Pub Date : 2022-06-10DOI: 10.3897/rrpharmacology.8.81358
E. Leonova, A. V. Chirinskaite, J. 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:
{"title":"Atherosclerosis is a side effect of cellular senescence","authors":"E. Leonova, A. V. Chirinskaite, J. Sopova","doi":"10.3897/rrpharmacology.8.81358","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.81358","url":null,"abstract":"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.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46133830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-31DOI: 10.3897/rrpharmacology.8.79641
P. Galenko-Yaroshevsky, K. V. Tseluiko, V. K. Leontev, Mark A. Zadorozhniy, V. Popkov, A. 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.
{"title":"The effectiveness of Soderm® – forte gel and a new injectable dosage form of Rexod® in the complex treatment of experimental periodontitis in rats","authors":"P. Galenko-Yaroshevsky, K. V. Tseluiko, V. K. Leontev, Mark A. Zadorozhniy, V. Popkov, A. Zelenskaya, Sergey A. Babichev, Andrey V. Zadorozhniy, Sonya V. Meladze","doi":"10.3897/rrpharmacology.8.79641","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.79641","url":null,"abstract":"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.\u0000 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®.\u0000 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.\u0000 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.\u0000 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.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47704944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-31DOI: 10.3897/rrpharmacology.8.80378
Olesya V. Shcheblykina, Dmitry V. Shcheblykin, K. S. Trunov, A. P. Danilenko, V. 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<0.05). Clinical observations were confirmed by the results of analysis of the S100b brain damage marker and morphometry. The efficacy of LKhT 3-15 was largely comparable to that of the reference drug Mexidol. The efficacy of LKhT 01-09 was significantly inferior to that of the reference drug Mexidol. Differences in the neuroprotective effects of the studied substances are related to the metabolism of their various pharmacophores. A hypothetical mechanism for the induction of their neuroprotective effects has been proposed. Conclusion: Three of the four 3-hydroxypyridine derivatives under study have a neuroprotective effect, which is manifested in a more rapid resolution of pathological symptoms and less pronounced signs of neurodegeneration.
{"title":"Experimental study of new derivatives of 3-hydroxypyridine as pharmacological agents for the correction of ischemic brain injury after intracerebral hemorrhage","authors":"Olesya V. Shcheblykina, Dmitry V. Shcheblykin, K. S. Trunov, A. P. Danilenko, V. S. Lipatov","doi":"10.3897/rrpharmacology.8.80378","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.80378","url":null,"abstract":"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.\u0000 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.\u0000 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<0.05). Clinical observations were confirmed by the results of analysis of the S100b brain damage marker and morphometry. The efficacy of LKhT 3-15 was largely comparable to that of the reference drug Mexidol. The efficacy of LKhT 01-09 was significantly inferior to that of the reference drug Mexidol. Differences in the neuroprotective effects of the studied substances are related to the metabolism of their various pharmacophores. A hypothetical mechanism for the induction of their neuroprotective effects has been proposed.\u0000 Conclusion: Three of the four 3-hydroxypyridine derivatives under study have a neuroprotective effect, which is manifested in a more rapid resolution of pathological symptoms and less pronounced signs of neurodegeneration.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42001551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-31DOI: 10.3897/rrpharmacology.8.75467
A. Kadushkin, A. Tahanovich, L. Movchan, V. Dziadzichkina, O. Levandovskaya, T. 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.
{"title":"Nortriptyline overcomes corticosteroid resistance in NK and NKT-like cells from peripheral blood of patients with chronic obstructive pulmonary disease","authors":"A. Kadushkin, A. Tahanovich, L. Movchan, V. Dziadzichkina, O. Levandovskaya, T. Shman","doi":"10.3897/rrpharmacology.8.75467","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.75467","url":null,"abstract":"Introduction: An antidepressant nortriptyline potentiates glucocorticoid (GC) action with synergistic suppression of inflammatory mediator release, but the precise molecular mechanism is unknown.\u0000 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.\u0000 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.\u0000 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.\u0000 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.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49528439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-31DOI: 10.3897/rrpharmacology.8.76237
Andri Prasetiyo, S. Kumala, E. Mumpuni, R. 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.
传统上，Brotowali (Tinospora crispa)一直被用作抗糖尿病药物。DPP-IV抑制剂作为抗糖尿病药物会增加胰岛素分泌。它间接增加了肠促胰岛素激素，如胰高血糖素样肽-1 (GLP-1)，它依赖于葡萄糖。本研究利用Molegro虚拟Docker (MVD)预测了Brotowali植物中潜在的化合物，如DPP-IV抑制剂。材料和方法:在分子对接模拟之前，需要进行内部验证和外部验证。通过在DPP-IV酶晶体结构(PDB代码3G0B、3W2T和3BJM)中重新对接天然配体进行内部验证。外部验证是通过同时对接A Directory of Useful decoys (DUD)数据库(PDB代码为3G0B)中的59种有效化合物和1918种非活性化合物(诱饵)，对16种组合、4种搜索算法和4种功能评分进行验证。结果与讨论:以Brotowali植物中50个化合物与PDB代码为3G0B的阿格列汀为标准化合物进行分子对接模拟。对接方法验证的最佳结果RMSD值为0.43,EF1%值为20.34,EF20%值为3.1(搜索算法Moldock优化器与评分函数Moldock评分相结合)。其中5个化合物(凤仙花苷C、凤仙花苷E、凤仙花苷F、凤仙花苷I和6′- o -乳基凤仙花苷B)的重排序得分为-107.7 kcal/mol;-105.4千卡/摩尔;-104.2千卡/mol和-102.8千卡/mol。阿格列汀(标准配体)的重秩评分为-101.6 kcal/mol。将搜索算法MolDock优化器与评分函数MolDock评分相结合是一种有效的协议，效果良好。与阿格列汀结合位点(Glu 205, Glu 206, Tyr 547)相比，Borapetoside E和6′- o -乳基Borapetoside B的结合位点相似性为75%。结论:基于重排序评分和结合位点的相似性，6′- o -乳酰基Borapetoside E和6′- o -乳酰基Borapetoside B具有作为DPP-IV抑制剂作用机制的潜在降糖药物的潜力。
{"title":"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","authors":"Andri Prasetiyo, S. Kumala, E. Mumpuni, R. R. Tjandrawinata","doi":"10.3897/rrpharmacology.8.76237","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.76237","url":null,"abstract":"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).\u0000 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.\u0000 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).\u0000 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.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47894325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-16DOI: 10.3897/rrpharmacology.8.71802
V. Kosman, N. M. Faustova, M. V. Karlina, V. Makarov, M. 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.
{"title":"Study of pharmacokinetic of new peptide drug 1-deamino-arginine-vasotocin for hypernatremia correction","authors":"V. Kosman, N. M. Faustova, M. V. Karlina, V. Makarov, M. Makarova","doi":"10.3897/rrpharmacology.8.71802","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.71802","url":null,"abstract":"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.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45280003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-16DOI: 10.3897/rrpharmacology.8.75981
A. Gerashchenko, D. Pozdnyakov, A. 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<0.05) higher than the physical activity of the mice treated with the reference drug ethylthiobenzimidazole hydrobromide (EBH). When assessing changes in the Open Field test, it was found that the test compound ATACL at a dosage of 100 mg/kg is also a leader in stabilizing the psychoemotional status of the animals, which is reflected in the improvement of the motor activity (the number of sectors crossed by 4.7 times (p< 0.05)), exploratory activity (an increase in the number of «peeps» and rearings by 8.5 times (p<0.05) and 12.7 times (p<0.05), respectively) and changes in the level of anxiety (a 2.5-time decrease in the number of short-term grooming acts (p<0.05)) in comparison with the negative control (NC) group. The results obtained in the EPM test are completely consistent with the results of the OF test; the most pronounced activity was observed for the ATACL compound at a dosage of 100 mg/kg. Conclusion: Based on the combination of reproducible methods, it can be concluded that the most pronounced actоprotective effect is exerted by the compound at a dosage of 100 mg/kg, not inferior, at the same time, to the reference drug EBН. Graphical abstract:
{"title":"Study of dose-dependent actoprotective effect of ATACL on physical performancend psychoemotional status of animals under exhausting exercise","authors":"A. Gerashchenko, D. Pozdnyakov, A. Voronkov","doi":"10.3897/rrpharmacology.8.75981","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.75981","url":null,"abstract":"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.\u0000 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.\u0000 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<0.05) higher than the physical activity of the mice treated with the reference drug ethylthiobenzimidazole hydrobromide (EBH). When assessing changes in the Open Field test, it was found that the test compound ATACL at a dosage of 100 mg/kg is also a leader in stabilizing the psychoemotional status of the animals, which is reflected in the improvement of the motor activity (the number of sectors crossed by 4.7 times (p< 0.05)), exploratory activity (an increase in the number of «peeps» and rearings by 8.5 times (p<0.05) and 12.7 times (p<0.05), respectively) and changes in the level of anxiety (a 2.5-time decrease in the number of short-term grooming acts (p<0.05)) in comparison with the negative control (NC) group. The results obtained in the EPM test are completely consistent with the results of the OF test; the most pronounced activity was observed for the ATACL compound at a dosage of 100 mg/kg.\u0000 Conclusion: Based on the combination of reproducible methods, it can be concluded that the most pronounced actоprotective effect is exerted by the compound at a dosage of 100 mg/kg, not inferior, at the same time, to the reference drug EBН.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46558511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-16DOI: 10.3897/rrpharmacology.8.72098
Pathanin Chantree, S. 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<0.001). Ch-DTP had the best effect by showing a response of more than 50% at a concentration of 0.3 mg/mL. Th-DTP had moderate effects at a concentration of lower than 0.6 mg/mL but worthwhile at higher concentrations, whereas Or-DTP had limited effects at concentrations of 0.4 mg/mL and downward, although the effects were significantly increased in the higher concentration range. Morphology of the Ch-DTP treated cells was greatly transformed both at low and high doses, but Th-DTP and Or-DTP showed definite alteration only at high doses. The morphological changes revealed apoptotic induction. In OUMS cells, no effects were recognized with any of the three DTPs. Conclusion: This study indicated that DTP extracts could induce cytotoxicity in cholangiocarcinoma, with a high potential of being an effective therapeutic agent. Graphical abstract:
{"title":"Cytotoxic activities of ethanolic crude extracts from fruiting bodies of bamboo mushrooms (Dictyophora spp.) against cholangiocarcinoma cells","authors":"Pathanin Chantree, S. Chumkiew, Mantana Jamklang, Pongsakorn Martviset","doi":"10.3897/rrpharmacology.8.72098","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.72098","url":null,"abstract":"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.\u0000 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.\u0000 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<0.001). Ch-DTP had the best effect by showing a response of more than 50% at a concentration of 0.3 mg/mL. Th-DTP had moderate effects at a concentration of lower than 0.6 mg/mL but worthwhile at higher concentrations, whereas Or-DTP had limited effects at concentrations of 0.4 mg/mL and downward, although the effects were significantly increased in the higher concentration range. Morphology of the Ch-DTP treated cells was greatly transformed both at low and high doses, but Th-DTP and Or-DTP showed definite alteration only at high doses. The morphological changes revealed apoptotic induction. In OUMS cells, no effects were recognized with any of the three DTPs.\u0000 Conclusion: This study indicated that DTP extracts could induce cytotoxicity in cholangiocarcinoma, with a high potential of being an effective therapeutic agent.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47003649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-02-16DOI: 10.3897/rrpharmacology.8.80504
A. D. Kravchenko, N. Pyatigorskaya, G. Brkich, L. Yevsieieva, A. Kyrychenko, S. 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:
{"title":"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","authors":"A. D. Kravchenko, N. Pyatigorskaya, G. Brkich, L. Yevsieieva, A. Kyrychenko, S. Kovalenko","doi":"10.3897/rrpharmacology.8.80504","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.80504","url":null,"abstract":"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).\u0000 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.\u0000 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.\u0000 Conclusion: The obtained data for substance HSV-DKH-0450 look promising for its further development as a potential therapeutic agent for pain relief.\u0000 Graphical abstract:","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41360835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-01DOI: 10.3897/rrpharmacology.8.73329
I. S. Stepanenko, S. A. Yamashkin, T. N. Platkova, A. I. Kiryutina, I. 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.
{"title":"Development of novel effective agents from 1H-indolylammonium trifluoroacetates effective against conditionally pathogenic microorganisms","authors":"I. S. Stepanenko, S. A. Yamashkin, T. N. Platkova, A. I. Kiryutina, I. Sorokvasha","doi":"10.3897/rrpharmacology.8.73329","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.73329","url":null,"abstract":"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.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70415229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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