Circulatory Factors Research Articles

Distinct soluble immune checkpoint profiles characterize COVID-19 severity, mortality and SARS-CoV-2 variant infections.

Over the past four years, the COVID-19 pandemic has posed serious global health challenges. The severe form of disease and death resulted from the failure of immune regulatory mechanisms, closely highlighted by the dual proinflammatory cytokine and soluble immune checkpoint (sICP) storm. Identifying the individual factors impacting on disease severity, evolution and outcome, as well as any additional interconnections, have become of high scientific interest. In this study, we evaluated a novel panel composed of ten sICPs for the predictive values of COVID-19 disease severity, mortality and Delta vs. Omicron variant infections in relation to hyperinflammatory biomarkers. The serum levels of sICPs from confirmed SARS-CoV-2 infected patients at hospital admission were determined by Luminex, and artificial neural network analysis was applied for defining the distinct patterns of molecular associations with each form of disease: mild, moderate, and severe. Notably, distinct sICP profiles characterized various stages of disease and Delta infections: while sCD40 played a central role in all defined diagrams, the differences emerged from the distribution levels of four molecules recently found and relatively less investigated (sCD30, s4-1BB, sTIM-1, sB7-H3), and their associations with various hematological and biochemical inflammatory biomarkers. The artificial neural network analysis revealed the prominent role of serum sTIM-1 and Galectin-9 levels at hospital admission in discriminating between survivors and non-survivors, as well as the role of specific anti-interleukin therapy (Tocilizumab, Anakinra) in improving survival for patients with initially high sTIM-1 levels. Furthermore, strong associations between sCD40 and Galectin-9 with suPAR defined the Omicron variant infections, while the positive match of sCD40 with sTREM-1 serum levels characterized the Delta-infected patients. Of importance, this study provides a comprehensive analysis of circulatory immune factors governing the COVID-19 pathology, and identifies key roles of sCD40, sTIM-1, and Galectin-9 in predicting mortality.

Acute partial sleep restriction does not impact arterial function in young and healthy humans.

Habitual short sleep durations are associated with several cardiovascular diseases. Experimental research generally supports these findings as metrics of arterial function are impaired after complete deprivation of sleep and after longer periods of partial sleep restriction. The acute influence of a single instance of partial sleep restriction (PSR), however, has not been defined. We evaluated arterial structure and function among 32 university-aged participants on two occasions: once after normal habitual sleep (NS), and again the morning after an acute partial sleep restriction (PSR) intervention involving only 3h of sleep for a single night. Endothelial function was measured using ultrasonography at the brachial artery via flow-mediated dilatation (FMD), and a ramp peak oxygen uptake test was used to evaluate cardiorespiratory fitness. Blood samples were collected from a subset of participants to investigate the influence of circulatory factors on cellular mechanisms implicated in endothelial function. Sleep duration was lower after a night of PSR compared to NS (P<0.001); however, there were no appreciable differences in any haemodynamic outcome between conditions. FMD was not different between NS and PSR (NS: 6.5±2.9%; PSR: 6.3±2.9%; P=0.668), and cardiorespiratory fitness did not moderate the haemodynamic response to PSR (all P>0.05). Ex vivo cell culture results aligned with in vivo data, showing that acute PSR does not alter intracellular processes involved in endothelial function. No differences in arterial structure or function were observed between NS and acute PSR in healthy and young participants, and cardiorespiratory fitness does not modulate the arterial response to acute sleep restriction.

Prognostic value of circulatory growth factors to predict responsiveness to chemotherapy and remission status of patients with acute myeloid leukemia

IntroductionTumor neovascularization, an essential requirement for malignant disease progression and metastasis, depends on the dysregulation of pro-angiogenic and anti-angiogenic activities. This study aimed to investigate the utilization of circulatory angiopoietins (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF-A and VEGF-C), and basic fibroblast growth factor (bFGF) as a prognostic tool for acute myeloid leukemia (AML).Material and methodsTwenty-four AML patients who were under chemotherapeutic intervention were included. Patients’ relapse status, responsiveness to chemotherapy, and remission status were obtained from their medical profiles. For comparative purposes, fifteen healthy subjects were included. Serum levels of growth factors were measured.ResultsAs compared to control subjects, AML patients had significantly lower average levels of Ang-1 (170.8 ±12.7 versus 59.2 ±12.5 ng/ml) and VEGF-A (56.0 ±13.1 versus 98.6 ±11.9 ng/dl) that coincide with a higher average level of Ang-2 (18.5 ±4.1 ng/ml versus 7.5 ±0.8 ng/ml). Spearman’s correlation analysis defined a significant association of sAng-1 and sAng-2 with patients’ response to chemotherapy ( = 0.488) and remission status ( = 0.476), respectively. According to the receiver operating characteristic (ROC) curve, downregulation of Ang-1 has good predictivity for poor responsiveness to chemotherapy (AUC = 0.781, p &lt; 0.05) while upregulation of sAng-2 has good predictivity for failed remission status (AUC = 0.779, p &lt; 0.05).ConclusionsIn the context of AML, dysregulated circulatory levels of Ang-1 and Ang-2 are suggested prognostic markers to provide useful predictivity of patients’ adverse responsiveness to chemotherapy and remission status, respectively.

#1043 Metabolomics and proteomics study on kidney function post-liver transplantation

Abstract Background and Aims Hepatorenal syndrome (HRS) is a serious complication characterized by kidney dysfunction in patients with advanced liver disease. The pathophysiology of HRS is poorly understood and involves a combination of hemodynamic, circulatory, inflammatory, and hormonal factors. While some patients with HRS restore kidney function after liver transplantation (LT), others continue to have impaired kidney function. Understanding the mechanisms associated with persistent kidney dysfunction is essential for developing effective treatments and stratifying patients for combined liver-kidney transplantation versus LT only. Method We analyzed serum samples from 10 patients of the multicenter prospective study (INAID CTOT14). Five of them had no HRS and maintained an eGFR &amp;gt; 50 ml/min post-LT. One patient with HRS recovered kidney function post-LT. Four patients with HRS failed to regain kidney function at one- and two-months post-LT (eGFR &amp;lt; 30 ml/min). We categorized the five patients without HRS and one patient with recovered eGFR as Normal Kidney Function (NKF) group and the other four patients as Impaired Kidney Function (IKF) group. Serum samples were collected at one (visit 1) and two months (visit 2) post-LT and stored at −80°C until analysis. Both untargeted metabolomics and proteomics analysis were conducted using quantitative liquid chromatography tandem mass spectroscopy (LC-MS/MS) on Agilent® Q-TOF 6546. Data was analyzed by Agilent® Qualitative Workflow 10, Agilent® Profinder 10, MetaboAnalyst (V6.0), and Spectrum Mill MS software. Results A total of 150 metabolites were identified by LC-MS/MS based metabolomics. Principal component analysis (PCA) did not show significant differences between visit 1 and visit 2 samples (Fig. 1A). Therefore, visit 1 and visit 2 samples were analyzed together. With 12 samples in NKF and 8 samples in IKF group, the PCA score plot showed distinct clustering of the two groups (Fig. 1B). Volcano plot analysis was conducted to analyze metabolite differences between NKF and IKF. P-values were calculated using a Student's t-test, and differential metabolites were identified with a P-value cut-off of &amp;lt; .05 and a fold change &amp;gt; 2.0. The result revealed 37 downregulated and 13 upregulated metabolites when comparing NKF and IKF (Fig. 1C). Notably, creatinine was among the downregulated metabolites in the NKF group, validating the accuracy of our analysis. Untargeted proteomics analysis was also performed on all 20 samples. Using a P-value cut-off of .05 and a fold change &amp;gt;1.25, 43 proteins were found to be upregulated, and four proteins to be downregulated when comparing NKF to IKF. Fig. 2A lists the top 10 regulated proteins, with beta-2-microglobulin as the most significantly changed. Reactome® pathway analysis of these 47 proteins highlighted potential impacts on various biological pathways (Fig. 2B), providing potential valuable insights into the molecular alterations associated with kidney function post-LT. Conclusion Our comprehensive metabolomics and proteomics study characterized the molecular alterations associated with kidney function post-LT. The identified metabolites and proteins may provide valuable insights for understanding persistent kidney damage. Future research is warranted to confirm and correlate these findings with clinical outcomes, enhancing the applicability and significance of our results in the broader context of HRS and LT.

Inflammatory Markers Involved in the Pathogenesis of Dupuytren's Contracture.

Dupuytren's disease is a common fibroproliferative disease that can result in debilitating hand deformities. Partial correction and return of deformity are common with surgical or clinical treatments at present. While current treatments are limited to local procedures for relatively late effects of the disease, the pathophysiology of this connective tissue disorder is associated with both local and systemic processes (e.g., fibrosis, inflammation). Hence, a better understanding of the systemic circulation of Dupuytren related cytokines and growth factors may provide important insights into disease progression. In addition, systemic biomarker analysis could yield new concepts for treatments of Dupuytren that attenuate circulatory factors (e.g., anti-inflammatory agents, neutralizing antibodies). Progress in the development of any disease modifying biologic treatment for Dupuytren has been hampered by the lack of clinically useful biomarkers. The characterization of nonsurgical Dupuytren biomarkers will permit disease staging from diagnostic and prognostic perspectives, as well as allows evaluation of biologic responses to treatment. Identification of such markers may transcend their use in Dupuytren treatment, because fibrotic biological processes fundamental to Dupuytren are relevant to fibrosis in many other connective tissues and organs with collagen-based tissue compartments. There is a wide range of potential Dupuytren biomarker categories that could be informative, including disease determinants linked to genetics, collagen metabolism, as well as immunity and inflammation (e.g., cytokines, chemokines). This narrative review provides a broad overview of previous studies and emphasizes the importance of inflammatory mediators as candidate circulating biomarkers for monitoring Dupuytren's disease.

Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M

The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise. In cultured human adipocytes, oncostatin-M enhances MAPK signaling and regulates lipolysis. Oncostatin-M expression arises predominantly from adipose tissue immune cell fractions, while the corresponding receptors are expressed in adipocytes. Oncostatin-M expression increases in cultured human Thp1 macrophages following exercise-like stimuli. Our results suggest that immune cells, via secreted factors such as oncostatin-M, mediate a crosstalk between skeletal muscle and adipose tissue during exercise to regulate adipocyte metabolism and adaptation.

Exercise training reduces systemic inflammation and improves general health status in female migraineurs: a randomised controlled trail.

The objectives of this study were to assess the effect of 8 weeks of moderate-intensity aerobic training on permeability inflammatory indicators of matrix metalloproteinases (MMPs) and specific tissue inhibitors of MMPs in female migraineurs. Female migraineurs (n = 28, age 32 ± 6) were randomised into two groups: migraine with exercise training (EXE + Mig, n = 13) and migraine without exercise training (NON-EXE + Mig, n = 15). Matched healthy women were also recruited as a healthy control group (CON, n = 15). The EXE-Mig group performed 8weeks of aerobic training. Pre and post intervention, serum matrix metalloproteinases (MMP-2 and 9) and specific tissue inhibitors of MMPs (TIMP-1 and 2) were measured. In addition, body composition indices and VO2max were determined. Exercise training reduced serum MMP-9 in female migraineurs with between-group changes and a time x group interaction (p < 0.05). In addition, exercise training reduced the serum MMP-9/TIMP-1 ratio in female migraineurs with between-group changes and time x group interaction(p < 0.05). However, no training-induced effect was observed in serum TIMP-1, TIMP-2, MMP-2 contents (p > 0.05) and MMP-2/TIMP-2 ratio (p > 0.05). Finally, exercise training reduced body fat content, WHR and BMI, and improved VO2max (p < 0.01). Our results demonstrated beneficial effects of aerobic exercise training on some circulatory inflammation factors (MMP9, MMP-9/TIMP-1) and some health indicators in female migraineurs, suggesting that such training can be employed as a non-pharmacological therapeutic method.

Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer’s patients

BackgroundAge-associated deterioration of the immune system contributes to a chronic low-grade inflammatory state known as “inflammaging” and is implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD). Whether changes in the tissue environment caused by circulatory factors associated with aging may alter the innate immune response is unknown. Monocyte-derived macrophages (Mo-MФs) infiltrating the brain alongside microglia are postulated to play a modulatory role in LOAD and both express triggering receptor expressed on myeloid cells 2 (TREM2). Apolipoprotein E (APOE) acts as a ligand for TREM2, and their role in amyloid beta (Aβ) clearance highlights their importance in LOAD. However, the influence of the patient's own milieu (autologous serum) on the synthesis of TREM2 and APOE in infiltrating macrophages remains unknown.ObjectivesTo functionally assess patient-specific TREM2 and APOE synthesis, we designed a personalized assay based on Mo-MФs using monocytes from LOAD patients and matched controls (CO). We assessed the influence of each participant’s own milieu, by examining the effect of short- (1 day) and long- (10 days) term differentiation of the cells in the presence of the donor´s autologous serum (AS) into M1-, M2- or M0-macrophages. Additionally, sex differences and Aβ-uptake ability in short- and long-term differentiated Mo-MФs were assessed.ResultsWe showed a time-dependent increase in TREM2 and APOE protein levels in LOAD- and CO-derived cells. While AS did not differentially modulate TREM2 compared to standard fetal calf serum (FCS), AS decreased APOE levels in M2 macrophages but increased levels in M1 macrophages. Interestingly, higher levels of TREM2 and lower levels of APOE were detected in female- than in male- LOAD patients. Finally, we report decreased Aβ-uptake in long-term differentiated CO- and LOAD-derived cells, particularly in APOEε4(+) carriers.ConclusionsWe demonstrate for the first time the suitability of a personalized Mo-MФ cell culture-based assay for studying functional TREM2 and APOE synthesis in a patient's own aged milieu. Our strategy may thus provide a useful tool for future research on diagnostic and therapeutic aspects of personalized medicine.

Aging, longevity, and the role of environmental stressors: a focus on wildfire smoke and air quality.

Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied. Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD + boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions.

Therapeutic Plasma Exchange and Multiple Sclerosis Dysregulations: Focus on the Removal of Pathogenic Circulatory Factors and Altering Nerve Growth Factor and Sphingosine-1-Phosphate Plasma Levels.

Multiple sclerosis (MS) is predominantly an immune-mediated disease of the central nervous system (CNS) of unknown etiology with a possible genetic predisposition and effect of certain environmental factors. It is generally accepted that the disease begins with an autoimmune inflammatory reaction targeting oligodendrocytes followed by a rapid depletion of their regenerative capacity with subsequent permanent neurodegenerative changes and disability. Recent research highlights the central role of B lymphocytes and the corresponding IgG and IgM autoantibodies in newly forming MS lesions. Thus, their removal along with the modulation of certain bioactive molecules to improve neuroprotection using therapeutic plasma exchange (TPE) becomes of utmost importance. Recently, it has been proposed to determine the levels and precise effects of both beneficial and harmful components in the serum of MS patients undergoing TPE to serve as markers for appropriate TPE protocols. In this review we discuss some relevant examples, focusing on the removal of pathogenic circulating factors and altering the plasma levels of nerve growth factor and sphingosine-1-phosphate by TPE. Altered plasma levels of the reviewed molecular compounds in response to TPE reflect a successful reduction of the pro-inflammatory burden at the expense of an increase in anti-inflammatory potential in the circulatory and CNS compartments.

Personalized prediction of the probability of developing arterial hypertension and coronary heart disease in miners with anthracosilicosis using an automated system

Introduction. The remaining high level of production-related cardiovascular morbidity necessitates timely preventive measures. The development of an automated forecasting technique will make it possible to implement personalized and differentiated approaches in the prevention of cardiovascular pathology in persons in contact with harmful production factors.&#x0D; Materials and methods. The object of the study were workers employed in underground coal mining: One hundred sixty eight miners with previously diagnosed anthracosilicosis and 151 miners of the control group without lung pathology (a total of 319 people). Identification of diseases of the circulatory system and risk factors was carried out using clinical, laboratory, instrumental methods. The Bayes method was used to develop a forecasting system. The forecasting software as developed in the Lazarus environment using object-oriented programming methods.&#x0D; Results. The most informative markers associated with a high probability of developing arterial hypertension and coronary heart disease in workers with anthracosilicosis have been identified. A software “Automated system for personalized prediction of the probability of developing arterial hypertension and coronary heart disease in miners with anthracosilicosis” has been developed. An automated forecasting system determines the degree of risk of diseases based on the results of the sum of prognostic coefficients.&#x0D; Limitations. The limitation of the study was related to the sample of coal mine workers examined in the clinic of the Institute, namely: age from 40 to 54 years, long-term (more than 15 years) work experience in harmful working conditions. The study did not include miners who had other occupational diseases besides anthracosilicosis.&#x0D; Conclusions. An automated system of personalized forecasting ensures the formation of high cardiovascular risk groups with minimal time costs, which allows starting primary prevention of cardiological pathology in a timely manner.

Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall

Exercise promotes learning and memory recall as well as rescues cognitive decline associated with aging. The positive effects of exercise are mediated by circulatory factors that predominantly increase Brain Derived Neurotrophic Factor (BDNF) signaling in the hippocampus. Identifying the pathways that regulate the release of the circulatory factors by various tissues during exercise and that mediate hippocampal Mus musculus Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that two weeks of voluntary exercise in male mice activates autophagy in the hippocampus by increasing LC3B protein levels (p = 0.0425) and that autophagy is necessary for exercise-induced spatial learning and memory retention (p < 0.001; exercise + autophagy inhibitor chloroquine CQ versus exercise). We place autophagy downstream of hippocampal BDNF signaling and identify a positive feedback activation between the pathways. We also assess whether the modulation of autophagy outside the nervous system is involved in mediating exercise's effect on learning and memory recall. Indeed, plasma collected from young exercise mice promote spatial learning (p = 0.0446; exercise versus sedentary plasma) and memory retention in aged inactive mice (p = 0.0303; exercise versus sedentary plasma), whereas plasma collected from young exercise mice that received the autophagy inhibitor chloroquine diphosphate failed to do so. We show that the release of exercise factors that reverse the symptoms of aging into the circulation is dependent on the activation of autophagy in young animals. Indeed, we show that the release of the exercise factor, beta-hydroxybutyrate (DBHB), into the circulation, is autophagy-dependent and that DBHB promotes spatial learning and memory formation (p = 0.0005) by inducing hippocampal autophagy (p = 0.0479). These results implicate autophagy in peripheral tissues and in the hippocampus in mediating the effects of exercise on learning and memory recall and identify DBHB as a candidate endogenous exercise factor whose release and positive effects are autophagy-dependent.

Raynaud's Phenomenon: A Brush Up!

Raynaud's Phenomenon: A Brush Up!

What's New in Musculoskeletal Basic Science.

What's New in Musculoskeletal Basic Science.

Exercise and Dietary Factors Mediate Neural Plasticity Through Modulation of BDNF Signaling.

The term "neural plasticity" was first used to describe non-pathological changes in neuronal structure. Today, it is generally accepted that the brain is a dynamic system whose morphology and function is influenced by a variety of factors including stress, diet, and exercise. Neural plasticity involves learning and memory, the synthesis of new neurons, the repair of damaged connections, and several other compensatory mechanisms. It is altered in neurodegenerative disorders and following damage to the central or peripheral nervous system. Understanding the mechanisms that regulate neural plasticity in both healthy and diseased states is of significant importance to promote cognition and develop rehabilitation techniques for functional recovery after injury. In this minireview, we will discuss the mechanisms by which environmental factors promote neural plasticity with a focus on exercise- and diet-induced factors. We will highlight the known circulatory factors that are released in response to exercise and discuss how all factors activate pathways that converge in part on the activation of BDNF signaling. We propose to harness the therapeutic potential of exercise by using BDNF as a biomarker to identify novel endogenous factors that promote neural plasticity. We also discuss the importance of combining exercise factors with dietary factors to develop a lifestyle pill for patients afflicted by CNS disorders.

Sphingomyelinase activity promotes atrophy and attenuates force in human muscle fibres and is elevated in heart failure patients.

BackgroundActivation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease‐related loss of skeletal muscle mass and function in several clinical conditions including heart failure. Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients.MethodsThe effects of SMase on force production and intracellular Ca2+ handling were investigated in single intact human muscle fibres. Additional mechanistic studies were performed in single mouse toe muscle fibres. RNA sequencing was performed in human muscle bundles exposed to SMase. Intramuscular SMase activity was measured from heart failure patients (n = 61, age 69 ± 0.8 years, NYHA III‐IV, ejection fraction 25 ± 1.0%, peak VO2 14.4 ± 0.6 mL × kg × min) and healthy age‐matched control subjects (n = 10, age 71 ± 2.2 years, ejection fraction 60 ± 1.2%, peak VO2 25.8 ± 1.1 mL × kg × min). SMase activity was related to circulatory factors known to be associated with progression and disease severity in heart failure.ResultsSphingomyelinase reduced muscle fibre force production (−30%, P < 0.05) by impairing sarcoplasmic reticulum (SR) Ca2+ release (P < 0.05) and reducing myofibrillar Ca2+ sensitivity. In human muscle bundles exposed to SMase, RNA sequencing analysis revealed 180 and 291 genes as up‐regulated and down‐regulated, respectively, at a FDR of 1%. Gene‐set enrichment analysis identified ‘proteasome degradation’ as an up‐regulated pathway (average fold‐change 1.1, P = 0.008), while the pathway ‘cytoplasmic ribosomal proteins’ (average fold‐change 0.8, P < 0.0001) and factors involving proliferation of muscle cells (average fold‐change 0.8, P = 0.0002) where identified as down‐regulated. Intramuscular SMase activity was ~20% higher (P < 0.05) in human heart failure patients than in age‐matched healthy controls and was positively correlated with markers of disease severity and progression, and with several circulating inflammatory proteins, including TNF‐receptor 1 and 2. In a longitudinal cohort of heart failure patients (n = 6, mean follow‐up time 2.5 ± 0.2 years), SMase activity was demonstrated to increase by 30% (P < 0.05) with duration of disease.ConclusionsThe present findings implicate activation of skeletal muscle SMase as a mechanism underlying human heart failure‐related loss of muscle mass and function. Moreover, our findings strengthen the idea that SMase activation may underpin disease‐related loss of muscle mass and function in other clinical conditions, acting as a common patophysiological mechanism for the myopathy often reported in diseases associated with a systemic inflammatory response.

Local and systemic transcriptomic responses from acute exercise induced muscle damage of the human knee extensors.

Skeletal muscle is adaptable to a direct stimulus of exercise-induced muscle damage (EIMD). Local muscle gene networks and systemic circulatory factors respond to EIMD within days, mediating anti-inflammation and cellular proliferation. Here we show in humans that local EIMD of one muscle group is associated with a systemic response of gene networks that regulate muscle structure and cellular development in nonlocal homologous muscle not directly altered by EIMD. In the nondominant knee extensors of seven males, EIMD was induced through voluntary contractions against an electric motor that lengthened muscles. Neuromuscular assessments, vastus lateralis muscle biopsies, and blood draws occurred 2 days prior and 1 and 2 days after the EIMD intervention. From the muscle and blood plasma samples, RNA-Seq measured transcriptome changes of differential expression using bioinformatic analyses. Relative to the time of the EIMD intervention, local muscle that was mechanically damaged had 475 genes differentially expressed, as compared with 33 genes in the nonlocal homologous muscle. Gene and network analysis showed that activity of the local muscle was related to structural maintenance, repair, and energetic processes, whereas gene and network activities of the nonlocal muscle (that was not directly modified by the EIMD) were related to muscle cell development, stress response, and structural maintenance. Altered expression of two novel miRNAs related to the EIMD response supported that systemic factors were active. Together, these results indicate that the expression of genes and gene networks that control muscle contractile structure can be modified in response to nonlocal EIMD in humans.

Hippocampal Physiological and Behavioral Deficits Related to Alcohol‐induced Disruption of Local Blood Perfusion

Despite preventative education, moderate‐heavy episodic alcohol (ethanol; EtOH) intake, such as in “binge” drinking, remains a major public health problem. Binge drinking, can lead to blood ethanol levels above legal intoxication and cause alcohol‐induced blackouts (AIB), a form of amnesia linked to dysfunction of the hippocampal CA1 region. The neurobiological bases of AIB, however, remain largely unknown. It is noteworthy that proper function of neurons in the brain, including the CA1 region, critically depends on aerobic metabolism and optimal blood flow (BF). Using rodent models, we previously showed that EtOH at intoxicating concentrations constricted cerebral arteries independently of circulatory, metabolic, and endothelial factors, but due to drug inhibition of large conductance Ca2+‐ and voltage‐gated K+ (BK) channels present in vascular smooth muscle. Using behavioral modeling of contextual fear conditioning with miniscope technology, the present study tests the hypothesis that EtOH‐induced anterograde memory dysfunction is coincidental to EtOH‐induced reduction in local blood flow and reduced neuronal activity in the CA1 region. Thus, we used Ca2+‐release imaging to map single neuron activity in combination with dynamic local BF recordings in awake and freely moving mice to simultaneously determine vascular, neurophysiological and behavioral effects of EtOH in a mouse model of AIB. Ca2+ imaging was conducted using GCaMP6, which provided a blue fluorescent light when neurons released Ca2+, indicating action potentials, while rhodamine dextran dye provided a red label for the vasculature within the CA1. AIB was modeled via contextual fear conditioning, in which mice were exposed to electric shocks after receiving intraperitoneal injections (IP) of saline or EtOH. Twenty‐four hours later, animals were placed into the same boxes, and their freezing behavior was recorded. Data revealed that IP injection of 2 mg/kg EtOH evoked a robust (&gt;50%) decrease in Ca2+ fluorescence which was coincidental to an 18% decrease in cerebral artery diameter. Reductions in neuronal activity and cerebral artery diameter were, indeed, accompanied by a 42.3% reduction in freezing behavior (P&gt;0.05). Thus, this study identifies both vascular and neurophysiological components of EtOH action on the hippocampus CA1 region in a behavioral model of AIB. More generally, our study is the first to investigate the simultaneous effects of EtOH on behavior, including anterograde memory, neuronal activity, and local BF dynamics in the brain.

Circulatory metabolites trigger ex vivo arterial endothelial cell dysfunction in population chronically exposed to diesel exhaust

BackgroundChronic exposure to diesel exhaust has a causal link to cardiovascular diseases in various environmental and occupational settings. Arterial endothelial cell function plays an important role in ensuring proper maintenance of cardiovascular homeostasis and the endothelial cell dysfunction by circulatory inflammation is a hallmark in cardiovascular diseases. Acute exposure to diesel exhaust in controlled exposure studies leads to artery endothelial cells dysfunction in previous study, however the effect of chronic exposure remains unknown.ResultsWe applied an ex vivo endothelial biosensor assay for serum samples from 133 diesel engine testers (DETs) and 126 non-DETs with the aim of identifying evidence of increased risk for cardiovascular diseases. Environmental monitoring suggested that DETs were exposed to high levels of diesel exhaust aerosol (282.3 μg/m3 PM2.5 and 135.2 μg/m3 elemental carbon). Surprisingly, chronic diesel exhaust exposure was associated with a pro-inflammatory phenotype in the ex vivo endothelial cell model, in a dose-dependent manner with CCL5 and VCAM as most affected genes. This dysfunction was not mediated by reduction in circulatory pro-inflammatory factors but significantly associated with a reduction in circulatory metabolites cGMP and an increase in primary DNA damage in leucocyte in a dose-dependent manner, which also explained a large magnitude of association between diesel exhaust exposure and ex vivo endothelial biosensor response. Exogenous cGMP addition experiment further confirmed the induction of ex vivo biosensor gene expressions in endothelial cells treated with physiologically relevant levels of metabolites cGMP.ConclusionSerum-borne bioactivity caused the arterial endothelial cell dysfunction may attribute to the circulatory metabolites based on the ex vivo biosensor assay. The reduced cGMP and increased polycyclic aromatic hydrocarbons metabolites-induced cyto/geno-toxic play important role in the endothelial cell dysfunction of workers chronic exposure to diesel exhaust.