Pub Date : 2022-10-05DOI: 10.3897/rrpharmacology.8.90241
M. V. Kustova, V. Perfilova, I. I. Prokofiev, Elena A. Musyko, A. S. Kucheryavenko, Elena E. Kusnetsova, Diana E. Tsetsera, I. Tyurenkov
Introduction: Acute alcohol intoxication (AAI) induces a number of myocardial disorders, which result in mitochondrial dysfunction in cardiomyocytes, oxidative stress, and decreased cardiac contractility. Nitric oxide produced by the nNOS is one of the major modulators of cardiac activity. New derivatives of GABA (RSPU-260 compound) and glutamate (glufimet) can be potentially regarded as such agents as the interaction between the NO system and the GABA and glutamatergic systems has been proved. Materials and methods: All the studies were performed on female white Wistar rats, aged 10 months, whose weight was 280–320g AAI intoxication was modeled of 32% ethanol (gavage, 4g/kg). Results and discussion: Glufimet and the RSPU-260 compound caused a significant improvement in myocardial contractility, increased oxygen consumption in the V3 state according to Chance, raised the respiratory control ratio and decreased the intensity of LPO intensity. Their effectiveness exceeded that of mildronate, their comparator. nNOS inhibition resulted in a pronounced aggravation of oxidative stress implicated in MDA accumulation in cardiac mitochondria and decreased activity of SOD; myocardial contractility and mitochondrial function indicators did not show a significant difference from the control group. The compounds under study coupled with nNOS inhibition had a cardioprotective effect. Conclusion: Glufimet and the RSPU-260 compound, derivatives of neuroactive amino acids, have a pronounced cardioprotective effect, restrict LPO processes, enhance SOD activity, improve the mitochondrial respiratory function after acute alcohol intoxication when coupled with neuronal NO-synthase inhibition, the expression of which persists after AAI. Graphical abstract:
{"title":"Pharmacological correction of the sequelae of acute alcohol-induced myocardial damage with new derivatives of neuroactive amino acids coupled with the blockade of the neuronal NO synthase isoform","authors":"M. V. Kustova, V. Perfilova, I. I. Prokofiev, Elena A. Musyko, A. S. Kucheryavenko, Elena E. Kusnetsova, Diana E. Tsetsera, I. Tyurenkov","doi":"10.3897/rrpharmacology.8.90241","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.90241","url":null,"abstract":"Introduction: Acute alcohol intoxication (AAI) induces a number of myocardial disorders, which result in mitochondrial dysfunction in cardiomyocytes, oxidative stress, and decreased cardiac contractility. Nitric oxide produced by the nNOS is one of the major modulators of cardiac activity. New derivatives of GABA (RSPU-260 compound) and glutamate (glufimet) can be potentially regarded as such agents as the interaction between the NO system and the GABA and glutamatergic systems has been proved.\u0000 Materials and methods: All the studies were performed on female white Wistar rats, aged 10 months, whose weight was 280–320g AAI intoxication was modeled of 32% ethanol (gavage, 4g/kg).\u0000 Results and discussion: Glufimet and the RSPU-260 compound caused a significant improvement in myocardial contractility, increased oxygen consumption in the V3 state according to Chance, raised the respiratory control ratio and decreased the intensity of LPO intensity. Their effectiveness exceeded that of mildronate, their comparator. nNOS inhibition resulted in a pronounced aggravation of oxidative stress implicated in MDA accumulation in cardiac mitochondria and decreased activity of SOD; myocardial contractility and mitochondrial function indicators did not show a significant difference from the control group. The compounds under study coupled with nNOS inhibition had a cardioprotective effect.\u0000 Conclusion: Glufimet and the RSPU-260 compound, derivatives of neuroactive amino acids, have a pronounced cardioprotective effect, restrict LPO processes, enhance SOD activity, improve the mitochondrial respiratory function after acute alcohol intoxication when coupled with neuronal NO-synthase inhibition, the expression of which persists after AAI.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46707199","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 : 2022-10-05DOI: 10.3897/rrpharmacology.8.78534
I. Belenichev, Andrii V. Abramov, A. Puzyrenko, N. Bukhtiyarova, N. Gorchakova, P. Bak
Introduction: Despite the success which was achieved in the treatment of arterial hypertension, for optimization of the treatment, it is necessary to study the pathogenesis of primary arterial hypertension and target organ damage on the molecular level. Materials and methods: Our team studied the molecular mechanisms of myocardial damage during arterial hypertension and metabolic disorders. We used the spontaneously hypertensive rats (SHR) as an experimental model, and, additionally, we modeled diabetes mellitus and atherosclerosis in these rats. Results and discussion: Our study obtained evidence of a much higher level of the energy imbalance in the cardiomyocytes and more intensive production of reactive oxygen species in the SHRs with diabetes mellitus and atherosclerosis compared with the healthy animals and the animals with only hypertension. The indicated defections create an environment for further cellular damage – mitochondrial dysfunction, depletion in the thiol-disulfide system, and formation of highly reactive NO products. At the same time, we have noticed a higher activity of the Hsp70 in the hypertensive groups compared with the normotensive animals. The source of these deviations is in the formation of mitochondrial dysfunction of cardiocytes, the cause of which is oxidative modification of the protein structures of mitochondria under conditions of activation of oxidative stress reactions, insufficiency of mPT pores, and impaired mitochondrial chaperone function. The presented data give reason to believe that mitochondrial dysfunction, which develops against the background of deficient HSP70, is an integral aspect of arterial hypertension, contributes to its aggravation, and triggers a cascade of molecular and biochemical mechanisms of myocardial damage. These mechanisms include disturbances in the L-arginine-NO-synthase-NO system, production of mitochondrial iNOS oxygen radicals, neutralization of the vasorelaxant effect of NO and its transformation into an active participant in nitrous stress due to reduced intermediates of the thiol-disulfide system. The question of cause-and-effect relationships of oxidative stress remains open for discussion. Conclusion: We envisage that studies in this direction may lead to a better insight into a pathogenetic therapy of essential hypertension, diabetes mellitus, and atherosclerosis. Graphical abstract:
{"title":"Molecular mechanisms of myocardial damage in the hypertensive rats and hypertensive rats with metabolic disorders (diabetes mellitus, atherosclerosis)","authors":"I. Belenichev, Andrii V. Abramov, A. Puzyrenko, N. Bukhtiyarova, N. Gorchakova, P. Bak","doi":"10.3897/rrpharmacology.8.78534","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.78534","url":null,"abstract":"Introduction: Despite the success which was achieved in the treatment of arterial hypertension, for optimization of the treatment, it is necessary to study the pathogenesis of primary arterial hypertension and target organ damage on the molecular level.\u0000 Materials and methods: Our team studied the molecular mechanisms of myocardial damage during arterial hypertension and metabolic disorders. We used the spontaneously hypertensive rats (SHR) as an experimental model, and, additionally, we modeled diabetes mellitus and atherosclerosis in these rats.\u0000 Results and discussion: Our study obtained evidence of a much higher level of the energy imbalance in the cardiomyocytes and more intensive production of reactive oxygen species in the SHRs with diabetes mellitus and atherosclerosis compared with the healthy animals and the animals with only hypertension. The indicated defections create an environment for further cellular damage – mitochondrial dysfunction, depletion in the thiol-disulfide system, and formation of highly reactive NO products. At the same time, we have noticed a higher activity of the Hsp70 in the hypertensive groups compared with the normotensive animals. The source of these deviations is in the formation of mitochondrial dysfunction of cardiocytes, the cause of which is oxidative modification of the protein structures of mitochondria under conditions of activation of oxidative stress reactions, insufficiency of mPT pores, and impaired mitochondrial chaperone function. The presented data give reason to believe that mitochondrial dysfunction, which develops against the background of deficient HSP70, is an integral aspect of arterial hypertension, contributes to its aggravation, and triggers a cascade of molecular and biochemical mechanisms of myocardial damage. These mechanisms include disturbances in the L-arginine-NO-synthase-NO system, production of mitochondrial iNOS oxygen radicals, neutralization of the vasorelaxant effect of NO and its transformation into an active participant in nitrous stress due to reduced intermediates of the thiol-disulfide system. The question of cause-and-effect relationships of oxidative stress remains open for discussion.\u0000 Conclusion: We envisage that studies in this direction may lead to a better insight into a pathogenetic therapy of essential hypertension, diabetes mellitus, and atherosclerosis.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48698008","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 : 2022-10-05DOI: 10.3897/rrpharmacology.8.81706
G. Temaj, R. Hadziselimovic, H. Nefic, N. Nuhii
Introduction: The process of protein synthesis is a vital process for all kingdoms of life. The ribosome is a ribonucleoprotein complex that reads the genetic code, from messenger RNA (mRNA) to produce proteins and to tightly regulate and ensure cells growth. The fact that numerous diseases are caused by defect during the ribosome biogenesis is important to understand this pathway. Materials and methods: We have analyzed the literature for ribosome biogenesis and its links with different diseases which have been found. Results and discussion: We have discussed the key aspect of human ribosome biogenesis and its links to diseases. We have also proposed the potential of applying this knowledge to the development of a ribosomal stress-based cancer therapy. Conclusion: Major challenges in the future will be to determine factors which play a pivotal role during ribosome biogenesis. Therefore, more anti-cancer drugs and gene therapy for genetic diseases will be developed against ribosomal biogenesis in the coming years. Graphical abstract:
{"title":"Ribosome biogenesis and ribosome therapy in cancer cells","authors":"G. Temaj, R. Hadziselimovic, H. Nefic, N. Nuhii","doi":"10.3897/rrpharmacology.8.81706","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.81706","url":null,"abstract":"Introduction: The process of protein synthesis is a vital process for all kingdoms of life. The ribosome is a ribonucleoprotein complex that reads the genetic code, from messenger RNA (mRNA) to produce proteins and to tightly regulate and ensure cells growth. The fact that numerous diseases are caused by defect during the ribosome biogenesis is important to understand this pathway.\u0000 Materials and methods: We have analyzed the literature for ribosome biogenesis and its links with different diseases which have been found.\u0000 Results and discussion: We have discussed the key aspect of human ribosome biogenesis and its links to diseases. We have also proposed the potential of applying this knowledge to the development of a ribosomal stress-based cancer therapy.\u0000 Conclusion: Major challenges in the future will be to determine factors which play a pivotal role during ribosome biogenesis. Therefore, more anti-cancer drugs and gene therapy for genetic diseases will be developed against ribosomal biogenesis in the coming years.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42070389","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 : 2022-09-13DOI: 10.3897/rrpharmacology.8.89997
E. Blinova, A. Epishkina, O. M. Tumutolova, O. Deryabina, S. Skachilova, Mihail Yu. Kudriavtsev, E. Shikh, O. S. Vavilova, Yulia S. Gilevskaya, G. Brykin, A. A. Makhrova, D. Blinov
Introduction: The study aim was to explore a toxicological property and antitumor action of the novel pyridine derivative LHT-17-19 in cell culture and on experimental models of lung cancer in mice. Materials and methods: The study was performed on male and female ICR(CD-1), male BALB/c, male BALB/c nu/nu mice. Pyridine derivative (LHT-17-19) was studied as water-soluble pharmaceutical substance. Acute toxicity was evaluated in groups of 5 animals, and the results were analyzed by Finney. Antitumor and antimetastatic activity was studied in syngeneic and xenograft models of lung cancer in mice. Results and discussion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with GOST 12.1.007–76. The substance demonstrated an antitumor and antimetastatic property in mice with syngeneic tumor Lewis lung carcinoma as well as on the heterotopic tumor model of non-small cell lung cancer in humanized animals. Conclusion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with WHO recommendation. LHT-17-19 exerts antitumor and antimetastatic property on both syngeneic and patient-derived lung cancer xenograft murine models. Graphical abstract
{"title":"Antitumor activity of the novel pyridine derivative","authors":"E. Blinova, A. Epishkina, O. M. Tumutolova, O. Deryabina, S. Skachilova, Mihail Yu. Kudriavtsev, E. Shikh, O. S. Vavilova, Yulia S. Gilevskaya, G. Brykin, A. A. Makhrova, D. Blinov","doi":"10.3897/rrpharmacology.8.89997","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.89997","url":null,"abstract":"Introduction: The study aim was to explore a toxicological property and antitumor action of the novel pyridine derivative LHT-17-19 in cell culture and on experimental models of lung cancer in mice.\u0000 Materials and methods: The study was performed on male and female ICR(CD-1), male BALB/c, male BALB/c nu/nu mice. Pyridine derivative (LHT-17-19) was studied as water-soluble pharmaceutical substance. Acute toxicity was evaluated in groups of 5 animals, and the results were analyzed by Finney. Antitumor and antimetastatic activity was studied in syngeneic and xenograft models of lung cancer in mice.\u0000 Results and discussion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with GOST 12.1.007–76. The substance demonstrated an antitumor and antimetastatic property in mice with syngeneic tumor Lewis lung carcinoma as well as on the heterotopic tumor model of non-small cell lung cancer in humanized animals.\u0000 Conclusion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with WHO recommendation. LHT-17-19 exerts antitumor and antimetastatic property on both syngeneic and patient-derived lung cancer xenograft murine models.\u0000 \u0000 Graphical abstract\u0000 \u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41899662","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 : 2022-09-13DOI: 10.3897/rrpharmacology.8.83872
E. Leonova, Vasily V. Reshetnikov, J. Sopova
Novel CRISPR-Cas-based genome editing tools made it feasible to introduce a variety of precise genomic modifications in the pig genome, including introducing multiple edits simultaneously, inserting long DNA sequences into specifically targeted loci, and performing nucleotide transitions and transversions. Pigs serve as a vital agricultural resource and animal model in biomedical studies, given their advantages over the other models. Pigs share high similarities to humans regarding body/organ size, anatomy, physiology, and a metabolic profile. The pig genome can be modified to carry the same genetic mutations found in humans to replicate inherited diseases to provide preclinical trials of drugs. Moreover, CRISPR-based modification of pigs antigen profile makes it possible to offer porcine organs for xenotransplantation with minimal transplant rejection responses. This review summarizes recent advances in endonuclease-mediated genome editing tools and research progress of genome-edited pigs as personalized test-systems for preclinical trials and as donors of organs with human-fit antigen profile. Graphical abstract:
{"title":"CRISPR/Cas-edited pigs for personalized medicine: more than preclinical test-system","authors":"E. Leonova, Vasily V. Reshetnikov, J. Sopova","doi":"10.3897/rrpharmacology.8.83872","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.83872","url":null,"abstract":"Novel CRISPR-Cas-based genome editing tools made it feasible to introduce a variety of precise genomic modifications in the pig genome, including introducing multiple edits simultaneously, inserting long DNA sequences into specifically targeted loci, and performing nucleotide transitions and transversions. Pigs serve as a vital agricultural resource and animal model in biomedical studies, given their advantages over the other models. Pigs share high similarities to humans regarding body/organ size, anatomy, physiology, and a metabolic profile. The pig genome can be modified to carry the same genetic mutations found in humans to replicate inherited diseases to provide preclinical trials of drugs. Moreover, CRISPR-based modification of pigs antigen profile makes it possible to offer porcine organs for xenotransplantation with minimal transplant rejection responses. This review summarizes recent advances in endonuclease-mediated genome editing tools and research progress of genome-edited pigs as personalized test-systems for preclinical trials and as donors of organs with human-fit antigen profile.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46984668","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 : 2022-08-25DOI: 10.3897/rrpharmacology.8.83332
T. Fatoki, S. Chukwuejim, O. Ibraheem, Christiana Oke, Blessing Ejimadu, Isaiah Olaoye, Oluwabukola Oyegbenro, Taiwo Salami, R. Basorun, Oluwafisayomi Oluwadare, Yetunde Salawudeen
Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches. Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation. Results and discussion: The results show that riluzole, β-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS. Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques. Graphical abstract:
{"title":"Harmine and 7,8-dihydroxyflavone synergistically suitable for amyotrophic lateral sclerosis management: An in silico study","authors":"T. Fatoki, S. Chukwuejim, O. Ibraheem, Christiana Oke, Blessing Ejimadu, Isaiah Olaoye, Oluwabukola Oyegbenro, Taiwo Salami, R. Basorun, Oluwafisayomi Oluwadare, Yetunde Salawudeen","doi":"10.3897/rrpharmacology.8.83332","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.83332","url":null,"abstract":"Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches.\u0000 Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation.\u0000 Results and discussion: The results show that riluzole, β-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS.\u0000 Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques.\u0000 Graphical abstract:","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44278922","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 : 2022-08-25DOI: 10.3897/rrpharmacology.8.81003
Yara Annouf, Shaza Al laham, E. Chatty
Introduction: It is a well-known phenomenon that nonsteroidal anti-inflammatory drugs cause gastric mucosal damage. Amlodipine is a third generation dihydropyridine-type calcium channel blocker; it can inhibit inflammatory cytokines and enhance antioxidant defenses. N-acetylcysteine can act both as a precursor of reduced glutathione and as a direct ROS scavenger. Moreover, N-acetylcysteine has been purported to have anti-inflammatory properties. Materials and methods: 34 albino Wistar rats were used. The model of gastritis was induced by subcutaneous Indomethacin prepared in 5% sodium bicarbonate administered at a dose rate of 9 mg/kg for two days at 24h intervals. N-acetylcysteine (500 mg/kg), Amlodipine (10 mg/kg) and N-acetylcysteine (500 mg/kg) combined with Amlodipine (5 mg/kg) were administrated for seven consecutive days beginning 24 h after the first Indomethacin injection. Rats were sacrificed under ether anesthesia on the 8th day. The stomach injury was assessed by macroscopic damage and histological study. Results and discussion: The results showed that macroscopic stomach damage scores caused by administration of Indomethacin did not significantly decrease by administration of N-acetylcysteine alone (p>0.05), but it decreased significantly by administration of Amlodipine alone or by its combination with N-acetylcysteine (p<0.05). Microscopic stomach damage scores did not significantly decrease by administration of Amlodipine or N-acetylcysteine alone (p>0.05), but they decreased significantly by administering the combination of Amlodipine with N-acetylcysteine (p<0.05). Administration of Amlodipine with N-acetylcysteine showed significant reduction in the severity of the gastric inflammation induced by Indomethacin, which was evidenced macroscopically and microscopically. Conclusion: This study concluded that administration of Amlodipine with N-acetylcysteine produce obvious enhancement in gastritis induced by Indomethacin. Graphical abstract:
{"title":"Efficiency evaluation of Amlodipine combined with N-acetylcysteine on Indomethacin-induced gastritis in rats","authors":"Yara Annouf, Shaza Al laham, E. Chatty","doi":"10.3897/rrpharmacology.8.81003","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.81003","url":null,"abstract":"Introduction: It is a well-known phenomenon that nonsteroidal anti-inflammatory drugs cause gastric mucosal damage. Amlodipine is a third generation dihydropyridine-type calcium channel blocker; it can inhibit inflammatory cytokines and enhance antioxidant defenses. N-acetylcysteine can act both as a precursor of reduced glutathione and as a direct ROS scavenger. Moreover, N-acetylcysteine has been purported to have anti-inflammatory properties.\u0000 Materials and methods: 34 albino Wistar rats were used. The model of gastritis was induced by subcutaneous Indomethacin prepared in 5% sodium bicarbonate administered at a dose rate of 9 mg/kg for two days at 24h intervals. N-acetylcysteine (500 mg/kg), Amlodipine (10 mg/kg) and N-acetylcysteine (500 mg/kg) combined with Amlodipine (5 mg/kg) were administrated for seven consecutive days beginning 24 h after the first Indomethacin injection. Rats were sacrificed under ether anesthesia on the 8th day. The stomach injury was assessed by macroscopic damage and histological study.\u0000 Results and discussion: The results showed that macroscopic stomach damage scores caused by administration of Indomethacin did not significantly decrease by administration of N-acetylcysteine alone (p>0.05), but it decreased significantly by administration of Amlodipine alone or by its combination with N-acetylcysteine (p<0.05). Microscopic stomach damage scores did not significantly decrease by administration of Amlodipine or N-acetylcysteine alone (p>0.05), but they decreased significantly by administering the combination of Amlodipine with N-acetylcysteine (p<0.05). Administration of Amlodipine with N-acetylcysteine showed significant reduction in the severity of the gastric inflammation induced by Indomethacin, which was evidenced macroscopically and microscopically.\u0000 Conclusion: This study concluded that administration of Amlodipine with N-acetylcysteine produce obvious enhancement in gastritis induced by Indomethacin.\u0000 Graphical abstract:","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48217985","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 : 2022-08-18DOI: 10.3897/rrpharmacology.8.85498
A. Spasov, A. A. Brigadirova, O. Zhukovskaya, A. S. Morkovnik, Yuliya V. Lifanova
Introduction: Biphenyl and imidazobenzimidazole derivatives attract ongoing attention as a combination of these two privileged substructures with promising pharmacological activities. The aim of this study was to synthesize and investigate in vitro antioxidant activity of promising novel compounds: 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles. Materials and methods: The newly synthesized compounds were characterized by IR, 1H NMR and CHBr(Cl)NO analyses. All newly synthesized compounds were screened for their in vitro antioxidant activity: inhibition of lipid peroxidation (LPO), 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) radical cation decolorization and inhibition of hemoglobin (Hb)-H2O2-induced luminol chemiluminescence. Results and discussion: 2-Amino-3-[(2-biphenyl-4-yl)-2-oxo-ethyl)]-1-R-1Н-benzimidazolium bromides were synthesized, and their cyclization into functionalized imidazo[1,2-a]benzimidazole derivatives was studied. The resulting compounds showed LPO inhibitory activity comparable to that of dibunol. Compounds 1a and 1d (see graphical abstract), containing a methyl or dimethylaminoethyl substituent in the N9 position also proved to be equally highly active in the Hb-H2O2-induced luminol chemiluminescence model, while compound 1a was somewhat more active than 1d in the ABTS• radical scavenging assay. Conclusion: The study showed that compounds 1a and 1d have the highest antioxidant activity. Thus, this new class of 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazole derivatives represents a valuable leading series with great potential for use as antioxidants and as promising candidates for further efficacy evaluation. Graphical abstract:
{"title":"Search for compounds with antioxidant and antiradical activity among N9-substituted 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles","authors":"A. Spasov, A. A. Brigadirova, O. Zhukovskaya, A. S. Morkovnik, Yuliya V. Lifanova","doi":"10.3897/rrpharmacology.8.85498","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.85498","url":null,"abstract":"Introduction: Biphenyl and imidazobenzimidazole derivatives attract ongoing attention as a combination of these two privileged substructures with promising pharmacological activities. The aim of this study was to synthesize and investigate in vitro antioxidant activity of promising novel compounds: 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles.\u0000 Materials and methods: The newly synthesized compounds were characterized by IR, 1H NMR and CHBr(Cl)NO analyses. All newly synthesized compounds were screened for their in vitro antioxidant activity: inhibition of lipid peroxidation (LPO), 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) radical cation decolorization and inhibition of hemoglobin (Hb)-H2O2-induced luminol chemiluminescence.\u0000 Results and discussion: 2-Amino-3-[(2-biphenyl-4-yl)-2-oxo-ethyl)]-1-R-1Н-benzimidazolium bromides were synthesized, and their cyclization into functionalized imidazo[1,2-a]benzimidazole derivatives was studied. The resulting compounds showed LPO inhibitory activity comparable to that of dibunol. Compounds 1a and 1d (see graphical abstract), containing a methyl or dimethylaminoethyl substituent in the N9 position also proved to be equally highly active in the Hb-H2O2-induced luminol chemiluminescence model, while compound 1a was somewhat more active than 1d in the ABTS• radical scavenging assay.\u0000 Conclusion: The study showed that compounds 1a and 1d have the highest antioxidant activity. Thus, this new class of 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazole derivatives represents a valuable leading series with great potential for use as antioxidants and as promising candidates for further efficacy evaluation.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45836247","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 : 2022-08-18DOI: 10.3897/rrpharmacology.8.79765
O. Edosuyi, Myung Choi, I. Igbe, A. Oyekan
Introduction: Fumarate, the tricarboxylic acid (TCA) cycle intermediary, has been linked to nitric oxide (NO) production. NO plays a prominent role in the physiological regulation of blood pressure and renal hemodynamics. This study is aimed to investigate any contribution of fumarate to blood pressure and renal hemodynamics in normotensive rats with a possible link to the nitrergic system. Materials and methods: Fumarate (1, 3 and 10 µmol) was injected into isolated perfused kidneys, pre-constricted with epinephrine (30 µM). The fumarase inhibitor, pyromellitic acid (PMA) (1, 3 and 10 µM), was used to perfuse the isolated kidney and perfusate was collected for nitric oxide and fumarate assays. An acute blood pressure study involved the injection of bolus doses of fumarate (0.1, 0.3 and 1 µg/kg, iv) or PMA (1, 3 and 10 µg/kg, iv) to normotensive rats in the presence of N(ω)-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, iv) or PMA (1, 3 and 10 µg/kg). Results and discussion: Fumarate reduced perfusion pressure and elicited a peak reduction at the highest dose. Perfusing the kidney with PMA caused a paradoxical increase in perfusion pressure (70%, p<0.05), compared to baseline. Bolus doses of fumarate reduced blood pressure (-29.3±6.2 mmHg, p<0.05), cortical blood flow (CBF) and increased medullary blood flow (MBF). L-NAME did not abolish the vasodilatory effect of fumarate, but reduced the magnitude of response (50%, p<0.05). PMA did not significantly affect the vasodilatory effect of fumarate (p>0.05). Conclusion: These data suggest that fumarate exerts a vasodilatory effect on renal and systemic hemodynamics that may partly involve the nitric oxide signaling. Graphical abstract:
{"title":"Effects of fumarate on renal vascular reactivity and the modulation of blood pressure in normotensive rats: Possible contribution of the nitric oxide synthase-nitric oxide system","authors":"O. Edosuyi, Myung Choi, I. Igbe, A. Oyekan","doi":"10.3897/rrpharmacology.8.79765","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.79765","url":null,"abstract":"Introduction: Fumarate, the tricarboxylic acid (TCA) cycle intermediary, has been linked to nitric oxide (NO) production. NO plays a prominent role in the physiological regulation of blood pressure and renal hemodynamics. This study is aimed to investigate any contribution of fumarate to blood pressure and renal hemodynamics in normotensive rats with a possible link to the nitrergic system.\u0000 Materials and methods: Fumarate (1, 3 and 10 µmol) was injected into isolated perfused kidneys, pre-constricted with epinephrine (30 µM). The fumarase inhibitor, pyromellitic acid (PMA) (1, 3 and 10 µM), was used to perfuse the isolated kidney and perfusate was collected for nitric oxide and fumarate assays. An acute blood pressure study involved the injection of bolus doses of fumarate (0.1, 0.3 and 1 µg/kg, iv) or PMA (1, 3 and 10 µg/kg, iv) to normotensive rats in the presence of N(ω)-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, iv) or PMA (1, 3 and 10 µg/kg).\u0000 Results and discussion: Fumarate reduced perfusion pressure and elicited a peak reduction at the highest dose. Perfusing the kidney with PMA caused a paradoxical increase in perfusion pressure (70%, p<0.05), compared to baseline. Bolus doses of fumarate reduced blood pressure (-29.3±6.2 mmHg, p<0.05), cortical blood flow (CBF) and increased medullary blood flow (MBF). L-NAME did not abolish the vasodilatory effect of fumarate, but reduced the magnitude of response (50%, p<0.05). PMA did not significantly affect the vasodilatory effect of fumarate (p>0.05).\u0000 Conclusion: These data suggest that fumarate exerts a vasodilatory effect on renal and systemic hemodynamics that may partly involve the nitric oxide signaling.\u0000 Graphical abstract:\u0000 \u0000 \u0000","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42172278","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 : 2022-07-20DOI: 10.3897/rrpharmacology.8.90214
N. Pyatigorskaya, O. Filippova, N. S. Nikolenko, A. 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.
{"title":"Transient receptor potential Ankyrin 1: structure, function and ligands","authors":"N. Pyatigorskaya, O. Filippova, N. S. Nikolenko, A. D. Kravchenko","doi":"10.3897/rrpharmacology.8.90214","DOIUrl":"https://doi.org/10.3897/rrpharmacology.8.90214","url":null,"abstract":"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.\u0000 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.\u0000 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.\u0000 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.","PeriodicalId":21030,"journal":{"name":"Research Results in Pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42674449","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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