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- Transient receptor potential Ankyrin 1: structure, function and
ligands
Abstract: Research Results in Pharmacology 8(3): 19-29
DOI : 10.3897/rrpharmacology.8.90214
Authors : Natalia V. Pyatigorskaya, Olga V. Filippova, Natalia S. Nikolenko, Aleksey D. Kravchenko : Introduction: Transient receptor potential ankyrin 1 (TRPA1) is a protein expressed in many living organisms. During the study of TRPA1, its unique biological role as a universal and polymodal sensor of various altering agents was found. The aim of this study is to search and generalize information about structural features and molecular determinants, mechanisms of activation, action and modulation of TRPA1 as a universal pain and inflammation sensor, as well as the nature of activators and antagonists of this target and their therapeutic potential. Materials and methods: This article presents an overview of the results of scientific research of TRPA1, its modulators, as well as an overview of their pharmacological potential over the period from the discovery of these channels to the present, with an emphasis on the last decade. Results and discussion: The main collected data on expression, structural features and molecular determinants, mechanisms of activation and action of TRPA1 indicate its role as a universal and labile element of the primary response of the body to adverse exogenous and endogenous factors. Regardless of the nature of the stimulus, hyperstimulation of TRPA1 channels can lead to such phenomena as pain, inflammation, itching, edema and other manifestations of alteration, and therefore TRPA1 blockade can be used in the treatment of various diseases accompanied by these pathological conditions. Currently, TRPA1 antagonists are being actively searched for and studied, as evidenced by a high patent activity over the past 14 years; however, the molecular mechanisms of action and pharmacological properties of TRPA1 blockers remain understudied. Conclusion: Acquire of new information about TRPA1 will help in the development of its modulators, which can become promising analgesics, anti-inflammatory drugs, bronchodilators, and agents for the treatment of cardiovascular diseases of new generations. HTML XML PDF
PubDate: Wed, 20 Jul 2022 13:55:17 +030
- Clinical and histopathological effects of ointment prepared from
kombucha floating cellulose layer on wound healing and the activity of
matrix metalloproteinase 1 in diabetic rats
Abstract: Research Results in Pharmacology 8(3): 9-18
DOI : 10.3897/rrpharmacology.8.81288
Authors : Soheila Rajaei, Monir Doudi, Mahbubeh Setorki, Ali Mohammad Ahadi : Introduction: High blood glucose results in high levels of matrix metalloproteinases. Clinical and histopathological effects of the kombucha ointment on the healing of diabetic wounds were evaluated. Materials and methods: This study was conducted at research Lab, Department of Micobiology, Falavarjan of Branch Islamic Azad University, Isfahan, Iran from October 2019 to September 2020. A 6 mm diameter ulcer was aseptically created on the back of forty-eight rats with streptozotocin-induced diabetes. The animals were randomly divided into 4 groups: the group that was treated with base ointment, the group that was treated with 10% kombucha ointment, the group that was treated with 20% kombucha ointment, and the group that received no ointment treatment. Then the rats in each group were divided to 4 sampling groups that were sampled on the second, fifth, tenth, and fourteenth days. Microscopic features, inflammation and vasculature and fibroblast infiltration, as well as the matrix metalloproteinase 1(MMP1) were evaluated on days 2, 5, 10, 14 after wound healing. Results: 20% kombucha ointment let to inflammation and an angiogenesis decrease compared to those in the basic group and 10%-kombucha-ointment group. Also 20% kombucha ointment led to an increase in vascular remodeling and penetration of fibroblasts. MMP1 levels increased on the second (p < 0.001) and fifth days after wounding when treatrd with 10% and 20% kombucha ointment (p > 0.05). The expression of MMP1 decreased on the ten and fourteenth days when using 20% kombucha ointment compared to the control, placebo, and 10% kombucha ointment groups (p > 0.05). Discussion: The histopatological finding indicated that both quantity and time duration of the treatment had significant effects on a degree of inflammation and angiogenesis. Сonclusion: Ointment prepared from 20% scoby improved the healing of diabetic ulcers within 14 days. HTML XML PDF
PubDate: Tue, 12 Jul 2022 23:25:45 +030
- Study of the effect of acetylsalicylic acid and a selective arginase II
inhibitor KUD 975 on the correction of hemostatic disorders in
experimental preeclampsia
Abstract: Research Results in Pharmacology 8(3): 1-8
DOI : 10.3897/rrpharmacology.8.87539
Authors : Anastasia V. Gureeva, Olga V. Severinova, Vladimir V. Gureev, Indira S. Kochkarova, Elena V. Avdeyeva : Introduction: The disruption of the functional state of the vascular endothelium is among the main causes of preeclampsia, which is one of the most common causes of maternal and perinatal mortality. It can be enhanced by the humoral factors secreted by the activated platelets. The use of acetylsalicylic acid is an effective way to prevent preeclampsia. However, its ability to activate eNOS is a prerequisite for researching its ability to correct the disorders in developing preeclampsia, including by reducing the platelet activity. In this case its effect can be enhanced through increasing the bioavailability of L-arginine by using a selective arginase II inhibitor KUD 975. These facts were the prerequisite for conducting this study. Materials and methods: The study was conducted on 180 female Wistar rats weighing 250–300 g. Acetylsalicylic acid was used at a dose of 7 mg/kg/day and 10 mg/kg/day, KUD 975 – at a dose of 1 mg/kg/day and 3 mg/kg/day. Adenosine diphosphate (ADP, 6.5 microns), arachidonic acid (ASPI, 0.5 mM), and collagen (3.2 mcg/ml) were used as aggregation inducers. Results and discussion: ADMA-like preeclampsia simulation led to an increase in platelet aggregation ability when using all aggregation inducers. This is evidenced by an increase in a degree, rate of aggregation, and a shortened time of thrombus formation. The use of acetylsalicylic acid and a selective arginase II inhibitor KUD 975 led to a decrease in the aggregation ability of platelets and an increase in thrombosis time, while the combined administration of the studied agents showed a more pronounced effect. Conclusion: The data obtained while performing a series of experiments strongly indicate a promising outlook for using acetylsalicylic acid and a selective arginase II inhibitor KUD 975 in order to correct emerging disorders in preeclampsia. HTML XML PDF
PubDate: Tue, 12 Jul 2022 13:27:54 +030
- Involvement of monoaminergic system in the antidepressant effect of
3-substituted thietane-1,1-dioxide derivative
Abstract: Research Results in Pharmacology 8(2): 87-94
DOI : 10.3897/rrpharmacology.8.81007
Authors : Irina L. Nikitina, Gulnara G. Gaisina : Introduction: The aim of the study was to assess the involvement of the monoaminergic system in the antidepressant effect of a new 3-substituted thietane-1,1-dioxide derivative (N-199/1) using tests with several pharmacological antagonists and agonists. Materials and methods: We conducted 3 sets of experiments in white outbred male mice. In Experiment 1, we assessed the antidepressant effect of N-199/1 in the forced swimming test (FST) and tail suspension test (TST) when administered repeatedly for 2 weeks intraperitoneally (i.p.). In Experiment 2, we evaluated the antidepressant effect of N-199/1 in FST and TST when co-administered with 5HT1A- (WAY100635, 0.1 mg/kg), 5HT2A/2C- (ketanserin, 5 mg/kg), 5HT3- (ondansetron, 1 mg/kg) serotonergic and α2-adrenergic (yohimbine, 1 mg/kg) receptors antagonists. In Experiment 3, we assessed the effect of N-199/1 on the hypothermia induced by i.p. injection of α2-adrenergic receptors agonist clonidine (0.3 mg/kg). Results and discussion: N-199/1 reduced immobility time (IT) and index of depression (ID) in FST, and did not affect IT in TST, either when administered repeatedly in Experiment 1, or acutely in Experiment 2. In Experiment 2, ketanserin enhanced the effect of N-199/1, decreasing ID by 36%, while WAY100635 and yohimbine antagonized it, increasing ID by 27% and IT by 115%, respectively, in comparison with N-199/1. N-199/1 attenuated the effect of ondansetron, increasing IT by 36%. In Experiment, 3 N-199/1 reduced clonidine-induced hypothermia 1 h after the injection of clonidine. N-199/1 exhibited pronounced antidepressant properties in FST, an agonism to 5HT1A-receptors and an antagonism to 5HT2A/2C- and α2-receptors in tests of neuropharmacological interaction, which indicates an atypical mechanism of its antidepressant action. Conclusion: The antidepressant effect of N-199/1 is due to the stimulation of 5HT1A-receptors and blockade of 5HT2A/2C- and α2-receptors. Graphical abstract: HTML XML PDF
PubDate: Thu, 30 Jun 2022 23:34:07 +030
- Combined anti-mediator therapy for severe destructive forms of acute
necrotizing pancreatitis in rats
Abstract: Research Results in Pharmacology 8(2): 95-110
DOI : 10.3897/rrpharmacology.8.79939
Authors : Tatiana I. Firsova, Sergey A. Alekhin, Dmitry P. Nazarenko, Lyudmila M. Danilenko, Antonina G. Chub, Elena S. Malyutina, Tatyana Yu. Lazareva, Leontiy V. Druzhikin : Introduction: Inflammatory mediators play a major role in pathogenesis of acute pancreatitis with TNF (tumor necrosis factor) as the most important one. Development of effective combined therapy could help to decrease tissue damage, improve results and, finally, diminish the mortality rate in this severe pathology. Materials and methods: All the studies were performed on 120 female white Wistar rats, weighing 250±25g. Acute pancreatitis reproduced by an intracanalicular injection of bile salts compound. Results and discussion: The data obtained in the course of the study on the pronounced pancreatoprotective effect of infliximab are explained by its key role in the onset of the systemic inflammatory response, and, therefore, with the blockade of tumor necrosis factor alpha in the early stages, there is no pronounced secondary damage to the pancreas, which is reflected in a significant decrease in edema from 4.87±0.03 in the model up to 2.75±0.04, and as a consequence, an improvement in the blood supply of the acinar tissue from 182.38±15.92 PU up to 287.92±14.64 PU, which is expressed in a decrease in the zones of necrosis and in a decrease in mortality and, finally, efficiency coefficient from 13480.000 to 4283.348. A selective blocker of cysteinyl leukotrienes has a less pronounced protective reaction against damage to pancreatocytes, but to a much greater extent than octreotide. That is expressed by changes in the efficiency coefficient to the level of 8621.18 in montelukast group and 12767.30 in octreotide group, respectively. On the other hand, the effect of the use of infliximab does not surpass that of montelukast, and their combined use has a pronounced additive effect, which is proved by the efficiency coefficient at the level of 2390.33. This reaction is explained by the fact that TNF alpha-mediated pathway of activation of leukotriene biosynthesis is the main, but not the only one. Conclusion: The combined anti-mediator therapy provides a great opportunity to improve the standard therapy of acute pancreatitis. HTML XML PDF
PubDate: Thu, 30 Jun 2022 14:02:56 +030
- Current view on the problem of treating fibrocystic breast disease in
terms of herbal medicine
Abstract: Research Results in Pharmacology 8(2): 77-85
DOI : 10.3897/rrpharmacology.8.79286
Authors : Olena P. Sokolik, Galina O. Prozorova : Introduction: Fibrocystic breast disease, commonly called fibrocystic breasts or fibrocystic change, is a benign (noncancerous) condition, which is the most common pathology in women of reproductive age. Treatment of fibrocystic breast disease and concomitant pathologies can involve using herbs. Materials and Methods: To make an analysis of literary sources on the development of fibrocystic breast disease in the pathogenesis of diseases of the female reproductive system (clinical human (75%) and animal studies (25%)) were published in the period of 2017–2021. Results and discussion: The diversity of plants in the world is a promising ground for therapeutic improvisation, allowing for an individual approach to each patient, but, most importantly, creates possibilities for maneuvering in the event of ineffectiveness of any means. In some situations, herbal medicine is not only possible or permissible, but strictly mandatory, and is essentially the only effective therapeutic method, which is relatively safe provided the correct selection of combinations and control by a doctor who applies a certain method of phytotherapy, especially given a duration of treatment. The need for a deeper study is long overdue for the pharmacological capabilities of various plant raw materials in the treatment of not only this pathology, but others as well. Conclusion: The development of phytotherapy should be based primarily on scientific developments, but this area can not be considered the prerogative of only phytotherapists, as herbal medicines should be in the arsenal of doctors of all specialties. HTML XML PDF
PubDate: Wed, 22 Jun 2022 16:57:11 +030
- Searching for novel antagonists of adenosine A1 receptors among
azolo[1,5-a]pyrimidine nitro derivatives
Abstract: Research Results in Pharmacology 8(2): 69-75
DOI : 10.3897/rrpharmacology.8.77854
Authors : Dmitry S. Yakovlev, Pavel M. Vassiliev, Yana V. Agatsarskaya, Anastasia A. Brigadirova, Kira T. Sultanova, Maria O. Skripka, Alexander A. Spasov, Konstantin V. Savateev, Vladimir L. Rusinov, Dmitriy V. Maltsev : Introduction: Ligands of adenosine A1Rs are potential candidates for the development of drugs for the treatment of paroxysmal supraventricular tachycardia, angina pectoris, hypertriglyceridemia, type 2 diabetes mellitus, neuropathic pain, and heart failure. At the same time, there is a deficiency of drugs that can regulate the functions of A1 receptors. A number of A1-antagonists are at the various stages of clinical trials; other drugs are not very selective or are characterized by an insufficient breadth of their therapeutic action. Therefore, the search for new medicinal compounds for the prevention and treatment of A1-depended diseases among nitro derivatives of tetrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine is of scientific interest. Materials and methods: The search for active compounds was carried out by in silico and in vitro methods. At the first stage, a computer forecast of A1-antagonistic activity was carried out using the Microcosm BioS software. At the second stage, the prediction results were verified in vitro in a model of isolated mouse atria. Results and discussion: Based on the results of the prediction by the method of maximum similarity to standards, the most active compounds III, VIII, and XVII were selected. After testing the prediction results by the isolated atria method, the compound VIII was characterized by A1-blocking effect in vitro at a concentration of 10 μmol/L. Conclusion: The most promising compound with A1-blocking effect in vitro was identified; it is a derivative of tetrazolo[1,5-a]pyrimidine under the code of VIII. It is of interest for us for further in-depth study of its pharmacological properties. HTML XML PDF
PubDate: Wed, 15 Jun 2022 12:56:28 +030
- Neuroprotective effects of a 40% ethanol extract of the black
walnut bark (Juglans nigra L.)
Abstract: Research Results in Pharmacology 8(2): 59-68
DOI : 10.3897/rrpharmacology.8.77172
Authors : Dmitry I. Pozdnyakov, Zhanna V. Dayronas, Denis S. Zolotych, Anastasya D. Geraschenko, Natalya B. Shabanova : Introduction: Neuroprotection is a promising area of adjuvant therapy of ischemic brain lesions. At the same time, among potentially effective neuroprotectors, herbal remedies are distinguished due to their high efficiency and safety of use. In this work, some aspects of the neuroprotective effect of 40% ethanol extract of black walnut bark were investigated in comparison with its major component juglone. Materials and methods: The work was performed on male Wistar rats, which were simulated with cerebral ischemia by irreversible occlusion of the middle cerebral artery. The acute toxicity of the extract was preliminarily evaluated. During the work, the following parameters were determined: changes in the behavior of animals in the Morris water maze, cerebral blood flow, brain necrosis zone area, the activity of mitochondrial complexes, citrate synthase activity, lactic, pyruvic, and ATP concentrations. The activity of the studied extract was compared with juglone in a concentration of 1 mg/kg (per os). Discussion: The study showed that the use of black walnut bark extract in conditions of cerebral ischemia contributed to an increase in the activity of mitochondrial complexes I-V, citrate synthase, which in turn led to the normalization of aerobic-anaerobic metabolism reactions. The increase in the activity of respiratory complexes is probably mediated by the antioxidant properties of juglone, which is a major component of the test extract of black walnut bark. Conclusion: Thus, the test extract can be a potentially effective neuroprotective agent and requires further study. HTML XML PDF
PubDate: Tue, 14 Jun 2022 17:49:27 +030
- Antiproliferative activity of a new derivative from the class of
N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles
Abstract: Research Results in Pharmacology 8(2): 49-57
DOI : 10.3897/rrpharmacology.8.79424
Authors : Marina P. Kiseleva, Larisa M. Borisova, Galina B. Smirnova, Yulia A. Borisova, Anna V. Lantsova, Ekaterina V. Sanarova, Lyudmila L. Nikolaeva, Lydia V. Ektova, Marina V. Komarova : Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice. Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an intravenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%). Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 substance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C
PubDate: Tue, 14 Jun 2022 17:49:11 +030
- Evaluation of methods of modeling and formation of experimental
allergic encephalomyelitis
Abstract: Research Results in Pharmacology 8(2): 37-48
DOI : 10.3897/rrpharmacology.8.77361
Authors : Oleksandr O. Nefodov, Igor F. Belenichev, Mykola P. Fedchenko, Olena O. Popazova, Victor P. Ryzhenko, Oksana V. Morozova : Introduction: Experimental autoimmune (allergic) encephalomyelitis (EAE) induced by intradermal injection of homogenate of the brain, spinal cord and peripheral nerve with Freund’s stimulator, refers to a true autoimmune disease of the nervous system. Materials and methods: Experimental studies were conducted on white nonlinear rats. To induce experimental allergic encephalomyelitis (EAE), homologous brain homogenates was used, which leads among other drugs (homologous, heterogeneous brain and spinal cord homogenates) by encephalitogenity. The connective tissue of the animal’s tail base was injected with a mixture of encephalitogenic suspension of 0.1 ml per 100 g of the body weight. Results and discussion: According to the results, in the rats, there was weight loss, and the abnormal neurological symptoms were found on an average of 10–12th days. Our experimental studies on the formation of EAE were confirmed morphologically by electron microscopy. Conclusion: Thus, the use of this technique allowed us to obtain a simulated pathologic condition of multiple sclerosis in the form of experimental allergic encephalomyelitis and can be used in future studies to identify appropriate laws, the extent and nature of changes in the immune and nervous systems of the body when inducing experimental pathological conditions. HTML XML PDF
PubDate: Tue, 14 Jun 2022 17:48:59 +030
- Remote ischemic preconditioning combined with atorvastatin improves
memory after global cerebral ischemia-reperfusion in male rats
Abstract: Research Results in Pharmacology 8(2): 27-35
DOI : 10.3897/rrpharmacology.8.75753
Authors : Azim Hedayatpour, Maryam Shiasi, Peyman Modarresi, Alieh Bashghareh : Introduction: Damage to hippocampus can occur through ischemia. Memory problems are among the most significant disabilities after stroke. Therefore, improving memory is of great interest in helping post-stroke patients. This study demonstrated that intraperitoneally injection of atorvastatin with a short cycle of ischemia-reperfusion in the left femoral artery improved hippocampal CA1 neurons injury and memory problems after global cerebral ischemia. Materials and methods: In this article survey, we used 64 animals. Rats were divided into 8 groups, (n=8). Group 1: control; group 2: sham; group 3: global cerebral ischemia (GCI) only; group 4: remote ischemic preconditioning (RIP) + GCI; group 5: GCI + atorvastatin (ATO); group 6: GCI + vehicle; group 7: RIP + GCI + ATO; group 8: RIP + GCI + vehicle. We created global cerebral ischemia (GCI) with 20 min occlusion of the Common carotid artery. Results and discussion: Remote ischemic preconditioning could improve rats performance in water maze tests along with a decrease in neuronal death. Also, atorvastatin combined with remote ischemic preconditioning was more effective for memory improvement and reduction of neuronal death. Inconsistent with our result, the function of the animals in the ischemia group was impaired. CA1 hippocampal neurons have an important role in memory and learning, and they can be damaged after cerebral ischemia. Therefore, ischemia can create memory problems. Remote ischemic preconditioning and atorvastatin had a neuroprotective effect and could improve rat performance in water maze test. Conclusion: This study showed that remote ischemic preconditioning with atorvastatin could improve CA1 neuronal injury and memory. Graphical abstract: HTML XML PDF
PubDate: Tue, 14 Jun 2022 17:48:27 +030
- Genetically modified animal models of hereditary diseases for testing
of gene-directed therapy
Abstract: Research Results in Pharmacology 8(2): 11-26
DOI : 10.3897/rrpharmacology.8.82618
Authors : Anna V. Polikarpova, Tatiana V. Egorova, Maryana V. Bardina : Disease-causing genes have been identified for many severe muscular and neurological genetic disorders. Advances in the gene therapy field offer promising solutions for drug development to treat these life-threatening conditions. Depending on how the mutation affects the function of the gene product, different gene therapy approaches may be beneficial. Gene replacement therapy is appropriate for diseases caused by mutations that result in the deficiency of the functional protein. Gene suppression strategy is suggested for disorders caused by the toxic product of the mutant gene. Splicing modulators, genome editing, and base editing techniques can be applied to disorders with different types of underlying mutations. Testing potential drugs in animal models of human diseases is an indispensable step of development. Given the specific gene therapy approach, appropriate animal models can be generated using a variety of technologies ranging from transgenesis to precise genome editing. In this review, we discuss technologies used to generate small and large animal models of the most common muscular and neurological genetic disorders. We specifically focus on animal models that were used to test gene therapies based on adeno-associated vectors and antisense nucleotides. HTML XML PDF
PubDate: Tue, 14 Jun 2022 17:48:15 +030
- Atherosclerosis is a side effect of cellular senescence
Abstract: Research Results in Pharmacology 8(2): 1-9
DOI : 10.3897/rrpharmacology.8.81358
Authors : Elena I. Leonova, Angelina V. Chirinskaite, Julia V. Sopova : Atherosclerosis is a systemic autoimmune disease of the arterial wall characterized by chronic inflammation, high blood pressure, oxidative stress, and progressive loss of cell and organ function with aging. An imbalance of macrophage polarization is associated with many aging diseases, including atherosclerosis. The polarization toward the pro-inflammatory M1 macrophage is a major promoter of the atheroma formation. It is known that efferocytosis, or ingestion of apoptotic cells, is stimulated by M2 macrophage polarization. A failure of efferocytosis leads to the prolongation of chronic pathology in tissue. In addition, fat-laden macrophages contribute to the plague progression by transforming into foam cells in response to excess lipid deposition in arteries. In spite of the generally accepted theory that macrophages capture oxidized low-density lipoprotein by phagocytosis and become foam cells, we postulate that the main source of lipid accumulation in foam cells are senescent erythrocytes. Senescent erythrocytes lose their plasticity, which affects the rheological blood properties. It is known that their membrane contains high levels of cholesterol. There is evidence that senescent erythrocytes play a pathogenic role in the atheroma formation after breaking down during flowing through an artery bifurcation. Here we review the current knowledge on the impact of age-associated immune cells and red blood cells modifications on atherogenesis. Graphical abstract: HTML XML PDF
PubDate: Fri, 10 Jun 2022 10:54:01 +030
- Validation of structural-based virtual screening protocols with the PDB
Code 3G0B and prediction of the activity of Tinospora crispa compounds as
inhibitors of dipeptidyl-peptidase-IV
Abstract: Research Results in Pharmacology 8(1): 95-102
DOI : 10.3897/rrpharmacology.8.76237
Authors : Andri Prasetiyo, Shirly Kumala, Esti Mumpuni, Raymond R. Tjandrawinata : Introduction: Brotowali (Tinospora crispa) has been traditionally used as an antidiabetic drug. DPP-IV inhibitor as an antidiabetic will increase insulin secretion. It indirectly escalates incretin hormones, such as Glucagon-Like peptide-1 (GLP-1) which depends on glucose. This study predicts potential compounds from the Brotowali plants, such as DPP-IV inhibitors, using the Molegro Virtual Docker (MVD). Materials and methods: Before the molecular docking simulation, internal validation and external validation are necessary. Internal validation was carried out by re-docking the native ligands in the DPP-IV enzyme crystal structure (PDB codes 3G0B, 3W2T, and 3BJM). The external validation was carried out by simultaneous docking of 59 active compounds and 1918 inactive compounds (decoys) from the A Directory of Useful Decoys (DUD) database with PDB code 3G0B on 16 combinations, four search algorithms, and four functions scoring. Results and discussion: The molecular docking simulation was carried out on 50 compounds from the Brotowali plant and alogliptin as standard compounds with PDB code 3G0B. The best results of the docking method validation yielded the RMSD values of 0.43 and EF1% of 20.34 and EF20% of 3.1 (the combination of search algorithm Moldock optimizer and scoring function Moldock score). The re-rank score of 5 compounds from the Brotowali plant (Rumphioside C, Borapetoside E, Borapetoside F, Rumphioside I, and 6’-O-Lactoyl Borapetoside B) were -107.7 kcal/mol; -105.4 kcal/mol; -104.2 kcal/mol, and -102.8 kcal/mol. Alogliptin (standard ligands) had a re-rank score of -101.6 kcal/mol. The combination of search algorithms MolDock optimizer and scoring function MolDock score is a valid protocol with a good result. The similarity of the binding sites of Borapetoside E and 6’-O-Lactoyl Borapetoside B is 75% when compared to the alogliptin binding sites (Glu 205, Glu 206, Tyr 547). Conclusion: Based on the re-rank score and binding sites similarity, Borapetoside E and 6’-O-Lactoyl Borapetoside B have potential as an antidiabetic drug with a mechanism of action of DPP-IV inhibitors. HTML XML PDF
PubDate: Thu, 31 Mar 2022 18:06:06 +030
- Evaluation of the pharmacological activity of hybrid organotin
compounds in a B16 melanoma model in the classical and metronomic
administration modes
Abstract: Research Results in Pharmacology 8(1): 85-93
DOI : 10.3897/rrpharmacology.8.76363
Authors : Margarita A. Dodokhova, Andrey V. Safronenko, Inga M. Kotieva, Margarita S. Alkhuseyn-Kulyaginova, Dmitry B. Shpakovsky, Elena R. Milaeva : Introduction: In modern medical chemistry, much attention is paid to the search for new antimetastatic agents based on metal compounds. Organotin compounds promise to be good candidates as the treatment of malignant neoplasms. In order to reduce a possible nonspecific toxic effect of tin compounds and to expand the intended therapeutic use, the paper presents hybrid tin (IV) complexes with Sn-S bond containing a fragment of 2,6-di-tert-butylphenol. The aim of the study was to evaluate the antitumor and antimetastatic effects of bis (3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethylolol (Me3) and (3,5-di-tert-butyl-4-hydroxyphenylthiolate) triphenylolol (Me5) in a model of transplanted melanoma tumor in B16 mice in classical and metronomic administration mode. Materials and methods: The efficacy of organotin compounds was studied in a model of a transplanted tumor with spontaneous metastasis of C57Bl/6 (female) melanoma B16 mice using the following indicators: average life expectancy, inhibition of tumor growth by weight, tumor mass, and metastasis inhibition index. Results and discussion: The most pronounced antimetastatic effect (54% and 36%) is achieved with a five-fold intraperitoneal injection of Me3 and Me5 at the total doses of 375 mg/kg and 250 mg/kg. The comparable results of the efficacy were obtained in the classical and metronomic modes of the injection of hybrid organotin compounds. With an increase in the injected dose, there is an effect of activating the tumor process with the generalized metastasis. Conclusion: Bis dimethylolol (Me3) and triphenylolol (Me5) compounds demonstrate both a pronounced antimetastatic activity and a multidirectional effect on the growth of the primary focus and the metastasis in lungs, depending on an injected dose. HTML XML PDF
PubDate: Thu, 31 Mar 2022 18:05:51 +030
- Experimental study of new derivatives of 3-hydroxypyridine as
pharmacological agents for the correction of ischemic brain injury after
intracerebral hemorrhage
Abstract: Research Results in Pharmacology 8(1): 71-83
DOI : 10.3897/rrpharmacology.8.80378
Authors : Olesya V. Shcheblykina, Dmitry V. Shcheblykin, Konstantin S. Trunov, Anton P. Danilenko, Vladimir S. Lipatov : Introduction: Limiting the action of secondary injury factors can improve the prognosis in acute cerebral accidents. The aim of the investigation is to study the neuroprotective effects of 3-hydroxypyridine derivatives. Materials and methods: The study was performed in Wistar rats. An intracerebral hemorrhage (ICH) model was used. The animals were once administered intraperitoneally with the test drugs 1 hour before the surgery and on the 1st, 2nd and 3rd days. The registration of behaviors and condition of the animals on days 1, 3, 7 and 14 and the morphological examination of the brain were performed. Results and discussion: The use of the substances LKhT 4-97 and LKhT 11-02 in the treatment of experimental ICH had a positive effect on the survival rate of the animals and on the resolution rate of pathological signs (p
PubDate: Thu, 31 Mar 2022 18:05:36 +030
- The effectiveness of Soderm® – forte gel and a new injectable dosage
form of Rexod® in the complex treatment of experimental periodontitis in
rats
Abstract: Research Results in Pharmacology 8(1): 51-58
DOI : 10.3897/rrpharmacology.8.79641
Authors : Pavel A. Galenko-Yaroshevsky, Kristina V. Tseluiko, Valeriy K. Leontev, Mark A. Zadorozhniy, Viktor L. Popkov, Anait V. Zelenskaya, Sergey A. Babichev, Andrey V. Zadorozhniy, Sonya V. Meladze : Introduction: Insufficient effectiveness of traditional drug therapy in a treatment of patients with chronic generalized periodontitis, as well as high social significance of this problem, determines the need to search for new drugs and their compositions aimed at solving it. Aim of the study: To increase the efficacy of complex treatment of periodontitis with the administration of Soderm®-Forte gel and a new injectable form of Rexod®. Materials and methods: Experiments were performed in 50 male Wistar rats. Experimental periodontitis (EP) was simulated by ligation of the necks of lower incisors. We studied the animals with intact periodontium, untreated EP, and when traditional drug therapy (TDT), as well as the combinations of TDT with Soderm®-Forte gel and additionally with the new injectable dosage form (NIF) of Rexod® were administered. The general condition, behavior, nutrition and body weight of the animals were evaluated. The Schiller-Pisarev test and the Muhlemann-Cowell bleeding index were used, and the amount of crevicular fluid (CF) was measured. The contamination of the marginal gum with microorganisms was determined. Results and discussion: The TDT in EP has a moderate therapeutic effect, which does not lead to a sufficiently high pharmacotherapeutic effect, whereas the combinations of TDT with Soderm®-Forte and, to a greater extent, TDT with Soderm®-Forte and NIF of Rexod® have high therapeutic efficacy, which is statistically confirmed by a sharp decrease in the amount of CF, the Schiller-Pisarev test and the Muhlemann-Cowell bleeding index, as well as absolute suppression of pathogenic microorganisms. Conclusion: The combinations of TDT with Soderm®-Forte gel and NIF of Rexod® in EP in rats can significantly increase the effectiveness of the treatment. The data obtained indicate the expediency of the administration of Soderm®-Forte gel, as well as its combination with NIF of Rexod® in dental practice in the complex therapy of patients with periodontitis. HTML XML PDF
PubDate: Thu, 31 Mar 2022 18:05:23 +030
- Nortriptyline overcomes corticosteroid resistance in NK and NKT-like
cells from peripheral blood of patients with chronic obstructive pulmonary
disease
Abstract: Research Results in Pharmacology 8(1): 59-70
DOI : 10.3897/rrpharmacology.8.75467
Authors : Aliaksei G. Kadushkin, Anatoli D. Tahanovich, Lyudmila V. Movchan, Volha V. Dziadzichkina, Olga V. Levandovskaya, Tatsiana V. Shman : Introduction: An antidepressant nortriptyline potentiates glucocorticoid (GC) action with synergistic suppression of inflammatory mediator release, but the precise molecular mechanism is unknown. Materials and methods: Peripheral blood cells from patients with chronic obstructive pulmonary disease (COPD) (n = 21) were incubated with nortriptyline (1 µM or 10 µM), budesonide (10 nM), or their combinations, followed by stimulation with phorbol myristate acetate (PMA) and ionomycin. Cytokine production, glucocorticoid receptor β (GRβ), histone deacetylase 2 (HDAC2) and histone H4 acetylation of K8 (HAT) expression, p65 NF-kB and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation in NK (CD3-CD56+) and NKT-like (CD3+CD56+) cells were analyzed by flow cytometry. Results: We observed that nortriptyline (10 µM) significantly attenuated the effects of PMA/ionomycin on the synthesis of interferon γ (IFNγ), interleukin 4 (IL-4), and IL-8, expression of GRβ and HAT, as well as p65 NF-kB and p38 MAPK phosphorylation in NK and NKT-like cells, whereas nortriptyline (1 µM) only inhibited IL-4 production by NK and NKT-like cells. Discussion: The combination of nortriptyline (10 µM) and budesonide decreased IFNγ, tumor necrosis factor α, IL-4, IL-8, and GRβ expression, as well as phosphorylated p38 MAPK and p65 NF-κB levels by NK and NKT-like cells above that of budesonide alone. Furthermore, the same association of drugs enhanced HDAC2 expression in NK and NKT-like cells. Conclusion: Collectively, our results show that nortriptyline might enhance GC function through modulation of HAT, HDAC2, GRβ, phospho-p38 MAPK expression. These data provide a strong rationale for combining nortriptyline with budesonide to treat COPD. HTML XML PDF
PubDate: Thu, 31 Mar 2022 18:05:09 +030
- Cytotoxic activities of ethanolic crude extracts from fruiting bodies
of bamboo mushrooms (Dictyophora spp.) against cholangiocarcinoma cells
Abstract: Research Results in Pharmacology 8(1): 33-41
DOI : 10.3897/rrpharmacology.8.72098
Authors : Pathanin Chantree, Sirilak Chumkiew, Mantana Jamklang, Pongsakorn Martviset : Introduction: Cholangiocarcinoma (CCA) is a highly progressive tumor. The standard chemotherapy varies in its effectiveness, with generally low efficacy. So, the discovery of novel chemotherapy is still required. The objective of this preliminary study was to determine the cytotoxic effects induced by three kinds of bamboo mushrooms (Dictyophora indusiata or Chinese bamboo mushroom; Ch-DTP, Short skirt bamboo mushroom (Thai isolate); Th-DTP, and orange skirt bamboo mushroom; Or-DTP) on CCA cells. Materials and methods: CCA cell lines, including CL-6, HuCCT1, HuH28, and OUMS normal fibroblast cells, were treated with various concentrations of DTP extracts. The MTT assay was used to determine cytotoxicity, and cell morphology was observed by using phase-contrast microscopy. Results and discussion: The results suggested that Ch-DTP effectively killed all three CCA cell lines in both low (0.3 mg/mL) and high (0.6 mg/mL) doses, but Th-DTP and Or-DTP had significantly reduced cell viability only at high doses (p
PubDate: Wed, 16 Mar 2022 23:53:21 +020
- Study of dose-dependent actoprotective effect of ATACL on physical
Abstract: Research Results in Pharmacology 8(1): 13-22
DOI : 10.3897/rrpharmacology.8.75981
Authors : Anastasia D. Gerashchenko, Dmitry I. Pozdnyakov, Andrey V. Voronkov : Introduction: The aim of the study was to investigate the dose-dependent actoprotective effect of ATACL on physical performance and psychoemotional status of animals under conditions of exhausting exercise. Materials and methods: Outbred male mice (23–25 g) were used in the experiment. The test compound in various dosages, as well as the reference drug, were administered intragastrically 60 minutes before the forced swimming test for 10 days of the experiment. At the end of the physical activity, the psychoemotional status of the animals was assessed in the Open Field (OF) and Elevated plus maze (EPM) tests. Results and discussion: In the course of the experiment, it was found that under conditions of exhausting physical execise, a smooth increase in performance was observed in the group that had received the test compound 4-hydroxy-3,5-di-tert butyl cinnamic acid (ATACL) at a dosage of 100 mg/kg for 10 days. The peak of performance was recorded on the 8th day, which was 47.3% (p
PubDate: Wed, 16 Mar 2022 16:29:45 +020
- Development of novel effective agents from 1H-indolylammonium
trifluoroacetates effective against conditionally pathogenic
microorganisms
Abstract: Research Results in Pharmacology 8(1): 43-50
DOI : 10.3897/rrpharmacology.8.73329
Authors : Irina S. Stepanenko, Semen A. Yamashkin, Tatyana N. Platkova, Anastasia I. Kiryutina, Ilya N. Sorokvasha : Introduction: The problem of antibiotic resistance of microorganisms is becoming more urgent in the twenty-first century. More and more pathogenic microbes are becoming resistant to two or more antibiotics. This problem has become worse into the COVID-19 pandemic. The search for new compounds with antimicrobial activity is one of the principles for overcoming the antibiotic resistance of microorganisms. Materials and methods: Methods for the preparation, isolation, and identification of salts of 2,3,5-trimethyl-, 1,2,3,5-tetramethyl-, 2,3-dimethyl-5-methoxy-, 5-methoxy-1,2,3-trimethyl-1H-indole-6-amines and trifluoroacetic acid were developed and laboratory microbiological studies of them for antimicrobial activity were carried out. Sensitivity of the test-strains of microorganisms to the new compounds was studied. A method of serial dilutions to determine the minimal inhibitory concentration (MIC) of the compounds under study was used in the study. Results and discussion: The compounds 5–8 showed a pronounced antibacterial activity against the test strains of microorganisms in vitro with MIC from 0.98 µg/mL to 125.0 µg/mL. The prospects for targeted synthesis of biologically active compounds which are derivatives of 1H-indolylamines with a trifluoromethyl group in the molecule were determined, and after additional studies, the compounds 5–8 may find application as water-soluble synthetic antimicrobial agents. Conclusion: The laboratory microbiological screening of showed that they have an antimicrobial effect that exceeds the activity of the reference drug, dioxidine. The presence of molecular mechanisms predicted in silico in the spectrum of biological activity of the studied compounds, such as Pseudolysin inhibitor, Omptin inhibitor, Undecaprenyldiphospho-muramoylpentapeptide beta-N-acetylglucosaminyltransferase inhibitor, UDP-epimerase inhibitor, Bacterial efflux pump inhibitor, suggests the presence of antimicrobial activity against gram-positive and gram-negative microorganisms. Trifluoroacetates 2,3,5-trimethyl-1H-indole-6-ammonium (5), 1,2,3,5-tetramethyl-1H-indole-6-ammonium (6), 2,3-dimethyl-5-methoxy-1H-indole-6-ammonium (7), 1,2,3-trimethyl-5-methoxy-1H-indole-6-ammonium (8), after additional studies, may find application as water-soluble synthetic antimicrobial agents. HTML XML PDF
PubDate: Wed, 16 Mar 2022 11:45:06 +020
- Study of pharmacokinetic of new peptide drug
1-deamino-arginine-vasotocin for hypernatremia correction
Abstract: Research Results in Pharmacology 8(1): 23-31
DOI : 10.3897/rrpharmacology.8.71802
Authors : Vera M. Kosman, Natalya M. Faustova, Marina V. Karlina, Valery G. Makarov, Marina N. Makarova : Introduction: The pharmacokinetics studies are some of the necessary parts of the drugs preclinical investigations. Pharmacokinetic properties of new peptide drug 1-deamino-arginine-vasotocin (dAVT) in the form of an injection solution for intravenous and intramuscular administration for hypernatremia correction were investigated. Materials and methods: The study was carried out on male rats and rabbits with a single intravenous administration of the drug in three doses, a single intramuscular administration in one dose and multiple administration to rats in one dose. To determine natriiuretic peptide concentration in blood plasma, tissues, and excretes, assays based on a sodium level change measurement using a biochemical analyzer have been developed and validated. Pharmacokinetic parameters were calculated by the model-independent method of statistical moments. Results and discussion: The pharmacokinetics of the drug was found to be linear after a single administration of dAVT drug in the dose range 3–10 μg/kg for rats and rabbits. The relative bioavailability of dAVT after intramuscular and intravenous administrations was more than 30%. After a biomarker content change, the active substance was intensively distributed into highly vascularized organs (spleen), the organs that provide metabolism and subsequent excretion (liver and kidneys), whereas it hardly reached moderately and weakly vascularized tissues (muscles, omentum). Less than 10% dAVT was excreted with urine; no dAVT was determined in feces; and repeated administration did not lead to its cumulation. Conclusion: Pharmacokinetics parameters of new nonapeptide drug 1-deamino-arginine-vasotocin were evaluated after original analytical biomarker approach. The study included all main areas necessary to characterize the original drug pharmacokinetic. HTML XML PDF
PubDate: Wed, 16 Mar 2022 11:09:04 +020
- Synthesis, molecular docking, ADMET study and in vitro pharmacological
research of
7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione
as a promising non-opioid analgesic drug
Abstract: Research Results in Pharmacology 8(1): 1-11
DOI : 10.3897/rrpharmacology.8.80504
Authors : Aleksey D. Kravchenko, Natalia V. Pyatigorskaya, Galina E. Brkich, Larysa V. Yevsieieva, Alexander V. Kyrychenko, Sergiy M. Kovalenko : Introduction: The discovery of novel drugs that can block the transmission of pain signals for treating the pain of various etiologies is an urgent topic in pharmaceutics. The aim of this paper is to synthesize and to investigate in vitro and in silico characteristics of a promising novel compound: 7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione (HSV-DKH-0450). Materials and methods: The specific activity and the inhibitory mechanism of HSV-DKH-0450 were studied using the HEK293 culture cells expressing the IPTG-induced TRPA1 ion channels. Cardiotoxicity was determined by estimating the binding of HSV-DKH-0450 to the hERG channel. Inhibition of human liver cytochromes was determined by the effect on the activity of cytochromes 1A2, 2C9, 2D6, 2C8, and 3A4. Cellular toxicity was assessed by the effect on the viability of human hepatocytes. ADMET properties were evaluated using admetSAR and SwissADME web-based tools. Molecular docking was carried out using AutoDock Vina tools to predict the binding affinity of all HSV-DKH-0450 stereoisomers toward the TRPA1 and TRPV1 receptors. Results and discussion: In silico predictions of ADMET properties of HSV-DKH-0450 showed that it has optimal pharmaceutical profiles. A series of in vitro pharmacological studies revealed that HSV-DKH-0450 is a promising antagonist of the TRPA1 ion channel with the IC50 of 91.3 nM. The molecular docking of HSV-DKH-0450 stereoisomers against the TRPA1 and TRPV1 receptors demonstrates that they all are characterized by an approximately similar high binding affinity. Conclusion: The obtained data for substance HSV-DKH-0450 look promising for its further development as a potential therapeutic agent for pain relief. Graphical abstract: HTML XML PDF
PubDate: Wed, 16 Feb 2022 11:36:20 +020
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