Acute Aseptic Inflammation Research Articles

Bioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines

Background: Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe the development of promising new bioactive molecules through the bioisosteric replacement of a carbon atom with a sulfur atom in anti-inflammatory agents, specifically 3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)butanoate. Methods: Design and synthetic studies have led to the series of previously unknown substituted 2-[((3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)methyl)thio]carboxylic acids and their esters. These compounds were synthesized by reacting 6-chloroalkyl-3-R-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones with sulfanylalkyl carboxylic acids and their functional derivatives. The purity and structure of the obtained compounds were confirmed using a set of physicochemical methods, including elemental analysis, HPLC-MS, and 1H NMR spectroscopy. Molecular modeling, predicted toxicity, drug-likeness, and pharmacokinetics data were used to select compounds for evaluation of their effects on acute aseptic inflammation (carrageenan-induced paw edema test) and on markers of the inflammatory process. Results: The compound 2-((1-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)ethyl)thio)acetic acid (compound 2e) was identified as the most active anti-inflammatory agent (AA = 53.41%), demonstrating significant inhibition of both paw edema development and the generation of pro-inflammatory cytokines and mediators. Conclusions: Results from docking studies and analysis of “structure-affinity” correlations revealed that these compounds are promising candidates for further modification and detailed investigation of their anti-inflammatory activity

Anti-Inflammatory And Immunomodulating Activity of the 1(10) Β-Epoxy-5,7α,6β(Н)-Guai-3(4),11(13)-Dien-6,12-Olide

BACKGROUND: The article discusses the results of studies of the anti-inflammatory and immunomodulatory activity of the sesquiterpene lactone 1(10)β-epoxy-5,7α,6β(Н)-guai-3(4),11(13)-diene-6,12-olide (hereinafter referred to as epoxyguaianolide). AIM: The article discusses the results of studies of the anti-inflammatory and immunomodulatory activity of the sesquiterpene lactone 1(10)β-epoxy-5,7α,6β(Н)-guai-3(4),11(13)-diene-6,12-olide. MATERIALS AND METHODS: A non-steroidal anti-inflammatory drug diclofenac sodium at a dose of 25 mg/kg (ampoules, 2 mL each, manufactured by Germany) was used as a reference drug in models of acute aseptic inflammation and cotton ball granuloma. On the model of cyclophosphamide immunosuppression, the immunomodulator levamisole at a dose of 3 mg/kg, was used as a reference drug. The immunomodulating effect of the test samples was studied on outbred adult male rats and outbred mice. We calculated the arithmetic mean, the mean square error of the arithmetic mean, the significance of the difference between the mean Рt according to the student’s t-test (TTEST), and the significance of the difference in Pf variances according to the Fisher f-test. RESULTS: The results of the experiments indicate the presence of a pronounced immunomodulatory activity in epoxyguaianolide. When interacting with cells of the immune system, epoxyguaianolide activated the studied parameters in animals with immunosuppression, whereas in intact animals, it did not affect the above parameters. On the model of cyclophosphamide immunosuppression, it was found that epoxyguaianolide has a pronounced immunomodulatory effect, manifested in an increase in the number of T-lymphocytes and a subpopulation of theophylline-resistant T-lymphocytes, an increase in the number of theophylline-sensitive T- and B-lymphocytes, activation of phagocytosis processes, and increased cell migration. This action of epoxyguaianolide eliminates the minimal possibility of hyperactivation of the immune system, which is an important condition for its use as an immunotropic agent. CONCLUSIONS: The conducted experiments made it possible to recommend epoxyguaianolide for clinical trials as an immunomodulating agent in the treatment of chronic inflammatory diseases accompanied by secondary immunodeficiencies.

5+1-Heterocyclization as preparative approach for carboxy-containing triazolo[1,5-c]quinazolines with anti-inflammatory activity

Present article is devoted to the purposeful search of novel anti-inflammatory agents among carboxyl-containing partially hydrogenated [1,2,4]triazolo[1,5-с]quinazolines and products of their tandem cyclization. It has been shown that target compound’s could be obtained via interaction between [2-(3-R-1H-1,2,4-triazol-5-yl)phenyl]amines and oxo-containing carboxylic acids and their esters of various structure. The structures of synthesized compounds were verified by appropriate methods, the features of NMR-spectra patterns were discussed as well. The low predicted toxicity of obtained compounds has been estimated using in silico methods. In vivo study on the model of acute aseptic inflammation (carrageenan test) have been revealed that synthesized compounds expose anti-inflammatory activity in the range of 0.94–52.66%. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid has been identified as most active compound. Additionally, the effects of some (2-R-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acids (compounds 3) on the levels of key inflammatory markers have been estimated. It has been shown that studied compounds decrease the level of neutrophils, COX-2, nitrotyrosine, IL-1b, C-reactive protein and increase level of eNOS. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) has been identified as compound with most expressed anti-inflammatory activity and significant effect on the levels of marker of inflammatory processes. Molecular docking study towards СОХ-1 and СОХ-2 has been conducted to substantiate possible mechanism of obtained compounds anti-inflammatory activity. It has been found that fixation of 4-(2-(ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) molecule in active site of enzyme is outstandingly similar to the reference ligands. The essential value of carboxylic group for presence of anti-inflammatory activity has been estimated as result of SAR-analysis. It has been found that studied class of compounds is perspective for further structural modification aimed to the creation of novel anti-inflammatory agents.

Approaches to synthesis of ([1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids as potential anti-inflammators

Despite their high efficacy NSAIDs have significant side effects due to non-selective inhibition of COX-1 and COX-2. Due to this, medical chemists still pay considerable attention to their design and synthesis, in particular the creation of hybrid molecules that combine in their structure a fragment with anti-inflammatory activity and the quinazoline heterocycle.
 The aim of the present study is to develop methods for the synthesis of [1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids as potential anti-inflammatory agents.
 Quinazolin-4(3H)-ylidene)hydrazides (hydrazones) of benzenedicarboxylic acids, their esters, products of their heterocyclization and nucleophilic degradation were the subjects of the study. The structure of the synthesized compounds was confirmed by elemental analysis and NMR spectroscopy. Anti-inflammatory activity was studied in a model of acute aseptic inflammation («carrageenan test») in rats.
 Possibilities and limitations of synthesis of [1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids and their esters via hetero­cyclization of the corresponding hydrazides and hydrazones oxidative cyclization are shown. It was found that the hydrolysis of 4-[(1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acid esters is not a preparative method for the synthesis of the target acids, due to the hydrolytic cleavage of the pyrimidine cycle. Compounds 3, 4 and 6 with moderate anti-inflammatory activity have been identified, which can be used for further structural modification.
 Conclusions. It was found that quinazolin-4(3H)-ylidene)hydrazides (hydrazones) of benzenedicarboxylic acids and their esters under the conditions of heterocyclization and oxidative cyclization form [1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids and their esters. The synthesized compounds are carriers of anti-inflammatory activity and promising for further research.

Comparative Assessment of Morphological Changes in the Pleura and Lung Tissue after Pleurodesis with Various Solutions in the Experiment

Introduction. Currently, spontaneous pneumothorax occurs in 6,2-7,1% of patients with nonspecific lung diseases. There has been a steady increase in prevalence of this disease. The relevance of preventing recurrence of spontaneous pneumothorax is still beyond doubt. Most authors recommend performing chemical pleurodesis when nonspecific spontaneous pneumothorax occurs, especially if it is recurrent. At the present time, the issue of choosing the optimal chemical agent for performing pleurodesis remains important.The aim of the study was to analyse the nature and severity of the inflammatory reaction from the lungs, pleura and adjacent subpleural tissues of the chest wall in experimental animals during chemical pleurodesis with 4% sodium bicarbonate, 6% hydrogen peroxide and 5-fluorouracil solutions.Materials and methods. The experiment was conducted at the experimental laboratory of Voronezh Regional Clinical Hospital № 1. The study involved 200 experimental rats (WISTAR type) with simulated spontaneous pneumothorax; after a fixed time, one of the preparations was sprayed into the pleural cavity. All animals were divided into 3 groups depending on the method of pleurodesis (5-fluorouracil solution, 4% sodium bicarbonate solution and 6% hydrogen peroxide solution) and control (0,9% sodium chloride solution). Groups of animals were withdrawn from the experiment in accordance with the rules of humane treatment of animals in 3, 5, 7, 10, 30 days with sampling of organs and tissues of the chest for histological examination to compare severity of inflammatory reactions in the pleura and adjacent areas of the lungs depending on the drug used for pleurodesis. The main criterion for assessing the comparative effectiveness of chemical agents was the morphological picture of inflammation presented by counting free cell populations (lymphocytes, macrophages, neutrophils, histiocytes) in the pleura and adjacent areas of the lung tissue of the studied animals.Quantitative results were statistically processed using parametric and nonparametric methods with STATISTICA 10. The main statistical parameters of the studied data were estimated by the methods of descriptive statistics. Comparison of the studied samples was conducted with the Kruskal-Wallis test. Differences between the compared samples were considered significant at p0,05.Results. The morphology of the inflammatory reaction in the pleura and adjacent lung tissue in all the studied groups of animals was characterized by the predominance of neutrophils over other cells in the first days of the experiment; the fact supporting acute aseptic inflammation in response to drug administration. Further, the content of lymphocytes, macrophages and their inactive forms (histiocytes) increased, and the content of neutrophils decreased, which was typical for the transition of acute inflammation to chronic. Compared dynamics in the number of analyzed immunocompetent cells evidenced that the number of lymphocytes, macrophages and histiocytes increased faster. After pleurodesis with a 6% hydrogen peroxide solution, the lowest content of immunocompetent cells in the studied tissue samples was noted if compared with the samples obtained from other groups in the same period. In all cases, pleurodesis with 6% hydrogen peroxide resulted in the minimal number of neutrophils, and the dynamics of their decrease was the most pronounced. In the control group, the number of studied cells fluctuated within the average value for this group.Conclusion. The dynamics in the number of studied cell populations in all comparison groups was assessed as common. The method of pleurodesis significantly affects the number of cellular elements involved in the inflammatory response. Clinical outcomes of pleurodesis performed with a 6% hydrogen peroxide solution are characterized by a shorter duration and severity of the inflammatory response from the pleura and adjacent parts of the chest wall, compared with 5-fluorouracil and 4% sodium bicarbonate solutions.

Hemoglobin Isoforms in Rat Erythrocytes in Acute Aseptic Inflammation.

Qualitative rearrangement in erythropoiesis (changes in the ratio between erythrocyte populations and hemoglobin isoforms) was revealed in male Wistar rats with modeled acute aseptic inflammation. It was found that the percentage of heavy hemoglobin isoforms prevailed over the light forms in the bloodstream. Deciphering of the mechanisms of these changes requires additional research.

Inflammation, Infiltration, Necrosis, Abscess and Nicolau Syndrome after Injection of Nonsteroidal Anti-inflammatory Drugs: What is the Reason?

It has been established that some nonsteroidal anti-inflammatory drugs (NSAIDs) when administered through injectable preparations have a local irritating effect, even though the preparations are considered high-quality. It seems that this local irritant action is not related to any specific pharmacological action but with the physicochemical properties of the preparation that grossly violate the homeostasis of the tissues. It seems that the local complications at injection sites can be caused by the nonspecific properties of the injectable preparations: denaturing (cauterizing), hypertonic and acidic activity. Each such property, or their combination, has a locally irritating effect, which can cause abscess, necrosis, and acute aseptic inflammation of reversible or irreversible nature, that follows immediately after subcutaneous or intramuscular administration, a condition named “Nicolau Syndrome”. Conversely, injectable preparations of NSAIDs having isotonic or hypotonic osmolarity associated with a neutral or weakly alkaline pH (about pH 7.4), produce a minimal short-term reversible local inflammatory effect and do not cause Nicolau Syndrome after administration.

Morphometric characteristics of the sciatic nerve trunk structural components with a single introduction of cryconserved placenta against the background of acute aseptic inflammation in rats

The study was carried out on 55 adult male rats. The dynamics of changes in morphometric parameters with a single administration of cryopreserved placenta against the background of acute aseptic inflammation in rats is presented. Thus, it was proved that a single administration of cryopreserved placenta against acute aseptic inflammation of the sciatic nerve trunk induced by a single intraperitoneal injection of λ-carrageenan led to a total change in the sciatic nerve trunk that reached its maximum on the 10th day with the reliable difference (р>0.05) and further reliable recovery on the 21st day. The term of 21 days after a single administration of cryopreserved placenta against the background of acute aseptic inflammation of the sciatic nerve in rats is sufficient to assess the final results of regenerative processes in the structure of the sciatic nerve damaged by the inflammatory process in the rat.

CHANGES IN HEMOMICROCIRCULATORY BED OF RAT ILEUM MUCOSA IN TRANSPLANTATION OF CRYOPRESERVED PLACENTA AGAINST THE BACKGROUND OF ACUTE ASEPTIC INFLAMMATION OF PERITONEUM

Hemomicrocirculatory bed (HMCB) in the modern sense is a complex organized system that provides ordered motion of blood, tissue fluids, absorption and excretion of biochemical substrates, metabolites, biologically active substances. Among the interrelated and interdependent processes in the system of HMCB, the main role belongs to the patterns of blood circulation in the vessels. The last decade has been marked by a completely new approach to solving problems associated with impaired blood filling. The use of tissue transplantation, in particular cryopreserved placenta grafts, as a corrective method, is quite effective. The latter was the basis for a comprehensive study of the ileal mucosa HMCB response to the cryopreserved placenta transplantation [11]. The aim of this study was to investigate the dynamics of the ileum mucosa hemo-microcirculatory bed parameters with a single administration of cryopreserved placenta and with the cryopreserved placenta administration against the background of acute aseptic experimental peritoneum inflammation in rats. Object and methods of the study. The object of the experimental study was the ileum wall sampled from 140 mature Wistar male rats. The animals were divided into four groups. Animals were euthanized on the 1st, 2nd, 3rd, 5th, 7th, 10th, 14th, 21st, 30th days. Measurements of the HMCB vessels internal diameter in the ileac mucosa were performed. The mathematical processing was performed by means of Student's t test (t). Differences at p <0.05 were considered reliable. Transplantation of cryopreserved placenta causes the reaction of all links of the hemomicrocirculatory bed by increasing their average diameter with maximum values for 5 days. Simulation of acute aseptic inflammation of the peritoneum initially led to a decrease in the diameter of arterioles by 5% and capillaries by 2.3%, by 2-3 days, and then by an increase in their diameters, by the 14th day of the study. During the experiment, the venular unit increased in diameter by the 14th day of the study. When transplanting cryopreserved placenta against acute aseptic inflammation of the peritoneum of the arterioles by 4% and capillaries by 2%, they first decrease in diameter by 2 days, and then increase in diameter by 3-10 days of the study. During the experiment, the venular unit significantly increased in diameter by the 14th day of the study. With the introduction of cryopreserved placenta on the background of acute aseptic inflammation of the peritoneum, the realization of inflammation decreased by 4-5 days.

Modeling of chronic prostatitis. Abacterial prostatitis in the aspects of reproduction of experimental hypofertility (review)

There is a problem of modeling of prostatitis in animals despite of the progress at the creation of prostatic protectors capable of correcting hypofertility. In this regard, modeling prostate gland pathology, monitoring its development and finding out factors causing a decrease in the generative function in prostatitis are topical issues. In this review, the important role of experimental modeling of prostatitis have been shown, the etiology, pathogenesis and clinical manifestations of prostatitis, the epidemiology of reproductive impairment in conditions of abacterial inflammatory process of the prostate gland have been reviewed, and data about methods of prostatitis modelling in laboratory animals. Such modeling of chronic abacterial prostatitis in rats has been reviewed: by rectal administration of dimexide and turpentine; by cryotrauma; piercing (traumatic) prostatitis; prostatitis after hypokinetic stress; autoimmune prostatitis; acute aseptic inflammation of the prostate gland; chronic prostatitis by applying metaxylene; as well as experimental models of prostatitis associated with hormonal effects. Summarizing the literature data, the authors conclude that the experimental modeling of chronic prostatitis is an issue of importance not only for the study of the course of this common disease, but also for the development of new methods and measures for the treatment of prostatitis and reproductive health disorders that occur on the background or accompanied by inflammation.

ВИВЧЕННЯ ПРОТИЗАПАЛЬНОЇ АКТИВНОСТІ СУХОГО ЕКСТРАКТУ З ЛИСТЯ САЛАТУ ПОСІВНОГО

Вступ. Проблема фармакологічної корекції запалення, як і раніше, залишається актуальною, оскільки сучасна медицина повністю її не вирішила. Одним із перспективних напрямів створення безпечних та ефективних протизапальних препаратів є фітотерапія. В останні роки підвищився інтерес до препаратів рослинного походження.
 Мета дослідження – вивчити протизапальну активність сухого екстракту з листя салату посівного в експерименті з модельованим карагеніновим набряком лапи щурів.
 Методи дослідження. При визначенні протизапальної активності екстракту з листя салату посівного використовували безпородних білих щурів-самців масою 180–200 г. Індукцію гострого асептичного запалення проводили шляхом субплантарної ін’єкції 0,1 мл 1 % розчину карагеніну. Досліджуваний зразок екстракту в дозі 100 мг/кг маси тіла вводили піддослідним щурам внутрішньошлунково у профілактичному режимі одноразово за 1 год до індукції запалення. Через 1, 3, 6 та 24 год вимірювали об’єм здорової та ураженої кінцівок за допомогою механічного онкометра. Антиексудативну активність екстракту визначали за ступенем зменшення набряку в піддослідних тварин порівняно з контрольними та виражали у відсотках. Як препарат порівняння використовували диклофенак натрію в дозі 8 мг/кг.
 Результати й обговорення. Встановлено, що у групі тварин, які отримували екстракт з листя салату посівного, максимальний позитивний вплив на розвиток набряку спостерігали через 3 год від початку запалення (31,22 %), і тривав він до кінця експерименту. Через 24 год від початку розвитку запалення ефект від застосування екстракту був дещо нижчим. Але найменш виражений його вплив на розвиток запалення відзначали через 1 год дослідження. Аналогічний вплив мав диклофенак натрію, щоправда значний ефект від його застосування проявився вже через 1 год від початку експерименту.
 Висновок. Доведено виразну протизапальну активність сухого екстракту з листя салату посівного, який найбільш активно пригнічує розвиток набряку лапи щурів через 1 год запалення.

New Herbal Preparation Pancafit and Its Anti-Inflammatory Efficacy

A quantitative determination method for total flavonoids recalculated as rutin standard in pancafit dry polyextract obtained from the aerial part of Panzerina lanata (L.) Sojak (Lamiaceae) and leaves of Cacalia hastata L. (Asteraceae) was developed. Intragastric administration of pancafit dry extract at a dose of 100 mg/kg to Wistar rats with acute aseptic inflammation was associated with anti-alterative and anti-exudative activity in addition to accelerated regeneration of damaged tissue. The results indicated that pancafit dry extract should be used as an anti-inflammatory agent in combination with other therapeutic and preventive treatments.

Synthesis of mono-and bis-derivatives of spiro-2-oxindole[3,3']pyrrole and their antioxidant and anti-inflammatory activities investigation

Aim. To synthesize range of mono- and bis-derivatives of spiro-2-oxindole[3,3']pyrrole and to study antioxidant and antiinflammatory activity of the obtained compounds.Materials and methods. Methods of organic synthesis and instrumental methods for the structure of organic compounds determination were used; the antioxidant properties of synthesized compounds was studied in vitro on the model of spontaneous lipid peroxidation oxidation; model of acute aseptic inflammation (carrageenan edema) was used for determination of antiinflammatory (anti-exudative) activity.Results and discussion. Series of novel spiro-2-oxindole[3,3']pyrrole derivatives was synthesized by means of three-component cascade interaction of isatin, α-amino acids and dipolarophils based on bis-maleimids. In order to broaden the obtained range of compounds nitroso derivatives of ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-methyl-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) 4 and hexamethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-benzyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) 5 were synthesized. The structure of the obtained compounds was reliably confirmed by instrumental methods (1H NMR, IR spectroscopy and chromatographic mass spectrometry). Screening studies of anti-inflammatory properties were produced, which included in vitro exploration of antioxidant action of synthesized compounds. Three of the tested substances revealed the highest antioxidant properties and were subsequently selected for further investigation of their anti-inflammatory activity. The data of the biological experiments showed their pronounced anti-inflammatory properties on the carrageenan edema model.Conclusions. Current research proved that the preparatory method, namely, the three-component cascade transformation of isatin, α-amino acids and dipolarophils based on bis-maleimides is effective for synthesis of spiro-2-oxindole[3,3']pyrrole mono- and bis-derivatives. Series of hexamethylene- and ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-4'-nitroso-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) symmetric derivatives were obtained. The structure of the obtained compounds was confirmed. Investigation of the antioxidant properties of the synthesized compounds revealed the most active substances: 1'-(hexamethylene-N-maleimido)-5'-benzyl-2a',5a'-dihydro-1'H-spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-2,2',6'(1H,3'H,5'H)-trione 1; ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-4'-nitroso-5'-methyl-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) 6; hexamethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-4'-nitroso-5'-benzyl-2a,5a'-dihydro-2,2',6(1H,1'H,5'H)-trione) 7. Compound 6 also showed anti-inflammatory properties on the reference drug level.

Prospects for Drugs Based on the Mitochondria-Targeting Antioxidant SkQ1 in Treatment of Wounds with Impaired Healing

Chronic wounds with impared wound healing that require prolong time for healing remain unsolved problem of modern medicine. Excessive oxidative stress plays an important role in the pathogenesis of chronic wounds caused by aging, diabetes and other pathologies. This review is aimed at the role of mitochondria in oxidative stress and to the future prospects for using the innovative mitochondria targeted antioxidants for treatment of impaired wounds. Recent studies in old mice and mice with type 2 diabetes showed that the mitochondrial antioxidant SkQ1 [10- (6'- plastoquinonyl) decyltriphenylphosphonium] stimulates healing of full-thickness dermal wounds. SkQ1 accelerates inflammatory stage of wound healing, maturation of granulation tissue, angiogenesis and epithelization of wounds. The anti-inflammatory effect of SkQ1 is possibly connected to decreased inflammatory activation of the vascular endothelium, which is typical for aging, diabetes and other pathologies. Local administration of SkQ1 also accelerates wound healing and provides strong anti-inflammatory effect in the model of acute aseptic inflammation. In addition, SkQ1 to stimulate apoptosis of neutrophils and suppresses their activation, as well as suppresses inflammatory activation of mast cells. In the wound model in vitro, SkQ1 accelerates movement of epithelial cells and fibroblasts into the «wound» and stimulates differentiation of human subcutaneous fibroblasts to myofibroblasts. Reviewed data suggest that SkQ1-based topical drugs have a great potential to treat wounds that exhibit impaired healing also in patients suffering from chronic critical illness.

Anti-Inflammatory and Analgesic Activities of the Complex of Flavonoids from Lychnis chalcedonica L.

Anti-inflammatory and analgesic activities of the complex of flavonoids from Lychnis chalcedonica L. were studied in the models of acute aseptic inflammation induced by carrageenan, histamine, and serotonin and acetic acid-induced painful chemical stimulation. It is demonstrated that course treatment with flavonoids derived from Lychnis chalcedonica L. produced a stable pharmacological effect comparable with that of the reference anti-inflammatory drug diclofenac.

Ultrastructural and immunohistochemical characteristics of the anterior abdominal wall tissue in experimental plastics of ventral hernias.

Background. The active retrieval of methods for the increase of the efficiency of ventral hernia alloplasty is performed now; however the structural-functional changes of scar and muscle tissues during their reorganization are still little studied. Objective. The purpose of the work was to determine cellular and ultrastructural changes in the anterior abdominal wall with experimental alloplasty of ventral defects. Methods. The morphological analysis was carried out during 1 year. Transmission electron microscopy and immunohistochemistry of vascular markers CD34 and VEGF were used. Results. Early tissue reactions after plastics of a large ventral defect include expressive manifestations of acute aseptic inflammation and degenerative changes in muscle-aponeurotic structures in conditions of significant biomechanical tissue tension in the healing zone of the wound, regardless of the presence or absence of prosthesis material. The use of polypropylene mesh without tension and alignment of the edges of the defect reduces the severity of early ultrastructural damage. Immunohistochemical characteristic of muscle tissue on markers VEGF and SD34 within 1 year after hernioplasty of large ventral defect under conditions of tension of tissues testifies to the preservation of pathological changes and violation of the microvascular component. Prevention of biomechanical stresses of the muscular-aponeurotic layer leads to normalization of the distribution and expression levels of VEGF and CD34. Conclusion. In conditions of significant tissue tension after the plastics of a large ventral defect, there is a preservation of destructive ultrastructural changes in the microvessels and muscle-aponeurotic structures, regardless of the presence or absence of a monofilament polypropylene mesh. The lack of significant tissue tension creates conditions for the full integration of the prosthesis to muscle-aponeurotic structures.

SYNTHESIS OF NEW N-HYDROXYPHENYL AND TOLYL DERIVATIVES OF PYRIMIDINE-4(1H) –ONE WITH ANTI-INFLAMMATORY ACTIVITY

In their structure pyrimidin-4-one derivatives are similar to the endogenous nitrogen bases. This makes it possible to predict a wide range of pharmacological activities characteristic for them. The compounds of this series exhibit neurotropic, immunotropic, actoprotective, hypotensive, antihypoxic, anti-infl ammatory and antioxidant activity. Within this framework, the search for and creation of highly effective and safe anti-infl ammatory drugs in the series of N-arylpyrimidin-4(1H)-one is of great current interest. The aim of the work is to carry out predictive studies and targeted synthesis of N-substituted derivatives of pyrimidine-4(1H)-one with anti-infl ammatory activity, as well as toconfi rm the validity of their molecular construction by the results of pharmacological tests. Materials and methods. The research was carried out using the logical-structural approach and information technologies. The computer analysis of biological activity was carried out by the PASS program. Synthesis of the target compounds was carried out using a modifi ed procedure. The structure of the synthesized compounds was confi rmed by 1 H NMR, IR and UV spectroscopy. The investigation of the anti-infl ammatory effect of the synthesized compounds was carried out on the model of acute aseptic infl ammation. The synthesized substances were injected intraperitoneally, the magnitude of the edema was the criterion for evaluating the anti-infl ammatory activity. Results and discussion . In the course of the research on the basis of the logico-structural approach, hydroxyphenyl and alkyl derivatives of pyrimidin-4(1H)-one with anti-infl ammatory properties were validated. A preliminary analysis of the pharmacological properties of the predicted structures was carried out using the PASS program and the most promising compounds were selected. To synthesize the tolyl and hydroxyphenyl derivatives of pyrimidin-4(1H)-one, a modifi ed procedure was used. Its essence consists in the use of catalytic amounts of dimethylsulfoxide in order to increase the nucleophilicity of the amine component of the reaction. In order to confi rm the reliability and expediency of the molecular construction, the antiexudative activity of the target compounds was studied. Conclusion. The results of pharmacological studies indicate the prospect of searching for and creating new biologically active compounds having anti-infl ammatory activity among the tolyl and hydroxyphenyl derivatives of pyrimidin-4(1H)-one.

Anti-cytokine therapy for prevention of atherosclerosis

BackgroundCurrently a chronic inflammation is considered to be the one of the most important reasons of the atherosclerosis progression. A huge amount of researches over the past few decades are devoted to study the various mechanisms of inflammation in the development of atherosclerotic lesions. PurposeTo review current capabilities of anti-inflammatory therapy for the prevention and treatment of atherosclerosis and its clinical manifestations. MethodsAppropriate articles on inflammatory cytokines in atherosclerosis and anti-inflammatory prevention of atherosclerosis were searched in PubMed Database from their respective inceptions until October 2015. Sections“The role of inflammatory cytokines in the development of atherosclerotic lesions” describes available data on the possible inflammatory mechanisms of the atherogenesis with a special attention to the role of cytokines. “Modern experience of anti-inflammatory therapy for the treatment of atherosclerosis” describes modern anti-inflammatory preparations with anti-atherosclerotic effect including natural preparations. In “the development of anti-inflammatory herbal preparation for atherosclerosis prevention” an algorithm is demonstrated that includes screening of anti-cytokine activity of different natural products, the development of the most effective combination and estimation of its effect in cell culture model, in animal model of the acute aseptic inflammation and in a pilot clinical trial. A natural preparation “Inflaminat” based on black elder berries (Sambucus nigra L.), violet tricolor herb (Viola tricolor L.) and calendula flowers (Calendula officinalis L.) possessing anti-cytokine activity was developed using the designed algorithm. The results of the following 2-year double blind placebo-controlled clinical study show that “Inflaminat” reduces carotid IMT progression, i.e. has anti-atherosclerotic effect. ConclusionAnti-cytokine therapy may be a promising direction in moderation of atherogenesis, especially when it begins on the early stages of subclinical atherosclerosis. The use of herbal preparations with anti-cytokine mechanism of action is the most perspective for timely prevention of atherosclerosis, as they have no significant side effects and can be prescribed for long-term administration.

Altered Inflammatory Responses to Citrobacter rodentium Infection, but not Bacterial Lipopolysaccharide, in Mice Lacking the Cyp4a10 or Cyp4a14 Genes

Murine hepatic Cyp4a mRNAs are markedly downregulated during inflammation. Here, we investigated the roles of Cyp4a10 and Cyp4a14 in the response to infection with C. rodentium. Absence of either Cyp4a gene attenuated or abrogated the changes in spleen weight, colon crypt length, hepatic cytokine, and acute phase protein mRNAs, and serum acute phase proteins and cytokines caused by infection. Cyp4a10(-/-) mice on a low-salt diet had a similar hepatic acute phase response as those mice on a high-salt diet, suggesting that hypertension associated with this genotype is not the cause of their altered inflammatory response. In contrast, wild-type, Cyp4a10(-/-), and Cyp4a14(-/-) mice showed similar responses to injected LPS. These results implicate Cyp4a10 and Cyp4a14 in the regulation of the host inflammatory response to enteropathogenic bacterial infection but not to acute aseptic inflammation. Understanding the mechanism of this role may lead to novel therapeutic approaches in some inflammatory diseases.

Anti-Infl ammatory Activity of TS-13, ARE-Inducing Phenol Antioxidant

The protective effect of water-soluble TS-13 monophenol inducing the antioxidant-responsive element (ARE) system was studied on the models of acute inflammation. Intragastric administration of TS-13 to rats significantly reduced the severity of acute aseptic inflammation induced by intravenous injection of zymosan particles: granulocyte blood count and volume density of infiltrates in the liver decreased on day 3, spontaneous production of activated oxygen metabolites and respiratory burst in blood granulocytes decreased on days 2 and 3. A single dose of TS-13 improved survival of mice with endotoxin shock induced by intraperitoneal injection of E. coli LPS. These results confirmed high anti-inflammatory activity of TS-13.