Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver

ABSTRACT We generated mice carrying a STAT3 allele amenable to Cre-mediated deletion and intercrossed them with Mx-Cre transgenic mice, in which the expression of Cre recombinase can be induced by type I interferon. Interferon-induced deletion of STAT3 occurred very efficiently (more than 90%) in the liver and slightly less efficiently (about 70%) in the bone marrow. Analysis of the induction of liver acute-phase genes in response to bacterial lipopolysaccharide unequivocally identifies STAT3 as a fundamental mediator of their induction. The different degrees of defectiveness displayed by the various genes allowed us to differentiate them into three separate groups according to their degree of dependence on STAT3. Induction was totally defective for group I genes, defective at 24 h but almost normal at earlier time points for group II genes, and only slightly defective for group III genes. This division was in good agreement with the known structures of the respective promoters. We also found that the overall induction of the transcription factors C/EBPβ and -δ was only minimally defective in the absence of STAT3. Finally, even though corticosterone levels and action were found to be normal in the conditional-mutant mice, production of both proinflammatory and antiinflammatory cytokines was increased and prolonged, probably as a result of STAT3 deletion in macrophages.

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Genoprotective role of vitamin E and selenium in rabbits anaesthetized with sevoflurane

Human & Experimental Toxicology ◽

10.1191/0960327104ht463oa ◽

2004 ◽

Vol 23 (8) ◽

pp. 413-419 ◽

Cited By ~ 9

Author(s):

Cetin Kaymak ◽

Ela Kadioglu ◽

Hulya Basar ◽

Semra Sardas

Keyword(s):

Dna Damage ◽

Vitamin E ◽

Comet Assay ◽

Antioxidant Supplementation ◽

Group Iii ◽

Sevoflurane Anaesthesia ◽

Group I ◽

The Mean ◽

Group Ii

In this study, genotoxic effects of repeated sevoflurane anaesthesia were investigated in rabbits with or without antioxidant supplementation. Twenty-one New Zealand male rabbits were included in the study and randomized into three groups as: placebo treated (Group I), vitamin E supplemented (Group II) and selenium supplemented (Group III). Vitamin E and selenium were given intraperitoneally for 15 days before anaesthesia treatment. Anaesthesia was administered using 3% sevoflurane in 4 L/min oxygen for a 3-hour period and continued for 3 days. Blood samples were collected before anaesthesia (Sample 1), after the first, second and third days of sevoflurane administration (Sample 2, Sample 3 and Sample 4 respectively) and the last samples were taken 5 days after the last sevoflurane administration (Sample 5). Genotoxic damage was examined using the comet assay. The degree of damage is assessed by grading the cells into three categories of no migration (NM), low migration (LM) and high migration (HM) depending on the fraction of DNA pulled out into the tail under the influence of the electric field. The number of comets in each sample was calculated (1 × number of comets in category NM + 2 × number of comets in category LM + 3 ×number of comets in category HM) and expressed as the total comet score (TCS), which summarizes the damage frequencies. In Group I, a significant increase in the mean TCSs was observed for Samples 3 and 4 as compared with Sample 1. However, there were no significant differences between Samples 1, 2 and 5. The mean TCS of Sample 4 was significantly higher than Sample 1, 2 and 3 in Group II. Group III demonstrated no significant mean TCSs for any experimental conditions. Statistical differences were also observed between the groups with significant P values. This experimental study points out the presence of DNA damage with repeated sevoflurane anaesthesia and the genoprotective role of antioxidant supplementation on DNA damage in mononuclear leukocytes of rabbits by highly sensitive comet assay.

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Role of insulin and branched-chain amino acids in regulating protein metabolism during fasting

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.6.e907 ◽

1990 ◽

Vol 258 (6) ◽

pp. E907-E917 ◽

Cited By ~ 2

Author(s):

M. Frexes-Steed ◽

M. L. Warner ◽

N. Bulus ◽

P. Flakoll ◽

N. N. Abumrad

Keyword(s):

Amino Acids ◽

Protein Metabolism ◽

Insulin Dose ◽

Group Iii ◽

Group I ◽

Tissue Sensitivity ◽

Branched Chain ◽

Independent Effects ◽

Dose Dependent

This study examines the independent effects of insulin and amino acids on protein metabolism after a 12-h and 4-day fast in healthy volunteers. Leucine (Leu) kinetics were examined during sequential insulin infusions of 0 (group I) or 0.0125 (groups II and III), 1.2, and 10 mU.kg-1.min-1. Plasma Leu was maintained at 12-h fasted levels in groups I and II and at 84-h fasted levels in group III. Four-day fast (vs. 1 day, P less than 0.01) was associated with a 79% drop in plasma insulin and elevations in plasma Leu (122%), Leu rates of appearance (Ra) (21%), and Leu oxidation (56%), and no change in nonoxidative rates of disappearance (Rd). Insulin resulted in a dose-dependent suppression of endogenous Leu Ra with group III = I greater than II. Leu oxidation rose 1.7-fold in group III at the highest insulin dose but remained stable in the two other groups. In conclusion, 4-day fasting is associated with enhanced proteolysis and Leu oxidation with no change in nonoxidative Rd (protein synthesis). Elevated branched-chain (and other) amino acids were required to restore tissue sensitivity and specificity to the effects of insulin on protein metabolism after 4 days of fasting.

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Endothelin effects in isolated, perfused lamb lungs: role of cyclooxygenase inhibition and vasomotor tone

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.261.2.h443 ◽

1991 ◽

Vol 261 (2) ◽

pp. H443-H450 ◽

Cited By ~ 2

Author(s):

H. Toga ◽

J. Usha Raj ◽

R. Hillyard ◽

B. Ku ◽

J. Anderson

Keyword(s):

Vasomotor Tone ◽

Cyclooxygenase Inhibition ◽

Group Iii ◽

Group I ◽

Before And After ◽

Pulmonary Arterial ◽

Group Ii ◽

Sites Of Action ◽

Arteries And Veins

We have determined the sites of action of endothelin-1 (ET) in the lamb pulmonary circulation. The influence of cyclooxygenase inhibition and baseline vasomotor tone on ET effects was also studied. Lungs of 14 lambs (6-9 wk of age, 12.1 +/- 0.6 kg body wt) were isolated and perfused with blood. Group I lungs (n = 5) were untreated, group II lungs (n = 5) were treated with indomethacin to inhibit cyclooxygenase, and group III lungs (n = 4) were treated with indomethacin and a thromboxane A2 analogue, U-46619, to elevate vasomotor tone. All lungs were perfused with constant flow in zone 3, with left atrial and airway pressures being 8 and 6 cmH2O, respectively. We measured pulmonary arterial pressure and, by the micropuncture servo-null method, pressures in 20- to 50-microns diameter subpleural venules, both before and after each dose of ET was infused (50, 100, 250, and 500 ng/kg). Group I lungs, with high baseline vasomotor tone, exhibited a biphasic response to ET; 50-100 ng/kg of ET dilated both arteries and veins, whereas 500 ng/kg of ET constricted both arteries and veins. In group II lungs with low vasomotor tone, all doses of ET caused constriction of arteries only. In group III lungs (indomethacin treated with elevated vasomotor tone), 50-100 ng/kg of ET caused dilation of arteries and veins, whereas 500 ng/kg of ET induced constriction, this time only in arteries. We conclude that ET has both dilator and constrictor effects in arteries and veins of isolated, perfused lamb lungs. ET-induced arterial and venous dilation is dependent on initial vasomotor tone but not on cyclooxygenase metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

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The prognostic role of inflammatory markers in COVID 19 patients – A retrospective analysis.

10.21203/rs.3.rs-1121729/v1 ◽

2021 ◽

Author(s):

Shivkumar Gopalakrishnan ◽

sangeetha kandasamy ◽

S.Malini ◽

S.Peer Mohamed ◽

k.velmurugan

Keyword(s):

Inflammatory Markers ◽

Severe Disease ◽

Radiation Hazard ◽

P Value ◽

Binary Logistic Regression Analysis ◽

Group Iii ◽

Group I ◽

Group Ii ◽

D Dimer

Abstract Background. Approximately 5% of COVID-19 patients suffer near fatal disease. Clinical and radiologic features may predict severe disease albeit with limited specificity and radiation hazard. Laboratory biomarkers are eyed as simple, specific and point of care triage tools to optimize management decisions.This study aimed to study the role of inflammatory markers in prognosticating COVID-19 patients.Methodology. A hospital based retrospective study was conducted on COVID-19 adult inpatients classified into three groups as mild disease-recovered [Group I], severe disease-recovered [Group II] and dead [Group III]. Categorical outcomes were compared using Chi square test. Univariate binary logistic regression analysis was performed to test the association between the explanatory and outcome variables. Unadjusted OR along with 95% CI was calculated. The utility of lab parameters (Ferritin, LDH, D dimer, N/L ratio and PLT/L ratio) in predicting severity of COVID-19 was assessed by Receiver Operative Curve (ROC) analysis. P value < 0.05 was considered statistically significant.Results. The mean age was 49.32 +/- 17.1 years. Among study population, 378 were Group I, 66 Group II, and 56 Group III. Median levels of Ferritin among the 3 groups were 62ng/mL, 388.50 ng/mL and 1199.50 ng/mL. Median value of LDH were 95U/L, 720 and 982.50(p <0.001). D-dimer values of 3 groups were 23.20ng/mL, 104.30 ng/mL and 197.10 ng/mL (p <0.001). CRP done qualitatively was positive in 2 (0.53%), 30 (45.45%) and 53 (94.64%) of patients. The odds of patients suffering severe COVID-19 rose with rising values of ferritin, LDH and D-dimer [unadjusted OR 1.007, 1.004 &1.020]Conclusion. One time measurement of serum ferritin, LDH, D-dimer and CRP is promising to predict outcomes for COVID 19 inpatients. Single qualitative CRP was equally good but more cost effective than quantitative CRP. The most specific combination was NLR, Lymphocyte percentage and D-dimer levels done between 7th – 10th day of symptoms.

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Dysmetabolic mechanisms of preeclampsia development

Obesity and metabolism ◽

10.14341/omet12330 ◽

2021 ◽

Vol 17 (4) ◽

pp. 346-356

Author(s):

I. S. Lipatov ◽

Yu. V. Tezikov ◽

A. R. Azamatov

Keyword(s):

Insulin Resistance ◽

Pregnant Women ◽

Metabolic Disorders ◽

Hematological Parameters ◽

Control Group ◽

Metabolic Disturbances ◽

Group Iii ◽

Inflammatory Status ◽

Group I

Background: An in-depth study of dismetabolic mechanisms in the genesis of pre-eclampsia (PE) has been updated because pregnancy is considered as a natural model of metabolic syndrome (MS), as well as the metabolic disorders are important in development of essential hypertension.Aims: to reveal clinical and laboratory parallels in pregnancy complicated by PE without MS and pregnancy proceeding on the background of MS to assess the role of metabolic disturbances in the development of PE.Materials and methods: 82 women with MS were examined in the dynamics of pregnancy and were divided into 2 groups depending on the implementation of PE: group I consisted of 50 women with PE on the background of MS, group II 32 women with MS without PE. We formed group III consisting of 44 pregnant women with PE without accompanying diseases to assess the pathogenetic value of metabolic disorders in the development of PE. The IV (control) group consisted of 30 healthy women with physiological pregnancy. Metabolic, hematological parameters, hormones, markers of the proinflammatory state, endothelial hemostasiological dysfunction, decidualization and placental angiogenesis, accumulation dynamics and distribution loci of adipose tissue were determined in all pregnant women.Results: In the groups of pregnant women with PE, changes similar to MS were revealed: pronounced diabetic and atherogenic disorders with the development of pathological insulin resistance, hyperinsulinemia and leptinemia, endothelial-platelet link hyperactivation, thrombotic and inflammatory status, visceral type of fat deposition, hyperuricemia, hypersympathicotonia. It is proved that in the hierarchy of mechanisms of PE formation, placental dysfunction is a secondary alteration factor, which additionally potentiates the insulin resistance increase and the effects of structural and functional destabilization of the vascular endothelium.Conclusions: The direction of metabolic changes during pregnancy, the common development of PE and MS indicate the important role of dismetabolic mechanisms in the formation of PE.

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Role of Tie2, CD14, Angiopoietin as Angiogenetic Markers in Hepatocellular Carcinoma Complicating Hepatitis C Virus Infection

Journal of Hematology and Oncology Research ◽

10.14302/issn.2372-6601.jhor-19-3084 ◽

2019 ◽

Vol 3 (2) ◽

pp. 23-34

Author(s):

El-Zahraa M. Meghezel ◽

Heba A. Ahmed ◽

Ashraf A Askar ◽

Emad Eldin Nabil ◽

Ashraf Elyamany

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis C ◽

High Risk Group ◽

P Value ◽

Group Iii ◽

Group I ◽

Angiopoietin 2 ◽

Chronic Hepatitis C Patients ◽

Potential Use

Background Identifying biomarkers for early detection of hepatocellular carcinoma (HCC) remains quite challenging. In this study we aimed to estimate the number of TIE2-expressing monocytes (TEMs) cells, which display pro-tumoral activities and are defined as CD14+, TIE2+, and angiopoietin-2; and its potential use as a possible diagnostic marker in HCC patients complicating HCV induced cirrhosis. Methods Current study was conducted on 112 patients. They were divided into two groups: Group I (78 patients) with HCC complicating HCV induced cirrhosis; and group II chronic hepatitis C patients (34 patients). Both groups were compared to (age and sex-matched) healthy persons as group III (38 persons). Result The number of the circulating TEMs: CD14+ and TIE2+ monocytes were significantly higher in the peripheral blood of HCC patients than HCV LC patients and healthy controls, sensitivity and specificity for HCC diagnosis were respectively: CD14 (89.7%, 83.3%), TIE 2 (76.9%, 83.3%), and Ang-2 (76.9%, 66.7%). Moreover, analysis of the P-value and the odd’s ratio showed that CD14 has the highest predictive value for HCC. Conclusion Our results suggest that TEMs and Ang-2can be used as diagnostic markers for HCC, especially among the high-risk group of patients.

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Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension

Circulation ◽

10.1161/circ.130.suppl_2.17285 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Lai-Ming Yung ◽

Samuel D Paskin-Flerlage ◽

Ivana Nikolic ◽

Scott Pearsall ◽

Ravindra Kumar ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Type I ◽

Rna Seq ◽

Differentiation Factor ◽

Group I ◽

Tgf Β1

Introduction: Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity. Hypothesis: We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH. Methods: Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling in vitro . Results: TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3 in vitro . In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH. Conclusions: These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.

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Porcine 2′,5′-oligoadenylate synthetase-like protein inhibits replication of porcine reproductive and respiratory syndrome virus

10.21203/rs.2.18823/v1 ◽

2019 ◽

Author(s):

huawei li ◽

ruining wang ◽

wenjia wang ◽

yinfeng kang ◽

mengmeng zhao

Keyword(s):

Alveolar Macrophages ◽

Respiratory Syndrome Virus ◽

Type I ◽

Oligoadenylate Synthetase ◽

Swine Industry ◽

Exogenous Expression ◽

Polymerase Chain ◽

Interfering Rna ◽

Inducible Gene

Abstract Background : Porcine reproductive and respiratory syndrome virus (PRRSV) is a serious pathogen that causes $664 million losses per year to the swine industry. There are few useful vaccines that can provide protection against PRRSV infection. 2′, 5′-oligoadenylate synthetase-like protein (OASL) has antiviral activity, this has not been shown for PRRSV and the mechanism is unknown. Methods : Expression of OASL in porcine alveolar macrophages induced by interferon (IFN)-b stimulation and PRRSV infection was examined by real-time polymerase chain reaction. Exogenous expression and knockdown of OASL were used to determine the role of OASL in the PRRSV replication cycle. The type I IFN signaling pathway was evaluated after OASL overexpression. Results : In this study, we found that the expression of OASL in porcine alveolar macrophages was significantly increased by IFN-b stimulation and PRRSV infection. Porcine-OASL-specific small interfering RNA (siRNA) promoted PRRSV replication, whereas exogenous expression of porcine OASL inhibited replication of the virus. The anti-PRRSV activity of porcine OASL was lost after knockdown of retinoic acid-inducible gene I ( DDX58 , also known as RIG-I ). Conclusions : Porcine OASL suppresses PRRSV replication.

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The role and effects of glucosinolates of Brassica species – a review

Plant Soil and Environment ◽

10.17221/4217-pse ◽

2011 ◽

Vol 48 (No. 4) ◽

pp. 175-180 ◽

Cited By ~ 1

Author(s):

H. Zukalová ◽

J. Vašák

Keyword(s):

Amino Acids ◽

Brassica Species ◽

Development Stage ◽

Decomposition Products ◽

Group Iii ◽

Indole Glucosinolates ◽

Group I ◽

Carcinogenic Effects ◽

In The Beginning

  Glucosinolates are the substituted esters of thio amino acids and their synthesis is based on the corresponding amino acids. Methionine and cysteine are the natural donors in the case of the Brassica plants and L-tryptophane in the indole glucosinolates, respectively. In Brassica genus, alkenyl glucosinolates are mostly present and their content and composition differ as far as the development stage and the part of the plant are concerned. The indole glucosinolates are present in a minority level. Their role of sulphur supply is questioned by their very low content between 2% in the beginning of vegetation and 0.1% in its end. Glucosinolates are discussed mostly from the aspect of their anti-nutrition, anti-microbial, anti-fungicidal, and anti-bacterial effects and as being natural bio-fumigants. Their decomposition products have the mentioned properties. The products originate by prepared passive protection by the two-component system. From the aspect of these properties, it is useful to divide them into the following three groups according to the characters of their decomposition products. The first group (I.), whose hydrolysis in the neutral and alkaline environment creates iso-thio-cyanates. These bioactive compounds form the natural protection of the plant with bio-fumigatory effects particularly. Their anti-nutritive effects can be compensated by iodine, contrary to the second group (II.). This group is created by hydroxy-glucosinolates, whose decomposition products – iso-thio-cyanates – are not stable and they cycle while producing substituted 2-oxazolidinethione (goitrine – VTO). These glucosinolates represent a serious problem in feed industry since the VTO has a strong goitrogenic property. The third group (III.) – glucosinolates containing the indole group or the benzene ring (Sinalbin), create thio-cyanates during their hydrolysis. The role of indole glucosinolates has not been completely clarified so far. Their anti-carcinogenic effects are studied and they fulfil the role of an active protection.

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The Patello-Femoral Joint Degeneration and the Shape of the Patella in the Population Needing an Arthroscopic Procedure

Medicina ◽

10.3390/medicina54020021 ◽

2018 ◽

Vol 54 (2) ◽

pp. 21 ◽

Cited By ~ 5

Author(s):

Rimtautas Gudas ◽

Laimonas Šiupšinskas ◽

Agnė Gudaitė ◽

Vladas Vansevičius ◽

Edgaras Stankevičius ◽

...

Keyword(s):

Physical Activity ◽

Articular Cartilage ◽

Knee Joint ◽

Cartilage Defects ◽

Type I ◽

Physically Active ◽

Group Iii ◽

Type Iii ◽

Group I ◽

Arthroscopic Procedures

Background: the main goal of the study was to investigate the prevalence of the articular cartilage defects (ACD) in the patellofemoral (PF) region of the knee joint based on the anatomical shapes of patella and its impact on the level of physical activity in the population needing arthroscopic procedures for all types of pathologies in the knee. Methods: The articular cartilage status of the PF region was obtained from 1098 arthroscopic procedures of the knee joint. The ACD were correlated to Wiberg’s shape of the patella and classified according to the degree, size and depth of the ACD in the PF region using the ICRS (International Cartilage Repair Society) system: group I consisting of patients with Wiberg type I shape (W1), group II—patients with Wiberg type II shape (W2) and group III—patients with Wiberg type III shape (W3). The Tegner physical activity scale was used to evaluate the physical activity of the patients. Results: The mean of ACD size (PF region) in the W3 group was 3.10 ± 0.99 cm2, which was a statistically significantly larger area in comparison with the W1 (1.90 ± 0.63 cm2; p < 0.0000) and W2 (1.95 ± 0.71 cm2; p < 0.0000). The patients from the W3 group (mean 3.10 ± 0.99) were less physically active (<4 Tegner) compared to the W2 group (mean of 4.48 ± 0.88; p = 0.004) and W1 group (mean of 4.55 ± 0.72; p = 0.002). Conclusions: The patients with the Wiberg type III patella shape had a higher incidence and larger size of ACD in the PF of the knee compared to the groups of Wiberg type I and II. Wiberg III patients with a lower level of physical activity had a larger size of ACD in the PF joint.

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