinetics or drug response can modulate treatment efficacy or predispose to adverse drug reactions. Besides common genetic polymorphisms, recent sequencing projects revealed a plethora of rare genetic variants in genes encoding proteins involved in drug metabolism, transport, and response.

Results: To understand the global importance of rare pharmacogenetic gene variants, we mapped the variability in 208 pharmacogenes by analyzing exome sequencing data from 60,706 unrelated individuals and estimated the importance of rare and common genetic variants using a computational prediction framework optimized for pharmacogenetic assessments.

Hypoxia regulates microRNA expression in the human carotid body.

The carotid body (CB) is the key sensing organ for physiological oxygen levels in the body. Under conditions of low oxygen (hypoxia), the CB plays crucial roles in signaling to the cardiorespiratory center in the medulla oblongata for the restoration of oxygen homeostasis. How hypoxia regulates gene expression in the human CB remains poorly understood.

The role of microRNAs in liver injury at the crossroad between hepatic cell death and regeneration.

The liver fulfills critical metabolic functions, such as controlling blood sugar and ammonia levels, and is of central importance for lipid metabolism and detoxification of environmental and chemical agents, including drugs. Liver injuries of different etiology can elicit a spectrum of responses. Some hepatocytes initiate molecular programs resulting in cell death, whereas others undergo cellular divisions to regenerate the damaged organ.

Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation.

Unlabelled: Hepatocytes are dynamic cells that, upon injury, can alternate between nondividing differentiated and dedifferentiated proliferating states in vivo. However, in two-dimensional cultures, primary human hepatocytes (PHHs) rapidly dedifferentiate, resulting in loss of hepatic functions that significantly limits their usefulness as an in vitro model of liver biology, liver diseases, as well as drug metabolism and toxicity. Thus, understanding the underlying mechanisms and stalling of the dedifferentiation process would be highly beneficial to establish more-accurate and relevant long-term in vitro hepatocyte models.

Sedation with Dexmedetomidine or Propofol Impairs Hypoxic Control of Breathing in Healthy Male Volunteers: A Nonblinded, Randomized Crossover Study.

Background: In contrast to general anesthetics such as propofol, dexmedetomidine when used for sedation has been put forward as a drug with minimal effects on respiration. To obtain a more comprehensive understanding of the regulation of breathing during sedation with dexmedetomidine, the authors compared ventilatory responses to hypoxia and hypercapnia during sedation with dexmedetomidine and propofol.

Methods: Eleven healthy male volunteers entered this randomized crossover study.

The CYP2W1 enzyme: regulation, properties and activation of prodrugs.

CYP2W1 is expressed in the course of development of the gastrointestinal tract, silenced after birth in intestine and colon by epigenetic modifications, but activated following demethylation in colorectal cancer (CRC). The expression levels in CRC positively correlate with the degree of malignancy, are higher in metastases and are predictive of colon cancer survival. The CYP2W1 transcripts have been detected also in hepatocellular carcinoma, adrenocortical carcinoma, childhood rhabdomyosarcoma and breast cancer; however, here the protein expression remains to be confirmed.

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease.

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability.

Membrane topology and search for potential redox partners of colon cancer-specific cytochrome P450 2W1.

Cytochrome P450 2W1 (CYP2W1) is a colon tumor-specific enzyme, suggested as a potential target for cancer therapy. In contrast to other endoplasmic reticulum P450s, we found completely inverted ER membrane topology of CYP2W1 using different approaches (redox sensitive luciferase assay and protease protection assay) and demonstrated that canonical CYP reductants, cytochrome P450 reductase, and cytochrome b5 cannot serve as electron donors for CYP2W1. Moreover, the reduced catalytic activity of the Asn177 mutant that is modified by glycan moieties in the wild-type enzyme indicates a functional relevance of CYP2W1 glycosylation.

Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran.

Recently two novel enzymes were identified in the outer mitochondrial membrane, mARC1 and mARC2. These molybdenum containing enzymes can reduce a variety of N-hydroxylated compounds, such as N-hydroxy-guanidines and sulfohydroxamic acids, as well as convert nitrite into nitric oxide (NO). However, their endogenous functions remain unknown.

The Human Carotid Body Gene Expression and Function in Signaling of Hypoxia and Inflammation.

Although animal carotid body oxygen sensing and signaling has been extensively investigated, the human carotid body remains essentially uncharacterized. Therefore, we aimed to study the human carotid body in terms of morphology, global and specific expression of sensing and signaling genes as well as inflammatory genes. The human carotid body response to brief or prolonged hypoxia was studied in carotid body slices from adult surgical patients and ACh, ATP and cytokine release was analyzed.

Developmental regulation and induction of cytochrome P450 2W1, an enzyme expressed in colon tumors.

Cytochrome P450 2W1 (CYP2W1) is expressed predominantly in colorectal and also in hepatic tumors, whereas the levels are insignificant in the corresponding normal human adult tissues. CYP2W1 has been proposed as an attractive target for colorectal cancer (CRC) therapy by exploiting its ability to activate duocarmycin prodrugs to cytotoxic metabolites. However, its endogenous function, regulation and developmental pattern of expression remain unexplored.