Monogenic Disorders of ROS Production and the Primary Anti-Oxidative Defense.

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular anti-oxidant defense mechanisms, plays a critical role in the pathogenesis of various human diseases. Redox metabolism, comprising a network of enzymes and genes, serves as a crucial regulator of ROS levels and maintains cellular homeostasis. This review provides an overview of the most important human genes encoding for proteins involved in ROS generation, ROS detoxification, and production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), and the genetic disorders that lead to dysregulation of these vital processes. Insights gained from studies on inherited monogenic metabolic diseases provide valuable basic understanding of redox metabolism and signaling, and they also help to unravel the underlying pathomechanisms that contribute to prevalent chronic disorders like cardiovascular disease, neurodegeneration, and cancer.

Endothelial barrier dysfunction in systemic inflammation is mediated by soluble VE-cadherin interfering VE-PTP signaling.

Breakdown of endothelial barrier integrity determines organ dysfunction and outcome of patients with sepsis. Increased levels of soluble vascular endothelial (VE)-cadherin fragments (sVE-cadherin) have previously been linked with inflammation-induced loss of endothelial barrier function. We provide evidence for a causative role of sVE-cadherin to induce loss of endothelial barrier function. In patients with sepsis, sVE-cadherin levels were associated with organ dysfunction and the need for volume resuscitation. Similarly, LPS-induced systemic inflammation in rats with microvascular dysfunction was paralleled by augmented sVE-cadherin levels. Newly generated recombinant human sVE-cadherin (extracellular domains EC1-5) induced loss of endothelial barrier function in both human microvascular endothelial cells in vitro and in rat mesenteric microvessels in vivo and reduced microcirculatory flow. sVE-cadherinEC1-5 disturbed VE-cadherin-mediated adhesion and perturbed VE-protein tyrosine phosphatase (VE-PTP)/VE-cadherin interaction resulting in RhoGEF1-mediated RhoA activation. VE-PTP inhibitor AKB9778 and Rho-kinase inhibitor Y27632 blunted all sVE-cadherinEC1-5-induced effects, which uncovers a pathophysiological role of sVE-cadherin via dysbalanced VE-PTP/RhoA signaling.

External validation of the REMEMBER score.

Background: The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) after coronary artery bypass grafting (CABG) is associated with high in-hospital mortality rates. The pRedicting mortality in patients undergoing venoarterial Extracorporeal MEMBrane oxygenation after coronary artEry bypass gRafting (REMEMBER) score has been created to predict in-hospital mortality in this subgroup of patients. The aim of this study is to externally validate the REMEMBER score. Methods: All CABG patients who received VA-ECMO during or after the operation at our center between 01/2012 and 12/2021 were included in the analysis. Discrimination was assessed using concordance statistics, visualized by ROC curve analysis. Calibration-in-the-large and Calibration slope were tested separately. Results: A total of 107 patients (male: n = 78, 72.9%) were included in this study. The in-hospital mortality rate in our cohort was 45.8% compared with 55% in the original study. The REMEMBER score median predicted mortality rate was 52% (76.9-36%). However, the REMEMBER score showed low discriminative ability [AUC: 0.623 (p = 0.0244; 95% CI = 0.524-0.715)] and inaccurate calibration (intercept = 0.25074; p = 0.0195; slope = 0.39504; p = 0.0303), indicating poor performance. Conclusions: The REMEMBER score did not predict in-hospital mortality and was therefore not applicable in our cohort of patients. Additional external validation studies in a multicenter setting are therefore advisable.

A model of porcine polymicrobial septic shock.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Mortality of patients with sepsis is high and largely unchanged throughout the past decades. Animal models have been widely used for the study of sepsis and septic shock, but translation into effective treatment regimes in the clinic have mostly failed. Pigs are considered as suitable research models for human diseases due to their high comparability and similarity to human anatomy, genetics, and the immune system. We here evaluated the previously reported models of septic shock in pigs and established a novel model of polymicrobial sepsis that meets the clinical criteria of septic shock in pigs. MATERIALS AND METHODS: The literature search was performed using the keywords "pig", "sepsis" and "septic shock". For the establishment of septic shock in n = 10 German landrace pigs, mechanical ventilation was initiated, central venous and arterial lines and invasive hemodynamic monitoring via pulse contour cardiac output measurement (PiCCO) established. Peritoneal polymicrobial faecal sepsis was induced by application of 3 g/kg body weight faeces into the abdominal cavity. Septic shock was defined according to the third international consensus definitions (Sepsis-3). Upon shock, pigs underwent the 1-h bundle for the treatment of human sepsis. Cytokine levels were measured by ELISA. RESULTS: Published porcine sepsis models exhibited high methodological variability and did not meet the clinical criteria of septic shock. In our model, septic shock developed after an average of 4.8 ± 0.29 h and was associated with a reproducible drop in blood pressure (mean arterial pressure 54 ± 1 mmHg) and significant hyperlactatemia (3.76 ± 0.65 mmol/L). Septic shock was associated with elevated levels of interleukin-6 (IL6) and initial cardiac depression followed by a hyperdynamic phase with significant loss of systemic vascular resistance index after initial resuscitation. In addition, organ dysfunction (acute kidney injury) occurred. CONCLUSIONS: We here established a model of septic shock in pigs that meets the clinical criteria of septic shock utilized in human patients. Our model may thus serve as a reference for clinically relevant sepsis research in pigs.

Iatrogenic lumbosacral infiltration with petroleum (hydrodesulfurized heavy) with secondary intrathecal distribution-a case report.

Petroleum is commonly used as a solvent, and primary intrathecal administration or secondary diffusion and subsequent clinical management has not been reported. We report the case of a male patient with intrathecal petroleum diffusion following accidental lumbar infiltration. After the onset of secondary myeloencephalopathy with coma and tetraparesis, continuous cranio-lumbar irrigation using an external ventricular and a lumbar drain was established. Cranial imaging revealed distinct supra- and infratentorial alterations. The patient improved slowly and was referred to rehabilitation. Intrathecal petroleum leads to myeloencephalopathy and continuous cranio-lumbar irrigation might be a safe treatment option.

Perioperative Tracking of Intravenous Iron in Patients Undergoing On-Pump Cardiac Surgery: A Prospective, Single-Center Pilot Trial.

BACKGROUND: Preoperative intravenous iron administration is a frequently used patient blood management procedure. If the timeframe of intravenous iron administration before surgery is short, (1) the concentration of the intravenous iron compound might still be high in patients' plasma when undergoing surgery and (2) this iron in patients' plasma is at risk to be lost due to blood loss. The aim of the current study was, therefore, to track the iron compound ferric carboxymaltose (FCM) before, during, and after cardiac surgery requiring cardiopulmonary bypass, with an emphasis on intraoperative iron losses in shed blood and potential recovery through autologous cell salvage. METHODS: Concentrations of FCM were analyzed in patients' blood using a hyphenation of liquid chromatography and inductively coupled plasma-mass spectrometry to distinguish between pharmaceutical compound FCM and serum iron. In this prospective, single-center pilot trial, 13 anemic and 10 control patients were included. Anemic patients with hemoglobin levels ≤12/13 g/dL in women and men were treated with 500 milligrams (mg) intravenous FCM 12 to 96 hours before elective on-pump cardiac surgery. Patients' blood samples were collected before surgery and at days 0, 1, 3, and 7 after surgery. One sample each was taken of the cardiopulmonary bypass, the autologous red blood cell concentrate generated by cell salvage, and the cell salvage disposal bag. RESULTS: Patients who had received FCM <48 hours before surgery had higher FCM serum levels (median [Q1-Q3], 52.9 [13.0-91.6]) compared to ≥48 hours (2.1 [0.7-5.1] µg/mL, P = .008). Of 500-mg FCM administered <48 hours, 327.37 (257.96-402.48) mg were incorporated compared to administration ≥48 hours with 493.60 (487.78-496.70) mg. After surgery, patients' plasma FCM concentration in the FCM <48 hours group was decreased (-27.1 [-30 to -5.9] µg/mL). Little FCM was found in the cell salvage disposal bag (<48 hours, 4.2 [3.0-25.8] µg/mL, equivalent to 29.0 [19.0-40.7] mg total; equivalent to 5.8% or 1/17th of the 500 mg FCM initially administered), almost none in the autologous red blood cell concentrate (<48 hours, 0.1 [0.0-0.43] µg/mL). CONCLUSIONS: The data generate the hypotheses that nearly all FCM is incorporated into iron stores with administration ≥48 hours before surgery. When FCM is given <48 hours of surgery, the majority is incorporated into iron stores by the time of surgery, although a small amount may be lost during surgical bleeding with limited recovery by cell salvage.

Differences in Cognitive Adverse Effects and Seizure Parameters Between Thiopental and Propofol Anesthesia for Electroconvulsive Therapy.

INTRODUCTION: Electroconvulsive therapy (ECT) is a well-established treatment option in case of severe and treatment-resistant psychiatric conditions. In this retrospective study, we compared the 2 anesthetics propofol and thiopental in terms of seizure quality, cognitive adverse effects, and clinical outcome. METHODS: Data collection was performed retrospectively by a chart review, including patient files and medical records. A total of 64 patients (female = 60.9%) treated with ECT within the period of February 2019 to March 2020 were included. Of these, 35 (54.7%) received thiopental for ECT narcosis and 29 (45.3%) were treated with propofol. RESULTS: Six hundred sixteen ECT treatments (mean number per case, 9.6) were performed in total. The mean electroencephalogram seizure duration (38.3 vs 28.1 seconds, t = 3.534, degrees of freedom [ df ] = 62, P < 0.001) and motor seizure duration (21.5 vs 12.0, t = 4.336, df = 62, P < 0.001) as well as postictal suppression index and heart rate increase were significantly higher in the thiopental group. Mean stimulation energy needed per session was higher in the propofol group (88.6% vs 73.0%, Mann-Whitney U test, P = 0.042). The ECT series was more likely to be interrupted due to cognitive adverse effects in the thiopental group ( P = 0.001, Pearson χ 2 = 10.514, df = 1). Number of patients achieving remission was significantly higher in the thiopental group (31.4% vs 6.9%, P = 0.015, χ 2 = 5.897, df = 1). CONCLUSIONS: Thiopental led to better seizure duration and quality and was associated with a higher rate of remission. As a downside, thiopental was also associated with a greater risk of cognitive adverse effects.

The Impact of Acute Nutritional Interventions on the Plasma Proteome.

CONTEXT: Humans respond profoundly to changes in diet, while nutrition and environment have a great impact on population health. It is therefore important to deeply characterize the human nutritional responses. OBJECTIVE: Endocrine parameters and the metabolome of human plasma are rapidly responding to acute nutritional interventions such as caloric restriction or a glucose challenge. It is less well understood whether the plasma proteome would be equally dynamic, and whether it could be a source of corresponding biomarkers. METHODS: We used high-throughput mass spectrometry to determine changes in the plasma proteome of i) 10 healthy, young, male individuals in response to 2 days of acute caloric restriction followed by refeeding; ii) 200 individuals of the Ely epidemiological study before and after a glucose tolerance test at 4 time points (0, 30, 60, 120 minutes); and iii) 200 random individuals from the Generation Scotland study. We compared the proteomic changes detected with metabolome data and endocrine parameters. RESULTS: Both caloric restriction and the glucose challenge substantially impacted the plasma proteome. Proteins responded across individuals or in an individual-specific manner. We identified nutrient-responsive plasma proteins that correlate with changes in the metabolome, as well as with endocrine parameters. In particular, our study highlights the role of apolipoprotein C1 (APOC1), a small, understudied apolipoprotein that was affected by caloric restriction and dominated the response to glucose consumption and differed in abundance between individuals with and without type 2 diabetes. CONCLUSION: Our study identifies APOC1 as a dominant nutritional responder in humans and highlights the interdependency of acute nutritional response proteins and the endocrine system.

Prolonged sedation with sevoflurane in comparison to intravenous sedation in critically ill patients - A randomized controlled trial.

BACKGROUND: Volatile anesthetics are used more commonly for sedation in the intensive-care-unit (ICU). However, evidence for long-term use remains low. We therefore conducted a randomized-controlled trial comparing sevoflurane with intravenous sedation with particular focus on efficacy and safety. METHODS: In this prospective, randomized-controlled phase-IIb monocentric clinical-trial ICU patients requiring at least 48 h of sedation were randomized to receive sevoflurane (S) or propofol/midazolam (P). Sedation quality was monitored using the Richmond-Agitation-Sedation-Scale. Following termination of sedation, the time to spontaneous breathing and extubation, opioid consumption, hemodynamics, ICU and hospital length of stay (LOS) and adverse events were recorded. RESULTS: 79 patients were eligible to randomization. Sedation quality was comparable between sevoflurane (n = 39) and propofol (n = 40). However, the use of sevoflurane lead to a reduction in time to spontaneous breathing (26 min vs. 375 min, P < 0.001). Patients sedated with propofol had lower opioid requirements (remifentanil:400 µg/h vs. 500 µg/h, P = 0.007; sufentanil:40 µg/h vs. 30 µg/h, P = 0.007) while hemodynamics, LOS or the occurrence of adverse events did not differ. CONCLUSION: ICU patients sedated with sevoflurane >48 h may return to spontaneous breathing faster, while the quality of sedation is comparable to a propofol-based sedation regime. Sevoflurane might be considered to be safe for long-term sedation in this patient population, while being non-inferior compared to propofol.

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents.

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

Procalcitonin mediates vascular dysfunction in obesity.

AIMS: Obesity is accompanied by a chronic low-grade inflammation associated with endothelial dysfunction and vascular complications. Procalcitonin is a marker of inflammation, secreted by adipose tissue and elevated in obese subjects. We here investigated whether visceral or perivascular fat-derived procalcitonin is a target to improve obesity-induced endothelial dysfunction. MATERIALS AND METHODS: Procalcitonin expression was identified by Western blot. Murine endothelial cells were isolated using CD31-antibody-coated magnetic beads and reactive oxygen species and nitric oxide (NO) determined by H2DCF- or DAF-FM diacetate loading. Endothelium-dependent vasorelaxation was analyzed using pressure myography of murine arterioles. Calcitonin gene-related peptide (CGRP) was used to activate the calcitonin receptor-like receptor (CRLR)/RAMP1 complex and olcegepant or the dipeptidyl-peptidase 4 (DPP4) inhibitor sitagliptin to block procalcitonin signaling or activation. KEY FINDINGS: In addition to visceral adipose tissue, procalcitonin was present in perivascular and epicardial tissue. In concentrations typical for obesity, procalcitonin doubled reactive oxygen species formation and decreased endothelial nitric oxide production in murine endothelial cells. Intravenous delivery of procalcitonin to mice in obesity-associated concentrations impaired endothelium-dependent vasorelaxation in a CRLR/RAMP1-dependent manner and antagonized CGRP-induced endothelial NO release in vitro. Use of CRLR/RAMP1-receptor antagonist olcegepant counteracted procalcitonin effects on vasodilation, nitric oxide production and reactive oxygen species formation. Similarly, blocking procalcitonin activation by the DPP4 inhibitor sitagliptin antagonized endothelial procalcitonin effects. SIGNIFICANCE: Procalcitonin, liberated either from visceral or perivascular adipose tissue, contributes to endothelial dysfunction by antagonizing CGRP signaling in obesity. Targeting hyperprocalcitonemia may be a means to preserve endothelial function and reduce comorbidity burden in obese subjects.

Global analysis of cytosine and adenine DNA modifications across the tree of life.

Interpreting the function and metabolism of enzymatic DNA modifications requires both position-specific and global quantities. Sequencing-based techniques that deliver the former have become broadly accessible, but analytical methods for the global quantification of DNA modifications have thus far been applied mostly to individual problems. We established a mass spectrometric method for the sensitive and accurate quantification of multiple enzymatic DNA modifications. Then, we isolated DNA from 124 archean, bacterial, fungal, plant, and mammalian species, and several tissues and created a resource of global DNA modification quantities. Our dataset provides insights into the general nature of enzymatic DNA modifications, reveals unique biological cases, and provides complementary quantitative information to normalize and assess the accuracy of sequencing-based detection of DNA modifications. We report that only three of the studied DNA modifications, methylcytosine (5mdC), methyladenine (N6mdA) and hydroxymethylcytosine (5hmdC), were detected above a picomolar detection limit across species, and dominated in higher eukaryotes (5mdC), in bacteria (N6mdA), or the vertebrate central nervous systems (5hmdC). All three modifications were detected simultaneously in only one of the tested species, Raphanus sativus. In contrast, these modifications were either absent or detected only at trace quantities, across all yeasts and insect genomes studied. Further, we reveal interesting biological cases. For instance, in Allium cepa, Helianthus annuus, or Andropogon gerardi, more than 35% of cytosines were methylated. Additionally, next to the mammlian CNS, 5hmdC was also detected in plants like Lepidium sativum and was found on 8% of cytosines in the Garra barreimiae brain samples. Thus, identifying unexpected levels of DNA modifications in several wild species, our resource underscores the need to address biological diversity for studying DNA modifications.

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation.

Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in maintaining organ integrity by regulating tissue perfusion. Permeability of the endothelial monolayer is strictly controlled and highly organ-specific, forming continuous, fenestrated and discontinuous capillaries that orchestrate the extravasation of fluids, proteins and solutes to maintain organ homeostasis. In the physiological state, the endothelial barrier is maintained by the glycocalyx, extracellular matrix and intercellular junctions including adherens and tight junctions. As endothelial cells are constantly sensing and responding to the extracellular environment, their activation by inflammatory stimuli promotes a loss of endothelial barrier function, which has been identified as a hallmark of systemic inflammation, leading to tissue edema formation and hypotension and thus, is a key contributor to lethal outcomes. In this review, we provide a comprehensive summary of the major players, such as the angiopoietin-Tie2 signaling axis, adrenomedullin and vascular endothelial (VE-) cadherin, that substantially contribute to the regulation and dysregulation of endothelial permeability during systemic inflammation and elucidate treatment strategies targeting the preservation of vascular integrity.

Targeting Procalcitonin Protects Vascular Barrier Integrity.

Rationale: Capillary leakage frequently occurs during sepsis and after major surgery and is associated with microvascular dysfunction and adverse outcome. Procalcitonin is a well-established biomarker in inflammation without known impact on vascular integrity. Objectives: We determined how procalcitonin induces endothelial hyperpermeability and how targeting procalcitonin protects vascular barrier integrity. Methods: In a prospective observational clinical study, procalcitonin levels were assessed in 50 patients who underwent cardiac surgery and correlated to postoperative fluid and vasopressor requirements along with sublingual microvascular functionality. Effects of the procalcitonin signaling pathway on endothelial barrier and adherens junctional integrity were characterized in vitro and verified in mice. Inhibition of procalcitonin activation by dipeptidyl-peptidase 4 (DPP4) was evaluated in murine polymicrobial sepsis and clinically verified in cardiac surgery patients chronically taking the DPP4 inhibitor sitagliptin. Measurements and Main Results: Elevated postoperative procalcitonin levels identified patients with 2-fold increased fluid requirements (P < 0.01), 1.8-fold higher vasopressor demand (P < 0.05), and compromised microcirculation (reduction to 63.5 ± 2.8% of perfused vessels, P < 0.05). Procalcitonin induced 1.4-fold endothelial and 2.3-fold pulmonary capillary permeability (both Ps < 0.001) by destabilizing VE-cadherin. Procalcitonin effects were dependent on activation by DPP4, and targeting the procalcitonin receptor or DPP4 during sepsis-induced hyperprocalcitonemia reduced capillary leakage by 54 ± 10.1% and 60.4 ± 6.9% (both Ps < 0.01), respectively. Sitagliptin before cardiac surgery was associated with augmented microcirculation (74.1 ± 1.7% vs. 68.6 ± 1.9% perfused vessels in non-sitagliptin-medicated patients, P < 0.05) and with 2.3-fold decreased fluid (P < 0.05) and 1.8-fold reduced vasopressor demand postoperatively (P < 0.05). Conclusions: Targeting procalcitonin's action on the endothelium is a feasible means to preserve vascular integrity during systemic inflammation associated with hyperprocalcitonemia.

An external validation study of the Utah Bleeding Risk Score.

OBJECTIVES: Gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices (CF-LVAD) impairs quality of life and increases hospitalization rate. The Utah Bleeding Risk Score (UBRS) has been created to predict gastrointestinal bleeding (GIB) in patients on left ventricular assist device. We here aimed to externally validate UBRS on our cohort of CF-LVAD patients. METHODS: Utah Bleeding Risk Score was calculated, GIB events summarized on follow-up and patients stratified into 3 risk groups. Predictive ability of UBRS was examined at 3 years and during whole support time and person time incidence rates correlated to UBRS. In a sub-analysis, single effects of UBRS variables on freedom from GIB were assessed. RESULTS: A total of 111 CF-LVAD patients were included. The median UBRS was 2 (3-1). Receiver operating characteristic curve analysis showed an area under the curve of 0.519 (P = 0.758, 95% confidence interval = 0.422-0.615) at 3 years and an area under the curve of 0.515 (P = 0.797, 95% confidence interval = 0.418-0.611) during whole support time. No significant difference was observed in UBRS between bleeders and non-bleeders (P = 0.80). No significant difference in freedom from GIB was observed (P3 years = 0.7; Psupport-time = 0.816) and no independent significance regarding the freedom from bleeding at 3 years for any variable was observed. Coronary artery disease was associated with higher risk of GIB beyond the 3rd year (P = 0.048). CONCLUSIONS: UBRS was not able to predict GIB and therefore not applicable in our cohort of patients. Coronary artery disease could lead to a higher risk for GIB during support time. An additional validation in a larger cohort is advisable.

A proteomic survival predictor for COVID-19 patients in intensive care.

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.

TRP Channels as Sensors of Aldehyde and Oxidative Stress.

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.

Development of heart failure with preserved ejection fraction in type 2 diabetic mice is ameliorated by preserving vascular function.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction and is frequent in people with type 2 diabetes mellitus. In diabetic patients, increased levels of the eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE) are linked to vascular dysfunction. Here, we aimed to identify the importance of 12-HETE in type 2 diabetic patients exhibiting diastolic dysfunction, and mice exhibiting HFpEF and whether targeting 12-HETE is a means to ameliorate HFpEF progression by improving vascular function in diabetes. MATERIAL AND METHODS: Subjects with diagnosed type 2 diabetes mellitus and reported diastolic dysfunction or healthy controls were recruited and 12(S)-HETE levels determined by ELISA. 12(S)-HETE levels were determined in type 2 diabetic, leptin receptor deficient mice (LepRdb/db) and HFpEF verified by echocardiography. Mitochondrial function, endothelial function and capillary density were assessed using Seahorse technique, pressure myography and immunohistochemistry in LepRdb/db or non-diabetic littermate controls. 12/15Lo generation was inhibited using ML351 and 12(S)-HETE action by using the V1-cal peptide. KEY FINDINGS: Endothelium-dependent vasodilation and mitochondrial functional capacity both improved in response to either application of ML351 or the V1-cal peptide. Correlating to improved vascular function, mice treated with either pharmacological agent exhibited improved diastolic filling and left ventricular relaxation that correlated with increased myocardial capillary density. SIGNIFICANCE: Our results suggest that 12-HETE may serve as a biomarker indicating endothelial dysfunction and the resulting cardiovascular consequences such as HFpEF in type 2 diabetic patients. Antagonizing 12-HETE is a potent means to causally control HFpEF development and progression in type 2 diabetes by preserving vascular function.

A time-resolved proteomic and prognostic map of COVID-19.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.