scholarly journals Erythropoietin Mimetic Peptide (pHBSP) Corrects Endothelial Dysfunction in a Rat Model of Preeclampsia

2020 ◽  
Vol 21 (18) ◽  
pp. 6759 ◽  
Author(s):  
Mikhail Korokin ◽  
Vladimir Gureev ◽  
Oleg Gudyrev ◽  
Ivan Golubev ◽  
Liliya Korokina ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Wistar Rats ◽  
Severe Disease ◽  
Late Pregnancy ◽  
New Drugs ◽  
Greater Omentum ◽  
Large Role ◽  
Morphological Pattern ◽  
Fetoplacental Complex ◽  
Prevention And Therapy

Preeclampsia is a severe disease of late pregnancy. Etiological factors and a pathogenetic pattern of events still require significant clarification, but it is now recognized that a large role is played by placentation disorders and emerging endothelial dysfunction. The administration of short-chain peptides mimicking the spatial structure of the B erythropoietin chain may become one of the directions of searching for new drugs for preeclampsia prevention and therapy. Simulation of ADMA-like preeclampsia in Wistar rats was performed by the administration of a non-selective NOS blocker L-NAME from the 14th to 20th day of pregnancy. The administration of the pHBSP at the doses of 10 µg/kg and 250 µg/kg corrected the established morphofunctional disorders. The greatest effect was observed at a dose of 250 µg/kg. There was a decrease in systolic and diastolic blood pressure by 31.2 and 32.8%, respectively (p < 0.0001), a decrease in the coefficient of endothelial dysfunction by 48.6% (p = 0.0006), placental microcirculation increased by 82.8% (p < 0.0001), the NOx concentration was increased by 42,6% (p = 0.0003), the greater omentum edema decreased by 11.7% (p = 0.0005) and proteinuria decreased by 76.1% (p < 0.0002). In addition, there was an improvement in the morphological pattern of the fetoplacental complex and the ratio of BAX to Bcl-2 expression which characterizes the apoptotic orientation of the cells.

scholarly journals CORRECTION OF MORPHOFUNCTIONAL DISORDERS IN EXPERIMENTAL PREECLAMPSY BY COMBINED USE OF TRIMETAZIDINE AND PURIFIED MICRONIZED FLAVONOID FRACTION AS WELL AS THEIR COMBINATIONS WITH METHYLAMPSY

2021 ◽  
Vol 8 (5) ◽  
pp. 304-315
Author(s):  
O. E. Antsiferova ◽  
M. P. Teleshchenko ◽  
Yu. M. Tsuverkalova ◽  
M. V. Pokrovsky ◽  
V. V. Gureev ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Research University ◽  
New Drugs ◽  
Greater Omentum ◽  
Functional Disorders ◽  
Urgent Task ◽  
Combined Use ◽  
Female Wistar Rats ◽  
Flavonoid Fraction

The aim of the experiment was to determine the effectiveness of the combined use of trimetazidine and a purified micronized flavonoid fraction, as well as their combinations with methyldopa, in comparison with monotherapy with the same drugs in the correction of morphofunctional disorders arising in the conditions of experimental preeclampsia. An integrated/multimethodology approach is the most effective way of treatment for preeclampsia. Therefore, an urgent task of modern pharmacology is to study the effectiveness of new drugs when used in combinations, as well as the drugs included in the standards for treatment.Materials and methods. The study was carried out at the Research Institute of Pharmacology of Living Systems of Belgorod State National Research University. The experiment was performed on 200 female Wistar rats, weighing 250–300 g, in which an ADMA-like model of preeclampsia had been reproduced. To assess the degree of correction of emerging morphological and functional disorders, the following parameters were involved: blood pressure, a coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid contents in the greater omentum, morphometric indicators of placental tissues and fetal height and weight parameters.Results. The combined use of trimetazidine (Preductal® MB) 6 mg/kg and a purified micronized flavonoid fraction (Detralex®) 260 mg/kg, as well as their combination with methyldopa (Dopegit®) 86 mg/kg, leads to a more pronounced decrease in the blood pressure, compared with a decrease in the coefficient of endothelial dysfunction by 2.22, 2.19 and 1.94 times, respectively, in relation to “untreated” animals. There was an increase in microcirculation indices in the placenta by 2.35, 2.21 and 2.03 times, respectively. In addition, there was an improvement in morphological parameters in the placenta and fetuses.Conclusion. The results of the study showed a greater effectiveness of the combined use of the studied drugs in experimental preeclampsia compared to their monotherapy. This indicates the prospects for the use of trimetazidine and purified micronized flavonoid fraction in the complex therapy for preeclampsia and the need for further research in this direction.

scholarly journals MBX-500, a Hybrid Antibiotic withIn VitroandIn VivoEfficacy against Toxigenic Clostridium difficile

2012 ◽  
Vol 56 (9) ◽  
pp. 4786-4792 ◽  
Author(s):  
Michelle M. Butler ◽  
Dean L. Shinabarger ◽  
Diane M. Citron ◽  
Ciarán P. Kelly ◽  
Sofya Dvoskin ◽  
...  
Keyword(s):  
Weight Gain ◽  
Clostridium Difficile ◽  
Severe Disease ◽  
Normal Weight ◽  
New Drugs ◽  
Hamster Model ◽  
Resistance Development ◽  
Content Type

ABSTRACTClostridium difficileinfection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, thein vitroandin vivoefficacies of MBX-500 were explored against the Gram-positive anaerobe,C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

scholarly journals P055 Effect of Mimosa caesalpiniifolia extract on DSS-induced colitis in Wistar rats

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S161-S162
Author(s):  
A Garnevi Fávero ◽  
T S Cordeiro ◽  
K N Silva ◽  
L Cardili ◽  
M J D Silva ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Clinical Symptoms ◽  
Statistical Significance ◽  
Clinical Signs ◽  
Operating Conditions ◽  
New Drugs ◽  
Histological Evaluation ◽  
Colon Tissue ◽  
Leaf Extracts ◽  
Anti Inflammatory

Abstract Background Iinflammatory bowel disease (IBD) is a chronic disease characterised by dysregulation of the immune function response and imbalanced release of cytokines and unresolved inflammatory progress associated with the intestinal mucosa. In this way, new drugs are constantly tested as a novel treatment option. Mimosa caesalpiniifolia (MC) has been described as a potent analgesic, anti-inflammatory, anti-haemorrhagic, astringent, anthelmintic and diuretic. This study aimed to evaluate the effect of MC extract on dextran sulphate sodium (DSS)-induced colitis in Wistar rats. Methods Forty male Wistar rats were randomised into five groups: Sham; 5% DSS-induced colitis; control MC extract (125 mg/kg/day); 5% DSS-induced colitis treated with MC (125 mg/kg/day); 5% DSS-induced colitis treated with MC + 5-ASA (125 mg/kg/day for both). Colitis was induced by administration of 5% DSS (MP Biomedicals), diluted in drinking water and offered ad libitum for 5 days. MC plant extract was diluted in water and administered by oral gavage per 6 days. The leaf extracts were prepared in 70 gl ethanol and dried in a Buchi B19 Mini-spray dryer using 20% aerosol. The selection of the operating conditions used was followed by the Laboratory of Medicinal and Phytotherapeutic Plants of Unifal-MG. After the induction of colitis, body weight, general health status and faecal characteristics will be evaluated daily. All rats were euthanised on the ninth day of the experiment. The entire colon was dissected and fixed in 10% neutral-buffered formalin at room temperature and embedded in paraffin to provide sections for histological evaluation (Ethics Committee on the Use of Animals number 4362180119). The severity of colitis was evaluated in sections stained with Hematoxylin and Eosin. Parameters such as inflammation extent, regeneration and crypt damage were graded according to Dieleman et al. Statistical analysis was performed by one-way analysis of variance (ANOVA), followed by Tukey post hoc test using Graph Pad Prism (version 6.0). Results MC extract treatment reduced significantly the severity of DSS-induced colitis evidenced by a decreased in clinical symptoms (p &lt; 0.0001). The rats treated with MC extract showed a decreased in diarrhoea episodes and rectal bleeding. We observed histopathological changes of colon tissue between the DSS-treatment and control groups, however, without statistical significance. The MC extract treatment reduced the damage to the colonic tissue evidenced by a decreased of inflammatory cells, ulcerations, and goblet cell preservation. Conclusion MC extract reduces the clinical signs and suggests a potential anti-inflammatory effect on DSS-induced colitis.

scholarly journals Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria

2007 ◽  
Vol 204 (11) ◽  
pp. 2693-2704 ◽  
Author(s):  
Tsin W. Yeo ◽  
Daniel A. Lampah ◽  
Retno Gitawati ◽  
Emiliana Tjitra ◽  
Enny Kenangalem ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Falciparum Malaria ◽  
Reactive Hyperemia ◽  
Severe Disease ◽  
Microvascular Endothelium ◽  
Tissue Ischemia ◽  
Exhaled No ◽  
No Bioavailability ◽  
Severe Falciparum Malaria

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia–peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33–1.47) than in MSM (1.82; 95% CI = 1.7–2.02) and controls (1.93; 95% CI = 1.8–2.06; P &lt; 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6–34; P = 0.006) and exhaled NO by 55% (95% CI = 32–73; P &lt; 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.

scholarly journals Role of Arginase 2 as a potential pharmacological target for the creation of new drugs to correct cardiovascular diseases

2020 ◽  
Vol 6 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Sergey A. Demchenko ◽  
Ivan S. Koklin ◽  
Natalia Yu. Koklina
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Relevant Information ◽  
Type Ii Diabetes Mellitus ◽  
New Drugs ◽  
History Of ◽  
Pharmacological Target

Introduction: The review provides relevant information about arginase 2, the role of this enzyme in the formation of endothelial dysfunction and, as a consequence, the development of cardiovascular diseases. History of the discovery of arginase and its functions: The discovery of arginase took place long before its active study as a substance that affects the formation of endothelial dysfunction. Role of arginase 2 in the development of a number of cardiovascular diseases: The role of NO synthase and arginase 2 in the formation of oxidative stress is determined. The pathophysiological mechanisms of the development of a number of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and aortic aneurysm, are described. The modern possibilities of treatment of endothelial dysfunction in the pathology of the cardiovascular system and the possibility of creation of new drugs are considered. An increase in the activity of arginase 2 was proven to occur in the case of the development of coronary heart disease (CHD), hypertension, type II diabetes mellitus, hypercholesterolemia, as well as in the process of aging. According to the WHO, coronary heart disease and apoplectic attack have topped the list of causes of death worldwide over the past 15 years. Arginase 2 as a potential pharmacological target: The purpose of this literature review is to determine the possibilities of use of arginase 2 as a new target for the pharmacological correction of cardiovascular diseases.

scholarly journals Experimental models for vascular endothelial dysfunction

2021 ◽  
Vol 16 (3) ◽  
pp. 65-83
Author(s):  
Anchal Garg ◽  
Vardan Gupta ◽  
Ritu Tomar ◽  
Mandeep Kumar Arora
Keyword(s):  
Endothelial Dysfunction ◽  
Animal Models ◽  
Underlying Mechanism ◽  
Cardiovascular Complications ◽  
Experimental Models ◽  
New Drugs ◽  
Vascular Endothelial ◽  
Vascular Endothelial Dysfunction ◽  
Vascular Integrity ◽  
Increased Risk

Vascular endothelial dysfunction is characterized by apoptosis of endothelial cells, an imbalance between vasoconstrictory and vasodilatory substances, the imbalance between ROS and antioxidants, vascular remodeling, loss of vascular integrity which leads to an increased risk of cardiovascular complications. To date, no therapeutic intervention is available as a promising agent. This may be due to a poor understanding of the underlying mechanism involved in vascular endothelial dysfunction in the pathogenesis. Animal models sharing identical features as that of humans are paramount to understand fundamental physiology, mechanism and to explore new targets for developing therapeutic agents. Thus, it becomes mandatory to re-explore the available animal models for a better understanding of molecular pathways involving vascular endothelial dysfunction. The purpose of this paper is to review different models for vascular endothelial dysfunction to the outlook for developing new drugs to treat vascular endothelial dysfunction.

scholarly journals Fetoplacental complex parameters’ changes during repeated increase of the blood volume in female rabbits

2020 ◽  
Vol 11 (6) ◽  
pp. 37-44
Author(s):  
Nataliya G. Pavlova ◽  
Anastasiya A. Yakovleva
Keyword(s):  
Blood Volume ◽  
Functional State ◽  
Saline Solution ◽  
Experimental Studies ◽  
Main Group ◽  
Placental Insufficiency ◽  
New Drugs ◽  
Control Group ◽  
Fetoplacental Complex ◽  
Preclinical Trials

One of the mandatory stages of introducing new drugs into obstetric practice is preclinical trials, the purpose of which is to study the effect of drugs on the development of fetuses and placentas. When conducting experimental studies, the main group of animals receiving the drug is compared with the control group of animals that do not receive drugs. At the same time, the volume of the test drug itself can significantly change the blood volume (BV) of an experimental animal, especially a small one, and such administration repeated repeatedly over several days can accumulate this effect, having an adverse effect on the functional state of the fetus. A model of chronic placental insufficiency created on the 18th day of pregnancy in female rabbits by ligating 1/3 of the preplacental vessels in one uterine horn was used to study the effect on the development of the brain and placenta of normally developed and retarded fetuses of multiple daily (1928 days of pregnancy) infusions of saline solution to females in a volume of 6% of the animals BV and comparable to the volume of medications used in the treatment of placental insufficiency in clinical practice (main group of rabbits). It was found that repeated daily administration of saline solution to a female rabbit in the second half of pregnancy, which is about 6% of the BV, causes a violation of the functional state of her normally developed and, to an even greater extent, retarded fetuses. This is manifested by a 1.4-fold reduced survival rate of fetuses in the intact horn of the uterus and a more pronounced violation of brain metabolism in fetuses of the intact and experimental horns compared to those of the control group of females.

Comparative Assessment of Endothelium-Associated Correction of Experimental Osteoporosis with Resveratrol and Etoksidol

2012 ◽  
Vol 19 (1) ◽  
pp. 8-11
Author(s):  
Aleksandr Vladimirovich Faytel'son ◽  
G M Dubrovin ◽  
O S Gudyrev ◽  
M V Pokrovskiy ◽  
A V Ivanov ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Bone Tissue ◽  
Bone Remodeling ◽  
Wistar Rats ◽  
Comparative Assessment ◽  
Experimental Osteoporosis ◽  
Female Wistar Rats ◽  
Bone Trabeculae

Osteoprotective action of resveratrol and etoksidol was studied on the model of experimental osteoporosis (140 female Wistar rats). It was detected that endothelial dysfunction of bone tissue microcirculation bed that led to osteoporosis development. In contrast to etoksidol, resveratrol prevented the reduction of bone tissue microcirculation level and the aggravation of bone remodeling processes in developing osteoporosis that was manifested by delayed bone trabeculae thinning and averting of microfractures in them.

scholarly journals Metabolites of Seaweeds as Potential Agents for the Prevention and Therapy of Influenza Infection

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 373 ◽  
Author(s):  
Natalia Besednova ◽  
Tatiana Zaporozhets ◽  
Tatiana Kuznetsova ◽  
Ilona Makarenkova ◽  
Lydmila Fedyanina ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Broad Spectrum ◽  
Influenza Infection ◽  
Biologically Active ◽  
New Drugs ◽  
New Therapeutic Approaches ◽  
Or Genes ◽  
Prevention And Therapy

Context: Seaweed metabolites (fucoidans, carrageenans, ulvans, lectins, and polyphenols) are biologically active compounds that target proteins or genes of the influenza virus and host components that are necessary for replication and reproduction of the virus. Objective: This review gathers the information available in the literature regarding to the useful properties of seaweeds metabolites as potential agents for the prevention and therapy of influenza infection. Materials and methods: The sources of scientific literature were found in various electronic databases (i.e., PubMed, Web of Science, and ScienceDirect) and library search. The retrospective search depth is 25 years. Results: Influenza is a serious medical and social problem for humanity. Recently developed drugs are quite effective against currently circulating influenza virus strains, but their use can lead to the selection of resistant viral strains. In this regard, new therapeutic approaches and drugs with a broad spectrum of activity are needed. Metabolites of seaweeds fulfill these requirements. This review presents the results of in vitro and in vivo experimental and clinical studies about the effectiveness of these compounds in combating influenza infection and explains the necessity of their use as a potential basis for the creation of new drugs with a broad spectrum of activity.

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