scholarly journals Ultrastructure of the hemomicrocirculatory bed and parenchymatous-stromal elements of the pancreas and liver in a model of acute pancreatitis using different doses of L-arginin

Morphologia ◽  
2021 ◽  
Vol 14 (4) ◽  
pp. 79-89
Author(s):  
I. V. Tverdokhlib ◽  
D. Yu. Zinenko
Keyword(s):  
Acute Pancreatitis ◽  
Blood Cells ◽  
Pancreatic Enzyme ◽  
Hepatic Parenchyma ◽  
Hepatic Microcirculation ◽  
Dose Dependent ◽  
Morphological Research ◽  
Dose Dependent Effect ◽  
Different Doses

Background. The development of acute pancreatitis is not limited to isolated damage to the pancreas. After creating models of acute pancreatitis using various substances that enhance the secretion of the gland, have a toxic or local activating effect, the researchers showed their dose-dependent effect. The question of the reaction of the hepatic microcirculation system during the development of acute pancreatitis, as well as their pathogenetic significance in the development of pathomorphological changes in the pancreas and liver in most aspects remains open. Objective. The purpose of the current study was to define the role of the hepatic mircocirculation in development of ultrastructural parenchymatous-stromal changes of the pancreas and liver in a model of acute pancreatitis using different doses of L-arginin. Methods. The variants of acute pancreatitis model were used with injection of L-arginin in dosage 3 g/kg; 4 g/kg and 5 g/kg. The morphological research of pancreas and liver were carried out in 1, 4, 8, 12, 24, 48 and 72 hours after initiation of inflammation. Results. The visible reaction of hepatic mircocirculation in the experimental model of acute pancreatitis was depended on character of pathomorphological changes in pancreas. This reaction demonstrated the phase character including: 1) activation of hepatic circulation, first of all in portal component, against a background of pancreatic enzyme toxemia; 2) development of inflammatory, dystrophic, destructive and necrotic changes in hepatic parenchyme together with mircocirculation disorders against a background of pancreatic necrotic toxemia; 3) recovery and adaptation or decompensation processes in mircocirculation system of liver and hepatic parenchyme depending on the degree of pancreatogenic toxemia|. Conclusion. Within 72 hours of the experiment, at the lowest and middling doses of L-arginin, in the context of reduction of acute pancreatitis, there is a gradual renovation of the structure of the microvessels and normalization of the microcirculation of the liver. In the maximum doses L-arginin cause degradation of the liver microvessels with the progression of hemorrhages, slit red blood cells and platelet aggregation, which causes blockage of the microcirculation and the development of necrotic changes in the hepatic parenchyma.

scholarly journals Microvascular Stasis Inhibition By Hemopexin in the Townes Mouse Model of Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
Thomas Gentinetta ◽  
Gregory M. Vercellotti ◽  
Chunsheng Chen ◽  
Julia Nguyen ◽  
Fuad Abdulla ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cells ◽  
Research Funding ◽  
Acute Treatment ◽  
Treatment Model ◽  
Cell Disease ◽  
Dependent Effect ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Different Doses

Polymerization of hemoglobin-S (HbS) in the deoxy conformation shortens the lifespan of sickle red blood cells and promotes intravascular and extravascular hemolysis. When sickle red blood cells are lysed intravascularly, HbS is released into the vascular space where it can consume nitric oxide and be oxidized to higher oxidative forms. During these reactions, ferric (Fe3+) HbS is formed, which readily releases heme. The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on endothelium, leading to P-selectin expression, NF-ĸB activation, and microvascular stasis in sickle cell disease (SCD) mice with implanted dorsal skin-fold chambers (DSFCs). Heme-induced TLR4 signalling and stasis are blocked by administering hemopexin with the heme. Plasma hemopexin has the highest binding affinity for free heme, rendering it relatively nonreactive and delivering it safely to the liver for endocytosis and degradation by heme oxygenase-1 (HO-1). Due to chronic hemolysis, hemopexin levels are depleted in SCD patients and mice. We previously reported that intravenous hemopexin induces hepatic HO-1 activity and inhibits ongoing, spontaneous stasis in the venules of SCD mice for up to 48 hours. Inhibition of HO-1 activity with tin protoporphyrin (SnPP) and the administration of carbon monoxide (CO) to SnPP-treated mice demonstrated that HO-1 and its reaction product CO play important roles in the protection against stasis. In the current studies, we asked the question how much of the hemopexin-mediated protection is due to preventing heme activation of TLR4 signalling versus induction of HO-1 and CO production. We wondered if hemopexin complexed with heme would be as effective as hemopexin alone in treating a vaso-occlusive crisis (VOC) induced with hemoglobin heme. First, in a stasis prevention model, we intravenously administered different doses of hemopexin in Townes SCD mice with a DSFC one hour prior to a hemoglobin challenge. Briefly, anesthetized mice were placed on an intravital microscopy stage, and 20-24 flowing subcutaneous venules were selected and mapped. After baseline selection of flowing venules and one hour after administration of different doses of hemopexin (0 - 160 mg/kg body weight), microvascular stasis was triggered by infusing hemoglobin (1 µmol/kg). The same vessels were re-examined for stasis (no flow) and percent stasis was calculated. Our results show that hemopexin effectively reduced stasis in a dose responsive manner when delivered one hour prior to the hemoglobin challenge (Figure 1A). Second, we evaluated hemopexin in a VOC acute treatment model by infusing various doses of hemopexin 30 minutes after the intravenous hemoglobin challenge. We found a dose-dependent effect of hemopexin to reduce and resolve microvascular stasis during an acute VOC one hour after hemopexin infusion (Figure 1B). We obtained similar results after inducing stasis with lipopolysaccharide (LPS) or hypoxia-reoxygenation in place of hemoglobin challenge. Third, we evaluated equimolar hemopexin-heme complexes in a VOC acute treatment model by infusing the same doses of hemopexin-heme 40 minutes after the intravenous hemoglobin challenge (1 µmol/kg) to further elucidate the effects of heme scavenging versus HO-1 induction. Our results showed a striking, dose-dependent reduction in stasis, albeit to a detectably lower degree than hemopexin free of heme (Figure 1C). In summary, hemopexin has a dose-dependent effect to prevent and treat vaso-occlusion induced in a mouse model of SCD by hemoglobin, LPS, and hypoxia-reoxygenation. This effect is partially replicated by hemopexin pre-complexed with heme, suggesting that the beneficial effect is not limited to clearance of circulating heme and prevention of TLR4 signalling. The partial effectiveness of hemopexin-heme complex is consistent with our prior published data implicating CO generation by HO-1 as playing a role in the relief of vaso-occlusion by hemopexin. We conclude that hemopexin shows promise for the treatment of VOC. Additional experiments are needed to clarify the activity of hemopexin in clearance-dependent and -independent mechanisms of resolution of vaso-occlusion. Clinical trials of hemopexin are warranted to evaluate its safety, tolerability and potential efficacy in relieving vaso-occlusive pain crisis in patients with SCD. Disclosures Gentinetta: CSL Behring: Current Employment. Vercellotti:CSL Behring: Research Funding. Kato:CSL Behring AG: Current Employment. Brinkman:CSL Behring: Current Employment. Zuercher:CSL Behring AG: Current Employment. Belcher:Mitobridge-Astellas: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Hillhurst Biopharmaceuticals: Consultancy.

scholarly journals Clinic immunological comparison when studying erosive affections of gastro duodenal zone in patients with bronchial asthma

2003 ◽  
Vol 2 (1) ◽  
pp. 39-45
Author(s):  
G. M. Chernyavskaya ◽  
E. I. Beloborodova ◽  
T. V. Perevozchikova ◽  
R. A. Pozdnyakov ◽  
E. A. Fait ◽  
...  
Keyword(s):  
Mucous Membrane ◽  
Bronchial Asthma ◽  
Immune Complexes ◽  
Local Immunity ◽  
Dependent Effect ◽  
Immunological Comparison ◽  
Dose Dependent ◽  
Dose Dependent Effect

The aim of the work is to study the condition of the local immunity of stomach when there is bronchial asthma and the role of affection of some its factors in the formation of gastro duodenal pathology in this category of patients. 302 patients, both male and female were examined in the age of 18—60 with exogenous and mixed bronchial asthma. Gastro duodenal zone of all patients and local immunity of stomach in 65 patients were examined. The condition of the local immunity of the stomach was evaluated according to the content of secretory antibody A (sIgA), antibody G (IgG), circling immune complexes, activity of lysozyme in stomachic secretion. 68 patients (22,5%) have erosive affections of gastro duodenal zone. It is revealed that pathology of gastro duodenal zone is developed with the local deficit sIgA and rise of the content IgG in stomachic secretion. Dose-dependent effect of the long term peroral therapy by the systematic glucocorticosteroids at bronchial asthma on the pathology of gastro duodenal zone and local immunity of the stomach is revealed. Lowering the content of IgG and circling immune complexes in stomachic secretion and immune complex reactions in mucous membrane of the stomach, physiological doses lower the frequency of erosive affections of gastro duodenal zone. Treatment by supraphysiological doses of systematic glucocorticosteroids brings on disruption of specific protection section in mucous membrane of the stomach. It leads to the rise of erosive affections of gastro duodenal zone in this category of patients. Revealed affections of the local humoral immunity of the stomach in the patients have general characteristics and one-directed character of changes with the local immunity of respiratory tract when there is bronchial asthma. It gives the opportunity to suppose the participation of immune system of mucous membrane when having bronchial asthma.

Endogenous cholecystokinin drives gallbladder emptying in dogs

1986 ◽  
Vol 251 (4) ◽  
pp. G553-G558
Author(s):  
K. Shiratori ◽  
S. Watanabe ◽  
W. Y. Chey ◽  
K. Y. Lee ◽  
T. M. Chang
Keyword(s):  
Corn Oil ◽  
Venous Blood ◽  
Gallbladder Emptying ◽  
Dependent Manner ◽  
Gallbladder Volume ◽  
Dose Dependent ◽  
Intraduodenal Administration ◽  
Different Doses ◽  
Cck Release

We investigated the effect of fat in the duodenum on the gallbladder emptying in seven dogs prepared with gastric, duodenal, and gallbladder cannulas. Gallbladder volume was measured at 15-min intervals, and venous blood samples were obtained at regular intervals for 2.5 h. Intraduodenal administration of Lipomul (pH 5.0, corn oil) in three different doses (1.1, 2.2, and 4.4 mmol/10 min) resulted in significant increases in gallbladder emptying in a dose-dependent manner (r = 0.8668, P less than 0.001). Likewise, the increase in integrated cholecystokinin (CCK) release in response to Lipomul was also dose dependent (r = 0.7334, P less than 0.001). A statistically significant correlation was found between integrated CCK release and gallbladder emptying in response to Lipomul (P less than 0.001). To determine the role of circulating endogenous CCK on gallbladder emptying effects of intravenous administration of proglumide and a rabbit anti-CCK serum on gallbladder emptying were studied. Gallbladder emptying was virtually abolished by the antiserum. Proglumide not only abolished the emptying but also increased gallbladder volume. Thus we conclude that in dogs the gallbladder emptying in response to fat in the upper small intestine depends on increased circulating endogenous CCK.

scholarly journals The Lipid Moiety of Haemozoin (Malaria Pigment) andP. falciparumParasitised Red Blood Cells Bind Synthetic and Native Endothelin-1

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Nicoletta Basilico ◽  
Silvia Parapini ◽  
Francesca Sisto ◽  
Fausta Omodeo-Salè ◽  
Paolo Coghi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vascular Endothelium ◽  
Blood Cells ◽  
Vascular Tone ◽  
Amino Acid Peptide ◽  
Lipid Moiety ◽  
Infected Rbcs ◽  
Malaria Pigment ◽  
Dose Dependent

Endothelin1 (ET-1) is a 21-amino acid peptide produced by the vascular endothelium under hypoxia, that acts locally as regulator of vascular tone and inflammation. The role of ET-1 inPlasmodium falciparummalaria is unknown, although tissue hypoxia is frequent as a result of the cytoadherence of parasitized red blood cell (pRBC) to the microvasculature. Here, we show that both synthetic and endothelial-derived ET-1 are removed by parasitized RBC (D10 and W2 strains, chloroquine sensitive, and resistant, resp.) and native haemozoin (HZ, malaria pigment), but not by normal RBC, delipidized HZ, or synthetic beta-haematin (BH). The effect is dose dependent, selective for ET-1, but not for its precursor, big ET-1, and not due to the proteolysis of ET-1. The results indicate that ET-1 binds to the lipids moiety of HZ and membranes of infected RBCs. These findings may help understanding the consequences of parasite sequestration in severe malaria.

The Role of 5-HT1A/BAutoreceptors in the Antinociceptive Effect of Systemic Administration of Acetaminophen

2003 ◽  
Vol 98 (3) ◽  
pp. 741-747 ◽  
Author(s):  
Aránzazu Roca-Vinardell ◽  
Antonio Ortega-Alvaro ◽  
Juan Gibert-Rahola ◽  
Juan A. Micó
Keyword(s):  
Antinociceptive Effect ◽  
Serotonin Release ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Plate Test ◽  
Way 100635 ◽  
New Strategy ◽  
Dose Dependent ◽  
Different Doses

Background It has been proposed that serotonin participates in the central antinociceptive effect of acetaminophen. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. In the presence of serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei leads to an increase in serotonin release in terminal areas, thus improving serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors in the antinociceptive effect of acetaminophen in mice. Methods The effects of acetaminophen (600 mg/kg intraperitoneal) followed by different doses of antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129 [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively, were determined in the hot-plate test in mice. Results Acetaminophen (300-800 mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B antagonist) induced a dose-related increase in the antinociceptive effect of acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased the antinociceptive effect of acetaminophen. Conclusions These results suggest that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B antagonist properties could be a new strategy to improve the analgesia of acetaminophen, thanks to its mild serotonergic properties.

scholarly journals Blood urea nitrogen as an early predictor of severity in acute pancreatitis

2021 ◽  
Vol 9 (4) ◽  
pp. 1015
Author(s):  
Syed Mushtaq A. Shah ◽  
Syed Aadil S. Andrabi ◽  
Azhar-un-Nisa Quraishi ◽  
Ravi Kumar ◽  
Tahir S. Khan ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Acute Abdominal Pain ◽  
Pancreatic Enzyme ◽  
P Value ◽  
Single Marker ◽  
The Difference ◽  
Systemic Examination ◽  
Early Predictor

Background: Acute pancreatitis presents as acute abdominal pain and is usually associated with raised pancreatic enzyme levels in the blood or urine. Aims and objectives of the study was to evaluate the role of serial BUN measurement as an early prognostic marker of acute pancreatitis.Methods: From each patient detailed history was taken, general and systemic examination were done and relevant investigations were conducted. BUN was repeated after 24 hours and the change in the level of BUN was noted. Imaging in the form of CT after 72 hours of admission were performed in each patient. The severity of acute pancreatitis was gauged by modified CTSI and the same was compared to the change in BUN values over first 24 hours of admission.Results: Mean BUN values at ‘0’ hour in severe acute pancreatitis and non-severe acute pancreatitis were 31.91±6.79 and 15.44±5.95 mg/dl, respectively. The difference between the two groups was statistically significant with p value of <0.001. Similarly, the difference in BUN values at ‘24’ hours between the two groups was statistically significant. BUN value ≥23 mg/dl at ‘0’ hour was found to be the optimal cut off for determining the severity of pancreatitis with sensitivity of 91.3%. BUN ≥25 mg/dl at 24 hours was found to be the optimal cut-off for determining the severity of acute pancreatitis with sensitivity of 95.7%.Conclusions: BUN as a single marker for acute pancreatitis can be useful as it is easy to perform and cheap marker to predict severity without the need for complex calculations. 

Abstract 3542: Role of Mitochondrial Oxidative Stress in Angiotensin II Mediated Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Anna E Dikalova ◽  
Alfiya T Bikineyeva ◽  
David G Harrison ◽  
Sergey I Dikalov
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Heart Association ◽  
Ang Ii ◽  
Mitochondrial Oxidative Stress ◽  
Bovine Endothelial Cells ◽  
Mouse Aorta ◽  
Dose Dependent ◽  
Dose Dependent Effect

Oxidative stress is strongly implicated in the pathogenesis of hypertension; however, the role of mitochondrial oxidative stress is not clear. We have investigated the role of mitochondria in endothelial dysfunction and hypetention using cultured bovine endothelial cells (BAECs) and mice infused with angiotensin II (AngII). Production of O 2 •− was measured by dihydroethidium and HPLC. Nitric oxide and H 2 O 2 were detected by ESR. Sytolic blood presure was measured in mice infused with saline, AngII (0.7mg/kg/day), AngII plus mitochondria targeted antioxidant mitoTEMPO or non-targeted antioxidant TEMPOL (50 μg/kg/day). AngII significantly increased mitochondrial H 2 O 2 . MitoTEMPO blocked AngII-induced oxidative stress and restored NO • production in BAECs and mouse aorta. Supplementation of BAECs with malonate, inhibitor of complex II, or rotenone abolished AngII induced oxidative stress. Interestingly, inhibition of mitochondrial oxidative stress decreased the activity of NADPH oxidases. Co-infusion of mitoTEMPO with AngII significantly attenuated the increase in the blood pressure by 30-mm Hg (Fig. 1 ), while i.p. injection to hypertensive mice decreased the blood presure by 20-mm Hg. We suggest that mitoTEMPO can be used as an effective inhibitor of the oxidative stress induced by Ang II as well as an antihypertensive agent and, thereby, can be effective in ameliorating hypertension-related nephrosclerosis, diabetic nephropathy, or atherosclerosis. Figure 1. (A) Attenuation of hypertensive effect of Ang II in C57Blk/6 mice by co-infusion of mitoTEMPO. (B) Dose dependent effect of mitoTEMPO (50, 150 and 500 μg/kg/day) after 14-days of Ang II and drug administration. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Single exposure to stressors causes long-lasting, stress-dependent reduction of food intake in rats

2000 ◽  
Vol 279 (3) ◽  
pp. R1138-R1144 ◽  
Author(s):  
Astrid Vallès ◽  
Octavi Martí ◽  
Arantxa García ◽  
Antonio Armario
Keyword(s):  
Food Intake ◽  
Sprague Dawley ◽  
Single Exposure ◽  
Total Recovery ◽  
Sprague Dawley Rats ◽  
Stress Dependent ◽  
Psychological Stressor ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Different Doses

A single exposure to severe stressors has been shown to cause anorexia in the next 24 h, but the duration of such alterations is not known. Male Sprague-Dawley rats were subjected to different stressors, and food intake was measured for several days after stress. In experiment 1, 2 h of immobilization (Imo) and lipopolysaccharide (LPS) administration (1,000 μg/kg) caused a marked anorexia in the 24 h after stress, which persisted on poststress day 3. In experiment 2, changes in food intake after LPS and Imo were followed until total recovery. As in experiment 1, LPS caused initially a greater degree of anorexia than Imo, but normal food intake recovered much faster (poststress day 3 vs. poststress day 9). Changing the period of exposure to Imo between 20 min and 6 h ( experiment 3) only slightly modified the pattern of response to the stressor. When different doses of LPS (50, 250, and 1,000 μg/kg) were tested in experiment 4, a dose-dependent effect on food intake was observed, the greatest doses causing the most marked and lasting effect. The present results showed stressor-specific lasting changes in food intake caused by a single exposure to some stressors, the effect of a severe psychological stressor such as Imo being more lasting than that of LPS, despite a lower initial anorexia. A severe psychological stressor and a physical stressor such as LPS appear to change food intake in different ways.

Nicotinamide improves NAD+ levels to protect against acetaminophen-induced acute liver injury in mice

2021 ◽  
pp. 096032712110145
Author(s):  
J Xu ◽  
L Zhang ◽  
R Jiang ◽  
K Hu ◽  
D Hu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Related Factor ◽  
Dependent Manner ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Apap Overdose ◽  
Hepatoprotective Effects ◽  
Dose Dependent ◽  
Different Doses

Acetaminophen (APAP) overdose causes acute liver injury (ALI). Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme, and NAD+ is oxidized type which synthesized from nicotinamide (NAM). The present study aimed to investigate the role of NAD+ in ALI and protective property of NAM. The mice were subjected to different doses APAP. After 8 hours, the serum activities of alaninetransaminase (ALT) and aspartate aminotransferase (AST), the hepatic NAD+ level and nicotinamide phosphoribosyltransferase (NAMPT) expression were determined. Then, the mice were pretreated with NAM (800 mg/kg), the hepatoprotective effects and the key antioxidative molecules were evaluated. Our findings indicated that APAP resulted in remarkable NAD+ depletion in a dose-dependent manner accompanied by NAMPT downregulation, and NAM pretreatment significantly elevated the NAD+ decline due to upregulation of NAMPT. Moreover, the downregulated Kelch-like ECH-associated protein-1 (Keap1), upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation activation after NAM administration were confirmed, which were in accordance with improved superoxide dismutase (SOD) and glutathione (GSH) levels. Finally, NAM dramatically exhibited hepatoprotective effects by reducing the liver index and necrotic area. This study has suggested that APAP impairs liver NAD+ level and NAM is able to improve hepatic NAD+ to activate antioxidant pathway against APAP-induced ALI.

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