Potential roles of serum ATPase and AMPase in predicting diagnosis of colorectal cancer patients.

Colorectal cancer (CRC) is a common gastrointestinal cancer with high incidence and mortality rates. CRC may be associated with regulation of circulating nucleotides. This study aimed to evaluate the serum levels of nucleotide-metabolizing enzymes (ATPase and AMPase) in patients with CRC and to explore the clinical diagnostic value of these enzymes. The gene set variation analysis (GSVA) score of the ATP-adenosine signature was calculated using tumor samples from The Cancer Genome Atlas (TCGA). ATP-adenosine signaling plays a central role in CRC progression. A total of 135 subjects, including 87 patients with CRC and 48 healthy controls, were included. The serum levels of ATPase and AMPase in the CRC group were significantly higher than those in the control group (P < 0.05). Furthermore, ATP and AMP hydrolysis levels significantly increased in the advanced CRC group (P < 0.05). ATP and AMP hydrolysis was decreased by the ENTPDase inhibitors (POM-1 and ARL67156) and CD73 inhibitor (APCP). The sensitivities of ATPase and AMPase were 95.4% and 75.9%, respectively, which were higher than those of CEA (67.8%) and CA19-9 (72.4%). The specificities of ATPase and AMPase were 69.9% and 73.9%, respectively, which were higher than that of CA19-9 (47.8%). The combination of CEA, ATPase, and AMPase demonstrated high sensitivity (92.0%) and specificity (87.0%). Collectively, ATPase and AMPase activities are upregulated in CRC with considerable diagnostic significance. The combination of CEA, ATPase, and AMPase may provide a novel approach for CRC screening.

Alterations in CD39/CD73 axis of T cells associated with COVID-19 severity.

Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in coronavirus disease 2019 (COVID-19) patients. Mild and severe COVID-19 patients had lower extracellular adenosine triphosphate and adenosine levels, and higher cytokines than healthy controls. Mild COVID-19 patients presented lower frequencies of CD4+ CD25+ CD39+ (activated/memory regulatory T cell [mTreg]) and increased frequencies of high-differentiated (CD27- CD28- ) CD8+ T cells compared with healthy controls. Severe COVID-19 patients also showed higher frequencies of CD4+ CD39+ , CD4+ CD25- CD39+ (memory T effector cell), and high-differentiated CD8+ T cells (CD27- CD28- ), and diminished frequencies of CD4+ CD73+ , CD4+ CD25+ CD39+ mTreg cell, CD8+ CD73+ , and low-differentiated CD8+ T cells (CD27+ CD28+ ) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8+ T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4+ Annexin-V+ and CD8+ Annexin-V+ T cells, indicating increased T-cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4+ and CD8+ T cells of a healthy donor. Interestingly, the in vitro incubation of peripheral blood mononuclear cell from severe COVID-19 patients with adenosine reduced the nuclear factor-κB activation in T cells and monocytes. Together, these data add new knowledge to the COVID-19 immunopathology through purinergic regulation.

Protection from benzene-induced immune dysfunction in mice.

Benzene can impair peripheral immunity and immune organs; however, the recovery of benzene impairment has rarely been reported. In this study, we developed an immune dysfunction mouse model using a benzene gavage (500 mg/kg). Female Balb/c mice were treated with Bombyx batryticatus (BB, 5 g/kg), raw pinellia (RP, 5 g/kg), or a combination of Valproic acid and Coenzyme Q10 (CM, 150 mg/kg VPA & 100 mg/kg CoQ10) medication for four weeks. The immune function of the peripheral blood mononuclear cells (PBMCs), spleen, and thymus was determined to evaluate whether the observed impairment could be altered by medications in the mouse model. Results showed that medications could alleviate benzene-induced structural and functional damage of spleen and thymus. Benzene exposure decreased the ATP level of PBMC, which can be improved by BB, RP or CM. Importantly, BB, RP or CM could relieve benzene induced-oxidative stress by increasing the activities of glutathione peroxidase (GSH) and superoxide dismutase (SOD) and decreasing the contents of malondialdehyde (MDA). In conclusion, BB, RP, and CM were able to alleviate the benzene-induced immune dysfunction and redox imbalance. Improvement of the oxidative and antioxidant imbalance may represent a mechanism by which medicine prevents benzene-induced immune dysfunction.

Changes in hemoglobin function and isoform expression during embryonic development in the American alligator, Alligator mississippiensis.

In the developing embryos of egg-laying vertebrates, O2 flux takes place across a fixed surface area of the eggshell and the chorioallantoic membrane. In the case of crocodilians, the developing embryo may experience a decrease in O2 flux when the nest becomes hypoxic, which may cause compensatory adjustments in blood O2 transport. However, whether the switch from embryonic to adult hemoglobin isoforms (isoHbs) plays some role in these adjustments is unknown. Here, we provide a detailed characterization of the developmental switch of isoHb synthesis in the American alligator, Alligator mississippiensis. We examined the in vitro functional properties and subunit composition of purified alligator isoHbs expressed during embryonic developmental stages in normoxia and hypoxia (10% O2). We found distinct patterns of isoHb expression in alligator embryos at different stages of development, but these patterns were not affected by hypoxia. Specifically, alligator embryos expressed two main isoHbs: HbI, prevalent at early developmental stages, with a high O2 affinity and high ATP sensitivity, and HbII, prevalent at later stages and identical to the adult protein, with a low O2 affinity and high CO2 sensitivity. These results indicate that whole blood O2 affinity is mainly regulated by ATP in the early embryo and by CO2 and bicarbonate from the late embryo until adult life, but the developmental regulation of isoHb expression is not affected by hypoxia exposure.

Red blood cell ATP release correlates with red blood cell hemolysis.

The precise matching of blood flow to skeletal muscle during exercise remains an important area of investigation. Release of adenosine triphosphate (ATP) from red blood cells (RBCs) is postulated as a mediator of peripheral vascular tone in response to shear stress, hypoxia, and mechanical deformation. We tested the following hypotheses: 1) RBCs of different densities contain different quantities of ATP; 2) hypoxia is a stimulus for ATP release from RBCs; and 3) hypoxic ATP release from RBCs is related to RBC lysis. Human blood was drawn from male and female volunteers (n = 11); the RBCs were isolated and washed. A Percoll gradient was used to separate RBCs based on cellular density. Density groups were then resuspended to 4% hematocrit and exposed to normoxia or hypoxia in a tonometer. Equilibrated samples were drawn and centrifuged; paired analyses of ATP (luminescence via a luciferase-catalyzed reaction) and hemolysis (Harboe spectrophotometric absorbance assay) were measured in the supernatant. ATP release was not different among low-density cells versus middle-density versus high-density cells. Similarly, hemoglobin (Hb) release was not different among the red blood cell subsets. No difference was found for either ATP release or Hb release following matched exposure to normoxic or hypoxic gas. The concentrations of ATP and Hb for all subsets combined were linearly correlated (r = 0.59, P ≤ 0.001). With simultaneous probing for Hb and ATP in the supernatant of each sample, we conclude that ATP release from RBCs can be explained by hemolysis and that hypoxia per se does not stimulate either ATP release or Hb release from RBCs.

A magnified aptamer fluorescence sensor based on the metal organic frameworks adsorbed DNA with enzyme catalysis amplification for ultra-sensitive determination of ATP and its logic gate operation.

With the development of frame materials, metal organic frameworks (MOFs) have been successfully applied in the fields of biological small molecule analysis and fluorescent DNA detection. In this work, in view of the good adsorption characteristics of MIL-101(Cr), the highly sensitive detection of adenosine triphosphate (ATP) assisted nucleic acid exonuclease amplification by MIL-101(Cr) on the different affinity of single stranded DNA and double stranded DNA was investigated. The detection limit of ATP reaches 1.7 µM, and the platform has good applicability in biological samples. On this basis, an "AND" logic gate was successfully constructed. Superior sensitivity to ATP in the presence of exonuclease was reflected, which greatly enhanced the system's fluorescence. Importantly, the fluorescence sensing application of this nanomaterial inspired other target detection and enriched the building blocks of fluorescence sensing platform.

A Novel Electrochemical Aptasensor for the Ultrasensitive Detection of Adenosine Triphosphate Based on DNA-Templated Copolymers.

Adenosine triphosphate (ATP) is a small but significant biological molecule that plays an important role in regulating cellular metabolism processes. Accurate and sensitive analytical techniques for detecting ATP are urgently needed. Herein, a new electrochemical aptasensor was designed in light of DNA-templated copolymers that parallel to the electrode for sensitive gauging of ATP. The ATP aptamer decorated by the electronic medium ferrocene can be regarded as a ″bridge″ connecting two DNA-templated copolymers. When ATP exists, because of the extraordinary binding selectivity of DNA-templated copolymers for target ATP, the rapid electron transfer of ferrocene was beneficial to the sensitive detection of target ATP. Specifically, our parallel DNA copolymers are more stable than upright DNA copolymers and have a faster signal transmission because of the close distance to the electrode; meanwhile, the nonspecific pollution is less. Consequently, the developed novel aptasensor exhibited a wide range of linear response toward ATP that was from 0.1 to 10 000 pM and high selectivity with a detection limit down to 11.5 fM. The electrochemical aptasensor has a broad application prospect in the detection of small biological molecules.

Mitochondrial Dynamics Markers and Related Signaling Molecules Are Important Regulators of Spermatozoa Number and Functionality.

Here, we study possible mechanisms of (in/sub)fertility related to the acute or repeated psychological stresses (the most common stresses in human society) by following the transcriptional profile of 22 mitochondrial dynamics/function markers and 22 signaling molecules regulating both mitochondrial dynamics and spermatozoa number/functionality. An in vivo study mimicking acute (once for 3 h) and repeated (3 h for 10 consecutive days) psychophysical stress was performed on adult rats. The analysis of hormones, the number/functionality of spermatozoa, and 44 transcriptional markers were performed on individual samples from up to 12 animals per group. Results showed that both types of stress reduced spermatozoa functionality (acute by 4.4-fold, repeated by 3.3-fold) and ATP production (acute by 2.3-fold, repeated by 14.5-fold), while only repeated stress reduces the number of spermatozoa (1.9-fold). Stress significantly disturbed transcription of 34-out-of-44 markers (77%). Mitochondrial dynamics and functionality markers: 18-out-of-22 =>82% (mitochondrial-biogenesis-markers ->6-out-of-8 =>75%; mitochondrial-fusion-markers ->3-out-of-3 =>100%; mitochondrial-fission-markers ->1-out-of-2 =>50%; mitochondrial-autophagy-markers ->3-out-of-3 =>100%; mitochondrial-functionality-markers ->5-out-of-6 =>83%). Markers of signaling pathways regulating both mitochondrial dynamics/functionality and spermatozoa number/functionality important for male (in/sub)fertility ->16-out-of-22 =>73% (cAMP-signaling-markers ->8-out-of-12 =>67%; MAPK-signaling-markers ->8-out-of-10 =>80%). Accordingly, stress-triggered changes of transcriptional profile of mitochondrial dynamics/functionality markers as well as signaling molecules regulating both mitochondrial dynamics and spermatozoa number and functionality represent adaptive mechanisms.

Pyruvate accumulation may contribute to acceleration-induced impairment of physical and cognitive abilities: an experimental study.

BACKGROUND: Fatigue can be induced after acceleration exposure, however its mechanism is still unclear. The aim of the present study was to examine whether metabolites' changes can decrease cognitive and physical function after acceleration. METHODS: Graybiel scale and Fatigue Self-rating scale were used to assess the seasickness and fatigue degrees of 87 male seafarers respectively after sailing. To test the effect of pyruvate on cognitive and physical functions, five different doses of pyruvate were administrated into rats. Insulin can reduce the accumulation of pyruvate. To observe the insulin effect on pyruvate, cognitive and physical functions after acceleration, insulin administration or treatment of promoting insulin secretion was used. Physical and cognitive functions were assessed using open field test (OFT), morris water maze (MWM) and loaded swimming test (LST) in animals. RESULTS: Physical and cognitive abilities were decreased obviously, and serum pyruvate increased mostly in human and rats after acceleration. Compared with vehicle group, physical and cognitive abilities were significantly decreased after pyruvate administration. Besides, we found a significant decline in adenosine triphosphate (ATP) concentration and pyruvate dehydrogenase (PDH) activity in the hippocampus, prefrontal cortex, liver, and muscle of rats treated with acceleration or pyruvate injection, while insulin administration or treatment of promoting insulin secretion markedly alleviated this decline and the impairment of physical and cognitive abilities, compared with the control group. CONCLUSION: Our results indicate that pyruvate has a negative effect on physical and cognitive abilities after acceleration. Insulin can inhibit pyruvate accumulation and cognitive and physical function after acceleration exposure.

Trimetazidine alone or in combination with gemcitabine and/or abraxane decreased cell viability, migration and ATP levels and induced apoptosis of human pancreatic cells.

BACKGROUND: Trimetazidine (TMZ) is an anti-ischemic agent that can inhibit the fatty acid oxidation. It has been stated that inhibition of fatty acid oxidation may be an acceptable approach to cancer treatment. METHODS: We examined the effects of TMZ alone or together with abraxane (ABX) and/or gemcitabine (GEM) on cell viability, apoptosis, adhesion, migration and ATP levels of human pancreatic cancer cell line PANC-1. RESULTS: TMZ significantly reduced the cell viability at higher concentrations. Lower cell viability values were found in cells co-treated with TMZ + GEM, TMZ + ABX and GEM + ABX. The combined treatment of TMZ with ABX and/or GEM significantly increased the apoptosis rates. The highest percentages of apoptosis were found in TMZ + ABX or TMZ + ABX + GEM treatments. TMZ alone or together with ABX and/or GEM significantly reduced the ATP levels. The lowest migration rates were also found at TMZ + ABX and TMZ + ABX + GEM treatments. CONCLUSIONS: Our study is the first study to indicate that TMZ can induce cytotoxicity and apoptosis and reduce migration and ATP levels, especially in cells co-treated with ABX and/or GEM. A combination strategy based on inhibition of fatty acid oxidation and anticancer drugs may be more effective in the treatment of pancreatic cancers.

Relationship between serum concentration, functional parameters and cell bioenergetics in IPEC-J2 cell line.

The foetal bovine serum (FBS) concentration could influence functional parameters of IPEC-J2 cells. IPEC-J2 is a non-transformed continuous epithelial cell line that represents an established in vitro model to study porcine gut inflammation and alterations of intestinal integrity. This cell line also represents a good translational model thanks to the high similitudes between pig and human gastrointestinal tract. With the aim to assess if the FBS-dependent functional variations are linked to the bioenergetic aspects, the addition of 5% and 10% FBS in the IPEC-J2 culture medium were tested. Doubling time and TEER measurement indicated that cells cultured at higher FBS dose grow faster and as a more compact monolayer. 10% FBS increases ATP production and mitochondrial oxidative phosphorylation (OxPhos) and does not affect glycolysis. Both at 5% and 10% FBS ATP production mainly comes from OxPhos and FBS concentration does not affect the cell respiration bioenergetic parameters. Noteworthy, IPEC-J2 treated with 5% and 10% FBS have a metabolic potential since both OxPhos and glycolysis increase by > 100% and < 50%, respectively in comparison with baseline metabolism. Moreover, glucose, fatty acids and glutamine constitute the preferred metabolic fuel for mitochondrial respiration at both FBS conditions tested. Accordingly, the cells flexibility to oxidize these substrates shows that IPEC-J2 mitochondria cannot maintain the basal ATP production without oxidizing all the substrates available irrespective of FBS concentration. To sum up, in IPEC-J2 cells OxPhos increases with the FBS-stimulated functional physiological parameters to fulfil ATP requirements.

Association of aryl hydrocarbon receptor transactivating activity, a potential biomarker for persistent organic pollutants, with the risk of gestational diabetes mellitus.

Persistent organic pollutants(POPs) are suggested to be potential risk factors for gestational diabetes mellitus(GDM). We examined the hypothesis that the aryl hydrocarbon receptor trans-activating(AhRT) activity, a potential biomarker for the presence of POPs, could be a GDM risk factor in pregnant women. A total of 390 GDM and 100 normal pregnant(non-GDM) subjects in the Korea National Diabetes Program cohort voluntarily participated. We measured AhRT activity and concentrations of ATP and reactive oxygen in the serum collected at the screening of the participants for GDM using recombinant Hepa1c1c7 cells. Odds ratios(ORs) and 95% confidence intervals(CIs) were estimated using multivariable logistic regression models. The sensitivity and specificity of AhRT activity for GDM diagnostics were measured by receiver operating characteristic(ROC) analysis. Body mass index at pre-pregnancy and delivery and systolic blood pressure were significantly higher in the GDM group. AhRT activity was higher, and ATP concentrations were lower in the GDM group than the non-GDM group(P < 0.0001). AhRT activity was significantly higher in the GDM group(OR 29.3, 95% CI 10.9-79.1) compared with non-GDM(P < 0.0001). Serum glucose concentration at 1 h after a 50 g glucose challenge(glucose-50) was moderately correlated with AhRT activity(r2 = 0.387) and negatively correlated with ATP production(r2 = -0.650). In the ROC curve, AhRT activity had 70.9% sensitivity and 90.0% specificity for glucose-50, a GDM screening method. In conclusion, this study suggests that serum AhRT activity is positively associated with the risk of GDM.

Pannexin 1 channels control the hemodynamic response to hypoxia by regulating O2-sensitive extracellular ATP in blood.

Pannexin 1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contribute to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to metabolic demand of tissue. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/-erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (n = 6) and WT (n = 6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16 ± 9% vs. -2 ± 8%; P < 0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (n = 6) vs. WT (n = 6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8 ± 6% vs. -10 ± 13%; P < 0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs. -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (n = 6) vs. WT mice (n = 6; P < 0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (n = 8) was 82% lower than that from WT (n = 8; P < 0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.NEW & NOTEWORTHY Export of vasodilator ATP from red blood cells requires pannexin 1. Blood plasma ATP elevations in response to hypoxia in mice require pannexin 1. Hemodynamic responses to hypoxia are accompanied by increased plasma ATP in mice in vivo and require pannexin 1.

Functional Assessment of Platelet Dense Granule ATP Release.

OBJECTIVES: This study was undertaken to explore the feasibility of assessing platelet dense granule release in response to platelet stimuli, using less than 1 mL of whole blood (WB). METHODS: Optimization of the luciferin-luciferase (LL) assay for ATP release, together with additional modifications, was applied to 1:10 diluted WB. RESULTS: LL assay optimization using nonstirred 1:10 diluted WB resulted in dense granule ATP release in response to thrombin receptor-activating peptide (TRAP) of similar magnitude to that observed using stirred platelet-rich plasma. Stirring of the 1:10 diluted WB restored collagen-induced dense granule secretion. Addition of lyophilized, formalin-fixed platelets, together with stirring, restored dense granule secretion responsiveness to ADP. TRAP, ADP, and collagen all stimulated ATP release in 1:10 diluted WB under the optimized conditions of this study at levels close to those observed using platelet-rich plasma. Blood sample reconstitution experiments offer hope that this assay may prove robust down to WB platelet counts as low as 50 × 103/µL. CONCLUSIONS: Platelet dense granule release in response to a number of classic stimuli, including ADP, was accomplished from less than 1 mL WB with minimal specimen processing, using widely available reagents and instrumentation.

Increased levels of plasma nucleotides in patients with rheumatoid arthritis.

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive non-targeted metabolomics approach combining capillary electrophoresis time-of-flight mass spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of a Japanese population [92 RA patients, 13 systemic lupus erythematosus (SLE) patients and 181 healthy controls). RA case-control association tests showed that seven metabolites exhibited significantly increased levels in RA samples compared with controls (P < 1.0 × 10-4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid and taurine), whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P < 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotide levels showed significant differences in SLE case-control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case-control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotide levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA.

Ticagrelor: a cardiometabolic drug targeting erythrocyte-mediated purinergic signaling?

Cardiometabolic diseases lead to vascular complications, which cause increasing morbidity and mortality worldwide. The underlying mechanisms are multifactorial and complex but may involve altered purinergic signaling that significantly contributes to cardiovascular dysfunction. Ticagrelor is a successful purinergic drug directly targeting ADP-mediated P2Y12R signaling for platelet aggregation and is widely used in patients with acute coronary syndrome. In addition, ticagrelor can target red blood cells (RBCs) to release ATP and inhibit adenosine uptake by RBCs, which subsequently activate purinergic signaling. This involvement in purinergic signaling may allow ticagrelor to mediate pleiotropic effects and contribute to the beneficial cardiovascular outcomes observed in clinical studies. Recent studies have established a novel function of RBCs, which is that RBCs act as disease mediators for the development of cardiovascular complications in type 2 diabetes (T2D). RBC-released ATP is defective in T2D, which has implications for the induction of vascular dysfunction by dysregulating purinergic signaling. Ticagrelor might target RBCs and restore the bioavailability of ATP and adenosine, thereby attenuating cardiovascular complications. The present perspective discusses the pleiotropic effect of ticagrelor, with a focus on the possibility of ticagrelor for the treatment of cardiometabolic complications by targeting RBCs and initiating purinergic activation. A better understanding of the proposed cardiometabolic effects could support novel clinical indications for ticagrelor application.

Exosomes in Sepsis.

Sepsis is a severe state of infection with high mortality. Pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) initiate dysregulated systemic inflammation upon binding to pattern recognition receptors. Exosomes are endosome-derived vesicles, which carry proteins, lipids and nucleic acids, and facilitate intercellular communications. Studies have shown altered contents and function of exosomes during sepsis. In sepsis, exosomes carry increased levels of cytokines and DAMPs to induce inflammation. Exosomal DAMPs include, but are not limited to, high mobility group box 1, heat shock proteins, histones, adenosine triphosphate, and extracellular RNA. Exosomes released during sepsis have impact on multiple organs, including the lungs, kidneys, liver, cardiovascular system, and central nervous system. Here, we review the mechanisms of inflammation caused by exosomes, and their contribution to multiple organ dysfunction in sepsis.

Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.

BACKGROUND: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects. METHODS: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmales = 11; nfemales = 19); 26 patients completed the study (nmales = 10; nfemales = 16). Each patient was administered febuxostat 20 mg and inosine 500 mg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment. RESULTS: Serum hypoxanthine concentrations were raised significantly after treatment (Pre = 11.4 µM; Post = 38.1 µM; P < .0001). MDS-UPDRS Part III score was significantly lower after treatment (Pre = 28.1 ±â€Š9.3; Post = 24.7 ±â€Š10.8; mean ±â€ŠSD; P = .0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment. CONCLUSIONS: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.

Nicotinic acid receptor agonists impair myocardial contractility by energy starvation.

Nicotinic acid receptor agonists have previously been shown to cause acute reductions in cardiac contractility. We sought to uncover the changes in cardiac metabolism underlying these alterations in function. In nine humans, we recorded cardiac energetics and function before and after a single oral dose of nicotinic acid using cardiac MRI to demonstrate contractile function and Phosphorus-31 (31 P) magnetic resonance spectroscopy to demonstrate myocardial energetics. Nicotinic Acid 400 mg lowered ejection fraction by 4% (64 ± 8% to 60 ± 7%, P = .03), and was accompanied by a fall in phosphocreatine/ATP ratio by 0.4 (2.2 ± 0.4 to 1.8 ± 0.1, P = .04). In four groups of eight Wistar rats, we used pyruvate dehydrogenase (PDH) flux studies to demonstrate changes in carbohydrate metabolism induced by the nicotinic acid receptor agonist, Acipimox, using hyperpolarized Carbon-13 (13 C) magnetic resonance spectroscopy. In rats which had been starved overnight, Acipimox caused a fall in ejection fraction by 7.8% (67.5 ± 8.9 to 60 ± 3.1, P = .03) and a nearly threefold rise in flux through PDH (from 0.182 ± 0.114 to 0.486 ± 0.139, P = .002), though this rise did not match pyruvate dehydrogenase flux observed in rats fed carbohydrate rich chow (0.726 ± 0.201). In fed rats, Acipimox decreased pyruvate dehydrogenase flux (to 0.512 ± 0.13, P = .04). Concentration of plasma insulin fell by two-thirds in fed rats administered Acipimox (from 1695 ± 891 ng/L to 550 ± 222 ng/L, P = .005) in spite of glucose concentrations remaining the same. In conclusion, we demonstrate that nicotinic acid receptor agonists impair cardiac contractility associated with a decline in cardiac energetics and show that the mechanism is likely a combination of reduced fatty acid availability and a failure to upregulate carbohydrate metabolism, essentially starving the heart of fuel.