Endotoxin-tolerant rats are still protected from oxygen toxicity by low-dose endotoxin treatment

1985 ◽  
Vol 58 (3) ◽  
pp. 819-822 ◽  
Author(s):  
L. Frank
Keyword(s):  
Low Dose ◽  
Protective Action ◽  
Lethal Dose ◽  
Oxygen Toxicity ◽  
Exposure Period ◽  
Lung Damage ◽  
Toxic Effects ◽  
Beneficial Effects ◽  
High Degree ◽  
Tolerant State

To determine if we could reduce endotoxin's potential for toxicity, we produced “endotoxin-tolerant” rats by administering progressively increasing daily doses of endotoxin (10 ng, 100 ng, 1 microgram, 10 micrograms/kg). This dosage regimen produced a high degree of tolerance to the toxic actions of endotoxin: whereas only 3/17 (18%) of control rats survived a normally lethal dose of endotoxin (25 mg/kg), survival for the endotoxin-tolerant rats was 16/16. When endotoxin-tolerant rats received a standard protective dose of 500 micrograms/kg endotoxin just before transfer to 96–98% O2, 19/20 survived the 72-h exposure period vs. 20–30% survival for controls. Thus whereas the endotoxin-tolerant state blocked the tested lethal and toxic effects of endotoxin, it did not nullify the O2 protective action of endotoxin. In addition, endotoxin's stimulatory effects on the lung antioxidant enzymes in the 96–98% O2-exposed rats was also not blocked by the endotoxin-tolerant state. Thus the therapeutic ratio (TR) of endotoxin as an experimental pharmacological treatment against O2-induced lung damage has been markedly enhanced (TR = ratio of dose producing beneficial effects to dose producing toxic effects).

scholarly journals Methotrexate Ameliorates Systemic Inflammation and Septic Associated-Lung Damage in a Cecal Ligation and Puncture Septic Rat Model

2021 ◽  
Vol 22 (17) ◽  
pp. 9612
Author(s):  
Josep Bringué ◽  
Raquel Guillamat-Prats ◽  
Maria Luisa Martinez ◽  
Eva Torrents ◽  
Marta Camprubí-Rimblas ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Low Dose ◽  
Cecal Ligation ◽  
Inflammatory Cells ◽  
Lung Damage ◽  
Source Control ◽  
Beneficial Effects ◽  
Group A ◽  
Cecal Ligation Puncture ◽  
Host Inflammatory Response

Background: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. Objective: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. Methods and main results: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. Conclusion: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling.

PRECLINICAL STUDY OF THE VETERINARY DRUGS TOXICITY

1970 ◽  
pp. 61-64
Author(s):  
E. K. Rakhmatullin ◽  
O. D. Sklyarov
Keyword(s):  
Lethal Dose ◽  
Clinical Manifestations ◽  
Preclinical Study ◽  
Veterinary Drugs ◽  
Toxic Effects ◽  
Laboratory Animals ◽  
Therapeutic Effects ◽  
Significant Information ◽  
Important Indicator ◽  
Organ Systems

Preclinical study of the drugs toxicity was analysed it allows predicting the safety of veterinary drugs in laboratory animals. The fundamental normative instruments in the field of preclinical study of drugs for veterinary medicine and animal husbandry are Order of the Ministry of Agriculture of the Russian Federation dated 06.03.2018 N 101 and GOST 33044-2014 Principles of Good Laboratory Practice. An important indicator of the preclinical study of the veterinary drugs is the determination (calculation) of median lethal dose value (lethal dose for half of the animals tested) or concentration (LD50 or LC50). Existing methods for determining this indicator make it possible at the initial study stage to determine the degree and class the drug of toxicity. Studying the symptoms of intoxication in the analysis of pharmacological substances one obtains significant information about the nature of the action of the future drug. The clinical manifestations of intoxication with damage to various organ systems are presented. As criteria for assessing the toxic effects of veterinary drugs it is recommended to determine LD50, cumulation coefficient, latitude index of therapeutic effects, dose level of toxic effects in the experiment which allows predicting the nature and degree of toxic effects of the drug even at the stage of preclinical veterinary drugs study.

Biochemical and histopathological effects of low dose vanadium in the healing of acetic acid-induced colitis in male wistar rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Tosan Peter Omayone ◽  
Samuel Babafemi Olaleye
Keyword(s):  
Acetic Acid ◽  
Untreated Control ◽  
Wistar Rats ◽  
Low Dose ◽  
Healing Process ◽  
Beneficial Effects ◽  
Male Wistar Rats ◽  
Haematological Changes ◽  
Therapeutic Properties ◽  
Histopathological Effects

Abstract Objectives Vanadium has been reported to possess relevant therapeutic properties such as anti-diabetic and anti-tumoral. This study aimed at determining the effects of vanadium on experimentally induced colitis in rats. Methods Forty-five male Wistar rats (103 ± 3.90 g, n=15) were used for this study and were divided into three groups. Group 1 (Untreated control) had nothing added to their drinking, while groups 2 and 3 received sodium metavanadate at a dose of 50 and 200 mg/L respectively in their drinking water for 10 weeks. Colitis was thereafter induced by intra colonic administration of 1.50 mL of 6% acetic acid. Animals were sacrificed on day 0 (pre-induction), three- and seven-days post induction. Blood samples were collected for haematological variables and the distal 8 cm of the colon was collected for macroscopic, histological and biochemical (malondialdehyde-MDA, superoxide dismutase-SOD, catalase-CAT, glutathione peroxidase- GPx and nitrite concentration- NO) assessment. Results Low dose vanadium proved beneficial in ameliorating acetic acid-induced colitis by improving both histopathological and haematological changes. Gross observation showed a faster healing rate in vanadium treated groups (50 and 200 mg/L) compared with untreated control at day 3 (40 and 26.20 vs. 2.50%) and day 7 (80 and 66.70 vs. 42%) respectively. Vanadium also appears to exert its beneficial effects on acetic acid-induced colitis via up regulation of antioxidant enzymes (SOD, CAT, GPx) and NO while decreasing the over production of MDA. Conclusions Vanadium at small concentration functions as an essential trace element and may be able to promote healing process during ulcerative colitis.

scholarly journals Antioxidant Strategies and Respiratory Disease of the Preterm Newborn: An Update

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Chiara Poggi ◽  
Carlo Dani
Keyword(s):  
Lung Damage ◽  
Preterm Newborn ◽  
Beneficial Effects ◽  
Melatonin Administration ◽  
Targeted Treatments ◽  
Wide Range ◽  
Nonenzymatic Antioxidants ◽  
Respiratory Outcomes ◽  
Preterm Newborns

Preterm newborns are challenged by an excessive oxidative burden, as a result of several perinatal stimuli, as intrauterine infections, resuscitation, mechanical ventilation, and postnatal complications, in the presence of immature antioxidant capacities. “Oxygen radical disease of neonatology” comprises a wide range of conditions sharing a common pathway of pathogenesis and includes bronchopulmonary dysplasia (BPD) and other main complications of prematurity. Antioxidant strategies may be beneficial in the prevention and treatment of oxidative stress- (OS-) related lung disease of the preterm newborn. Endotracheal supplementation or lung-targeted overexpression of superoxide dismutase was proved to reduce lung damage in several models; however, the supplementation in preterm newborn failed to reduce the risk of BPD, although long-term respiratory outcomes were improved. Also melatonin administration to small cohorts of preterm newborns suggested beneficial effects on lung OS. The possibility to identify single nucleotide polymorphism affecting the risk of BPD may help to identify specific populations with particularly high risk of OS-related diseases and may pose the basis for individually targeted treatments. Finally, surfactant replacement may lead to local anti-inflammatory and antioxidant effects, thanks to specific enzymatic and nonenzymatic antioxidants naturally present in animal surfactants.

Features of Bioaccumulation and Toxic Effects of Copper (II) Oxide Nanoparticles Under Repeated Oral Exposure in Rats

2021 ◽  
Vol 09 ◽  
Author(s):  
Mark Sergeevich Stepankov ◽  
Marina Aleksandrovna Zemlyanova ◽  
Nina Vladimirovna Zaitseva ◽  
Anna Mikhailovna Ignatova ◽  
Alena Evgenievna Nikolaeva
Keyword(s):  
Surface Area ◽  
Pore Volume ◽  
Mesangial Cells ◽  
Lethal Dose ◽  
Toxic Effects ◽  
Oral Exposure ◽  
Oxide Nanoparticles ◽  
Brown Pigment ◽  
Cuo Nps ◽  
Hematological Analysis

Background: Currently, the range of copper (II) oxide nanoparticles’ (CuO NPs) applications is expanding and the global production of CuO NPs is increasing. In this regard, the risk of exposure of the population to this nanomaterial increases. Objective: The aim of the study is to investigate the patterns of bioaccumulation and toxic effects of CuO NPs after multiple oral exposures. Methods: The particle size was determined by scanning electron microscopy and dynamic laser light scattering. Specific surface area was measured by the method of Brunauer, Emmett, Teller. Total pore volume - by the method of Barrett, Joyner, Khalenda. Twenty-four hours after the final exposure, blood samples were taken for biochemical and hematological analysis, and internal organs were taken to determine their mass, copper concentration and histological analysis. The study was carried out in comparison with copper (II) oxide microparticles (CuO MPs). Results: In terms of size, surface area, and pore volume, the studied copper (II) oxide sample is a nanomaterial. The median lethal dose of CuO NPs was 13187.5 mg/kg of body weight. Bioaccumulation occurs in the stomach, blood, intestines, liver, lungs, kidneys and brain. Pathomorphological changes in the liver are manifested in the form of necrosis, degeneration, hepatitis; kidney - proliferation of mesangial cells, dystrophy; stomach - gastritis; small intestine - hyperplasia, enteritis; large intestine - colitis; lungs - hyperplasia, abscess, pneumonia, bronchitis, vasculitis. Clumps of brown pigment were detected in the kidneys, stomach and lungs. The mass of the stomach and intestines increased, the mass of the liver, kidneys and lungs decreased. Pathomorphological changes in organs are likely to cause an increase in the levels of activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, amylase, malondialdehyde concentration and a decrease in plasma antioxidant activity. The proportion of segmented neutrophils, the number of leukocytes are raised, the proportion of lymphocytes is reduced. Conclusion: The degree of bioaccumulation and toxicity of CuO NPs are more expressed in relation to CuO MPs.

Ameliorative effect of low-dose spironolactone on obesity and insulin resistance is through replenishment of estrogen in ovariectomized rats

2019 ◽  
Vol 97 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Lawrence A. Olatunji ◽  
Oluwaseun A. Adeyanju ◽  
Olugbenga S. Michael ◽  
Taofeek O. Usman ◽  
Rita C. Tostes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Low Dose ◽  
Glycogen Synthase ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Atherogenic Dyslipidemia ◽  
Beneficial Effects ◽  
Ovx Rats ◽  
Ameliorative Effect ◽  
Hormonal Therapies

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-β, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17β-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.

scholarly journals Effect of vitamin D3 on lung damage induced by cigarette smoke in mice

Open Medicine ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. 827-832
Author(s):  
Xin Zheng ◽  
Nini Qu ◽  
Lina Wang ◽  
Guoli Wang ◽  
Rui Jiao ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Cigarette Smoke ◽  
Vitamin D3 ◽  
Lung Diseases ◽  
Low Dose ◽  
Lung Damage ◽  
Over Expression ◽  
Ifn Γ ◽  
Airway Model ◽  
Morphological Assessment

AbstractCigarette smoking is known to induce serious lung diseases, but there is not an effective method to solve this problem. The present study investigated vitamin D3 on over-expression of CXCR3 and CXCL10 in mice induced by cigarette smoking. A pulmonary airway model was designed, and morphological assessment of emphysema, IL-4, IFN-γ and CXCL10 concentration in bronchoalveolar lavage fluids, expression of CXCR3 and CXCL10 were detected. Emphysema of the mice only exposed to cigarette smoke was significant, and concentration of IL-4, IFN-γ and CXCL10 was also increased. In addition, CXCR3 and CXCL10 were over-expressed. The degree of emphysema, concentration of IL-4, IFN-γ and CXCL10, and expression of CXCR3 and CXCL10 in mice administrated with low dose vitamin D3 were similar to the normally treated mice. Low dose of vitamin D3 can effectively protect the lung from the damage induced by cigarette smoke.

scholarly journals Nanoparticle-mediated delivery of IL-2 to T follicular helper cells protects BDF1 mice from lupus-like disease

2021 ◽  
Vol 2 (3) ◽  
pp. 185-193
Author(s):  
Concetta Ferretti ◽  
David A. Horwitz ◽  
Sean Bickerton ◽  
Antonio La Cava
Keyword(s):  
T Cells ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
T Regulatory Cells ◽  
Plga Nanoparticles ◽  
Regulatory Cells ◽  
Beneficial Effects ◽  
Follicular Helper ◽  
New Strategy ◽  
Extended Survival

Abstract We recently reported that poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with interleukin (IL)-2 and targeted to T cells inhibited the development of lupus-like disease in BDF1 mice by inducing functional T regulatory cells (Tregs). Here we show that the protection from disease and the extended survival of BDF1 mice provided by IL-2-loaded NPs targeted to T cells is not only due to an induction of Tregs but also contributed by an inhibition of T follicular helper (TFH) cells. These results identify a dual protective activity of IL-2 in the control of lupus autoimmunity, namely the inhibition of effector TFH cells, in addition to the previously known induction of Tregs. This newly recognized activity of IL-2 delivered by NPs can help better explain the beneficial effects of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE), and might be considered as a new strategy to slow disease progression and improve outcomes in lupus patients.

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