The D‐vitamin metabolite 1,25(OH)2D in serum is associated with disease activity and Anti‐Citrullinated Protein Antibodies in active and treatment naïve,early Rheumatoid Arthritis Patients

Rationale

Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA ). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH )₂D.

Objective

To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHD ₂, 25OHD ₃ and 1,25(OH )₂D) was measured by isotope dilution mass spectrometry and radio‐immunoassays at baseline. Disease characteristics were gender, number of tender joints, number of swollen joints, DAS 28‐CRP , HAQ , VAS ‐scores, CRP , erosive status (Total Sharp Score; TSS ), ACPA and IgM‐RF ‐status. Associations were evaluated using Spearman's and Wilcoxon rank‐sum tests. The study was registered in clinical trials; trial registration number: NCT 00209859.

Findings

Statistically significant inverse associations were found between the active metabolite 1,25(OH )₂D and DAS 28‐CRP (P  = 0.004, rho = −0.23), HAQ (P  = 0.005, rho = −0.22), CRP (P  = 0.001, rho = −0.25), VAS _{patient‐pain} (P  = 0.008, rho = −0.21), and a positive association was found to ACPA ‐status (P  = 0.04).

Conclusion

The vitamin D metabolite 1,25(OH )₂D was inversely associated with disease activity and positively associated with ACPA in treatment naïve and inflammatory active early RA . The results indicate that in RA , both the degree of inflammatory activity, and the diagnostic sensitivity and specificity might affect—or might be affected by the level of vitamin 1,25(OH )₂D.

     

Biotransformation of ginsenosides Rb<Subscript>1</Subscript>, Rg<Subscript>3</Subscript> and Rh<Subscript>2</Subscript> in rat gastrointestinal tracts

Background  

Ginsenosides such as Rb₁, Rg₃ and Rh₂ are major bioactive components of Panax ginseng. This in vivo study investigates the metabolic pathways of ginsenosides Rb₁, Rg₃ and Rh₂ orally administered to rats.     

Recovery dynamics of skeletal muscle oxygen uptake during the exercise off-transient

The time course of muscle recovery from contractions (i.e., muscle off-kinetics), measured directly at the site of O₂ exchange, i.e., in the microcirculation, is unknown. Whereas biochemical models based upon creatine kinase flux rates predict slower off- than on-transients [Kushmerick, M.J., 1998. Comp. Biochem. Physiol. B: Biochem. Mol. Biol.] whole muscle data [Krustrup, et al. J. Physiol.] suggest on–off symmetry.

Purpose

We tested the hypothesis that the slowed recovery blood flow (Qm) kinetics profile in the spinotrapezius muscle [Ferreira et al., 2006. J. Physiol.] was associated with a slowed muscle recovery compared with that seen at the onset of contractions (time constant, τ  23 s, Behnke et al., 2002. Resp. Physiol.), i.e., on–off asymmetry.

Methods

Measurements of capillary red blood cell flux and microvascular pressure of O₂ (P_O2mv) were combined to resolve the temporal profile of muscle across the moderate intensity contractions-to-rest transition.

Results

Muscle decreased from an end-contracting value of 7.7 ± 0.2 ml/100 g/min to 1.7 ± 0.1 ml/100 g/min at the end of the 3 min recovery period, which was not different from pre-stimulation . Contrary to our hypothesis, muscle in recovery began to decrease immediately (i.e., time delay <2 s) and demonstrated rapid first-order kinetics (τ, 25.5 ± 2.6 s) not different (i.e., symmetrical to) to those during the on-transient. This resulted in a systematic increase in microvascular P_O2 during the recovery from contractions.

Conclusions

The slowed Qm kinetics in recovery serves to elevate the ratio and thus microvascular P_O2. Whether this Qm response is obligatory to the rapid muscle kinetics and hence speeds the repletion of high-energy phosphates by maximizing conductive and diffusive O₂ flux is an important question that awaits resolution.     

Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced cyclooxygenase-2 expression in mouse brain endothelial cells

Background  

Prostaglandin E₂ (PGE₂), an arachidonic acid metabolite converted by cyclooxygenase-2 (COX-2), plays important roles in the regulation of endothelial functions in response to bacterial infection. The enzymatic activity of COX-2 can be down-regulated by heme oxygenase-1 (HO-1) induction. However, the mechanisms underlying HO-1 modulating COX-2 protein expression are not known.     

Adaptive regression modeling of biomarkers of potential harm in a population of U.S. adult cigarette smokers and nonsmokers

Background  

This article describes the data mining analysis of a clinical exposure study of 3585 adult smokers and 1077 nonsmokers. The analysis focused on developing models for four biomarkers of potential harm (BOPH): white blood cell count (WBC), 24 h urine 8-epi-prostaglandin F_2α (EPI8), 24 h urine 11-dehydro-thromboxane B₂ (DEH11), and high-density lipoprotein cholesterol (HDL).     

Effects of 1,25-(OH)<Subscript>2</Subscript>D<Subscript>3</Subscript> on the expressions of vitamin D receptor,STAT5 and cytoskeletal rearrangement in human monocytes incubated with sera from type 2 diabetes patients and diabetic nephropathy patients with uremia

Objective  

To explore the effects of 1,25-(OH)₂D₃ and lipopolysaccharide (LPS) plus human recombinant interleukin-15 (IL-15) on expression of vitamin D receptor (VDR) and STAT5, and cytoskeletal rearrangement in human monocytes incubated with sera from type 2 diabetes (T2DM) patients and diabetic nephropathy (DN) patients with uremia.     

Dupilumab is effective in type 2-high asthma patients receiving high-dose inhaled corticosteroids at baseline

Background

Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation. In phase 2b (NCT01854047) and phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200/300 mg every 2 weeks (q2w) reduced severe exacerbations, improved prebronchodilator (pre-BD) forced expiratory volume in 1 second (FEV₁) and quality of life measures, and it was generally well tolerated in patients with uncontrolled, persistent (phase 2b), or moderate-to-severe (phase 3) asthma.

Methods

In patients on high-dose inhaled corticosteroids (ICS) with type 2-high asthma (subgroups including baseline blood eosinophils ≥150/300 cells/µL and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb), annualized severe exacerbation rates over the treatment period, changes from baseline in pre-BD FEV₁ and asthma control (5-item asthma control questionnaire [ACQ-5]) were analyzed.

Results

In high-dose ICS type 2-high subgroups, dupilumab 200/300 mg q2w vs placebo in the phase 2b (24 weeks) and phase 3 (52 weeks) studies significantly reduced severe exacerbations by 55%-69%/57%-60% (all P<.05) and 53%-69%/48%-66% (all P < .001), respectively, except in patients with ≥ 300 eosinophils/µL in phase 2b study (24%/50% (P = .52/0.15). Across subgroups, pre-BD FEV₁ improved by 0.18-0.22 L/0.19-0.24 L (all P < .05) and 0.23-0.36 L/0.15-0.25 L (all P < .01) and ACQ-5 scores were reduced by 0.46-0.55/0.47-0.85 (all P < .05) and 0.38-0.50/0.24-0.30 (all P < .05), respectively, except dupilumab 200 mg q2w in phase 2b in patients with FeNO ≥ 25 ppb (0.41; P = .09). Dupilumab was also effective in patients taking medium-dose ICS.

Conclusion

Dupilumab significantly reduced severe exacerbations and improved lung function and asthma control in patients with type 2-high asthma on high-dose ICS at baseline.

     

Cytosolic phospholipase A<Subscript>2</Subscript>alpha amplifies early cyclooxygenase-2 expression,oxidative stress and MAP kinase phosphorylation after cerebral ischemia in mice

Background  

The enzyme cytosolic phospholipase A₂ alpha (cPLA₂α) has been implicated in the progression of cerebral injury following ischemia and reperfusion. Previous studies in rodents suggest that cPLA₂α enhances delayed injury extension and disruption of the blood brain barrier many hours after reperfusion. In this study we investigated the role of cPLA₂α in early ischemic cerebral injury.     

Neurovascular hypoxia after mild traumatic brain injury in juvenile mice correlates with heart–brain dysfunctions in adulthood

Aim

Retrospective studies suggest that mild traumatic brain injury (mTBI) in pediatric patients may lead to an increased risk of cardiac events. However, the exact functional and temporal dynamics and the associations between heart and brain pathophysiological trajectories are not understood.

Methods

A single impact to the left somatosensory cortical area of the intact skull was performed on juvenile mice (17 days postnatal). Cerebral 3D photoacoustic imaging was used to measure the oxygen saturation (sO₂) in the impacted area 4 h after mTBI followed by 2D and 4D echocardiography at days 7, 30, 90, and 190 post-impact. At 8 months, we performed a dobutamine stress test to evaluate cardiac function. Lastly, behavioral analyses were conducted 1 year after initial injury.

Results

We report a rapid and transient decrease in cerebrovascular sO₂ and increased hemoglobin in the impacted left brain cortex. Cardiac analyses showed long-term diastolic dysfunction and a diminished systolic strain response under stress in the mTBI group. At the molecular level, cardiac T-p38MAPK and troponin I expression was pathologic modified post-mTBI. We found linear correlations between brain sO₂ measured immediately post-mTBI and long-term cardiac strain after 8 months. We report that initial cerebrovascular hypoxia and chronic cardiac dysfunction correlated with long-term behavioral changes hinting at anxiety-like and memory maladaptation.

Conclusion

Experimental juvenile mTBI induces time-dependent cardiac dysfunction that corresponds to the initial neurovascular sO₂ dip and is associated with long-term behavioral modifications. These imaging biomarkers of the heart–brain axis could be applied to improve clinical pediatric mTBI management.     

Can l(+)-lactate be used as a marker of experimentally induced inflammation in rats?

Objective  

The purpose of this study was to investigate if l(+)-lactate (lactate) can be used as a marker of progression of joint inflammation in comparison with a reference marker, prostaglandin E2 (PGE₂), and to analyse implications for drug treatments.     

The variation of AkT/TSC1-TSC1/mTOR signal pathway in hepatocytes after partial hepatectomy in rats

Objective

The aim of this study was to investigate the role and regulatory mechanisms of Akt/TSC1-TSC2/mTOR signal pathway on the hepatocyte growth and proliferation after partial hepatectomy in rats.

Methods

We used the animal model of 70% hepatectomy, separated and cultivated hepatocytes. According to the different time points after partial hepatectomy, it could be grouped into 0 h, 2 h, 6 h, 24 h and 72 h. According to the different kinds of specific inhibitor in the nutritive medium after the separation of hepatocytes, it could be grouped into Triciribine (TR), Rapamycin (RA) and Control (CO). We investigated ³H-Leucine incorporation into protein, the cross section areas of hepatocytes, and detected cell cycle through FCM. The expressions of phosphorylated protein TSC2 and mTOR were observed.

Results

(1) The content of phosphorylated protein TSC2 in group CO began to increase at 2 h and got to the peak at 6 h but declined at 24 h. The content of phosphorylated protein TSC2 in group RA had the same variation with that of phosphorylated protein TSC2 in group CO. (2) At the time point of 0 h, 2 h, 6 h and 24 h after operation, the incorporation efficiency of ³H-Leucine in groups RA and TR was different from that in group CO in statistics (P < 0.01). (3) It could be seen that the cross section areas of hepatocytes in groups RA and TR were different from that in group CO in statistics at 2 h and 6 h after operation (P < 0.05). (4) Comparing with the other two inhibitor groups (TR and RA), the number of cells during the period of G₀/G₁ in group CO became fewer, while the number of cells during the period of S and G₂/M grew obviously (referring to Fig. 8). After operation, each time point was different from the inhibitor groups obviously (P < 0.05 or P < 0.01). The peak declined greatly at 24 h and 72 h after operation.

Conclusions

These data strongly suggest the effects of Akt/TSC1-TSC2/mTOR signal pathway on hepatocyte growth, protein synthesis and cell cycle, and prove its contribution to liver regeneration.     

The effects of recruitment of renal functional reserve on renal cortical and medullary oxygenation in non-anesthetized sheep

Aim

Recruitment of renal functional reserve (RFR) with amino acid loading increases renal blood flow and glomerular filtration rate. However, its effects on renal cortical and medullary oxygenation have not been determined. Accordingly, we tested the effects of recruitment of RFR on renal cortical and medullary oxygenation in non-anesthetized sheep.

Methods

Under general anesthesia, we instrumented 10 sheep to enable subsequent continuous measurements of systemic and renal hemodynamics, renal oxygen delivery and consumption, and cortical and medullary tissue oxygen tension (PO₂). We then measured the effects of recruitment of RFR with an intravenous infusion of 500 ml of a clinically used amino acid solution (10% Synthamin® 17) in the non-anesthetized state.

Results

Compared with baseline, Synthamin® 17 infusion significantly increased renal oxygen delivery mean ± SD maximum increase: (from 0.79 ± 0.17 to 1.06 ± 0.16 ml/kg/min, p < 0.001), renal oxygen consumption (from 0.08 ± 0.01 to 0.15 ± 0.02 ml/kg/min, p < 0.001), and glomerular filtration rate (+45.2 ± 2.7%, p < 0.001). Renal cortical tissue PO₂ increased by a maximum of 26.4 ± 1.1% (p = 0.001) and medullary tissue PO₂ increased by a maximum of 23.9 ± 2.8% (p = 0. 001).

Conclusions

In non-anesthetized healthy sheep, recruitment of RFR improved renal cortical and medullary oxygenation. These observations might have implications for the use of recruitment of RFR for diagnostic and therapeutic purposes.     

An agonist sensitive,quick and simple cell-based signaling assay for determination of ligands mimicking prostaglandin E<Subscript>2</Subscript> or E<Subscript>1</Subscript> activity through subtype EP<Subscript>1</Subscript> receptor: Suitable for high throughput screening

Background  

Conventionally the active ingredients in herbal extracts are separated into individual components, by fractionation, desalting, and followed by high-performance liquid chromatography (HPLC). In this study we have tried to directly screen water-soluble fractions of herbs with potential active ingredients before purification or extraction. We propose that the herbal extracts mimicking prostaglandin E₁ (PGE₁) and E₂ (PGE₂) can be identified in the water-soluble non-purified fraction. PGE₁ is a potent anti-inflammatory molecule used for treating peripheral vascular diseases while PGE₂ is an inflammatory molecule.     

Clinical and Immunomodulatory Effects of Celecoxib Plus Interferon-Alpha in Metastatic Renal Cell Carcinoma Patients with COX-2 Tumor Immunostaining

Introduction  

Cycloxygenase-2 (COX-2) is an enzyme involved in prostaglandin E2 (PGE₂) synthesis associated with higher renal cell carcinoma stage. COX-2 inhibition enhances interferon (IFN-α) anti-tumor immune effects in pre-clinical models. A phase II trial of celecoxib and IFN-α in a targeted population of metastatic renal cell carcinoma patients with maximal COX-2 expression was conducted.     

Prostaglandin I<Subscript>2</Subscript> analogues suppress TNF-α expression in human monocytes via mitogen-activated protein kinase pathway

Objective and design  

Although treatment for asthma control has improved a lot recently, refractory asthma is still a challenge for clinicians. Evidence revealed that anti-tumor necrosis factor (TNF)-α therapy may have potential in treating refractory asthma. Recently in an animal model, prostaglandin I₂ (PGI₂) analogues can suppress the cardinal feature of asthma. However, whether PGI₂ analogues can regulate TNF-α expression in monocytes and the mechanism is not well-known.     

Healing Potential of <Emphasis Type="Italic">Picrorhiza kurroa</Emphasis> (Scrofulariaceae) rhizomes against indomethacin-induced gastric ulceration: a mechanistic exploration.

Background  

The present study was undertaken to evaluate the potential of the rhizomes of the Indian medicinal plant, Picrorhiza kurroa in healing indomethacin-induced acute stomach ulceration in mice and examine its capacity to modulate oxidative stress and the levels of prostaglandin (PGE₂) and EGF during the process.     

Inadequate cytoplasmatic calcium signals in alveolar macrophages after cardiac surgery

Objective and design  

Patients undergoing cardiac surgery have an elevated risk for pulmonary complications. A dysfunction of alveolar macrophages (AM) might promote postoperative infections. Therefore intracellular calcium [Ca²⁺]_i as an important second messenger in cellular signaling was assessed in AM.     

Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Aim

This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).

Methods

We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH_i of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR.

Results

CAIX‐knockout gastric surface epithelial cells showed significantly faster pH_i decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months.

Conclusions

We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO₂ and H₂O, contributing to tight junction protection and gastric epithelial pH_i regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.     

Sialic acid residues play a pivotal role in α1-acid glycoprotein (AGP)-induced generation of reactive oxygen species in chemotactic peptide pre-activated neutrophil granulocytes

Objective  

We have recently shown that terminal sialic acid residues are essential for α₁-acid glycoprotein (AGP)-induced Ca²⁺ mobilization in neutrophils. The aim of the present study was to establish the importance of sialic acid residues on AGP in modulating human neutrophil functions, with emphasis on the generation of reactive oxygen species (ROS).     

Multiple interactions between the alpha<Subscript>2C</Subscript>- and beta<Subscript>1</Subscript>-adrenergic receptors influence heart failure survival

Background  

Persistent stimulation of cardiac β₁-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α_2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively) on the risk of death/transplant in heart failure patients.