Pub Date : 2022-01-11DOI: 10.14218/jerp.2021.00053
Xiao-Juan Wang, Yong-Qiang Xue, He-Ling Zhang, Ying Yu, Peng Liu
Background and objectives
PTEN-induced putative kinase 1 (PINK1) is a mitochondrial kinase that regulates mitophagy. PINK1-deficient mAPP mice display low LC3B levels, and PINK1 overexpression enhances autophagy and increases the expression level of lysosome-associated membrane protein 1 (LAMP1). The present study evaluated whether altered PINK1 expression could modulate β-amyloid (Aβ)-treated mitophagy in PC12 cells, a simple cellular model to simulate pathological changes in neurodegenerative diseases in vitro.
Methods
PC12 cells were transfected with PINK1 siRNA for 48 h, and then incubated with 20 μM Aβ25–35 for 24 h. The relevant protein expression was determined by immunofluorescence, immunoelectron microscopy, and Western blot. Mitochondrial membrane potential (MMP) was tested by JC-1-based confocal fluorescent imaging.
Results
Following Aβ25–35 treatment, PINK1 silencing significantly decreased the levels of LC3B, Parkin, and LAMP1 as well as Parkin in mitochondria, p62 degradation, but increased OPTN and Parkin expression in PC12 cells, relative to that of the control PC12 cells. Furthermore, PINK1 silencing decreased MMP in PC12 cells.
Conclusion
PINK1 deficiency deteriorated the blockade of the Aβ25–35-induced mitophagy-lysosome pathway in PC12 cells. Aβ-treated PC12 cells might be a valuable cellular model to evaluate PINK1-mediated mitophagy and bioactive compound screening.
{"title":"PINK1 Deficiency Aggravates the β-amyloid-attenuated Mitophagy-lysosomal Degradation in PC12 Cells","authors":"Xiao-Juan Wang, Yong-Qiang Xue, He-Ling Zhang, Ying Yu, Peng Liu","doi":"10.14218/jerp.2021.00053","DOIUrl":"https://doi.org/10.14218/jerp.2021.00053","url":null,"abstract":"<abstract><sec>\u0000<title>Background and objectives</title>\u0000<p>PTEN-induced putative kinase 1 (PINK1) is a mitochondrial kinase that regulates mitophagy. PINK1-deficient mAPP mice display low LC3B levels, and PINK1 overexpression enhances autophagy and increases the expression level of lysosome-associated membrane protein 1 (LAMP1). The present study evaluated whether altered PINK1 expression could modulate β-amyloid (Aβ)-treated mitophagy in PC12 cells, a simple cellular model to simulate pathological changes in neurodegenerative diseases <i>in vitro</i>.</p>\u0000</sec><sec>\u0000<title>Methods</title>\u0000<p>PC12 cells were transfected with PINK1 siRNA for 48 h, and then incubated with 20 μM Aβ<sub>25–35</sub> for 24 h. The relevant protein expression was determined by immunofluorescence, immunoelectron microscopy, and Western blot. Mitochondrial membrane potential (MMP) was tested by JC-1-based confocal fluorescent imaging.</p>\u0000</sec><sec>\u0000<title>Results</title>\u0000<p>Following Aβ<sub>25–35</sub> treatment, PINK1 silencing significantly decreased the levels of LC3B, Parkin, and LAMP1 as well as Parkin in mitochondria, p62 degradation, but increased OPTN and Parkin expression in PC12 cells, relative to that of the control PC12 cells. Furthermore, PINK1 silencing decreased MMP in PC12 cells.</p>\u0000</sec><sec>\u0000<title>Conclusion</title>\u0000<p>PINK1 deficiency deteriorated the blockade of the Aβ<sub>25–35</sub>-induced mitophagy-lysosome pathway in PC12 cells. Aβ-treated PC12 cells might be a valuable cellular model to evaluate PINK1-mediated mitophagy and bioactive compound screening.</p>\u0000</sec></abstract>\u0000","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138527492","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: 10.14218/jerp.2021.00050
V. Kouznetsova, Aidan Zhang, Mark A Miller, M. Tatineni, J. Greenberg, I. Tsigelny
{"title":"Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs","authors":"V. Kouznetsova, Aidan Zhang, Mark A Miller, M. Tatineni, J. Greenberg, I. Tsigelny","doi":"10.14218/jerp.2021.00050","DOIUrl":"https://doi.org/10.14218/jerp.2021.00050","url":null,"abstract":"","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66777898","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}
{"title":"Traditional Herbal Medicines in Mood Disorders: A Promising Development Target","authors":"Zhi-hui Zhang, Zeng‐bo Ding, X. Wu, Ke Wang, Su-Xia Li, Wei‐li Zhu","doi":"10.14218/jerp.2021.00046","DOIUrl":"https://doi.org/10.14218/jerp.2021.00046","url":null,"abstract":"","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48207113","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 : 2021-12-09DOI: 10.14218/jerp.2021.00054
M. Stojanović, Vidosav Stojanović, Duska C. Stojanovic
{"title":"Subclinical Hyperthyroidism is One of the Modifiable Risk Factors for Atrial Fibrillation","authors":"M. Stojanović, Vidosav Stojanović, Duska C. Stojanovic","doi":"10.14218/jerp.2021.00054","DOIUrl":"https://doi.org/10.14218/jerp.2021.00054","url":null,"abstract":"","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42457019","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 : 2021-12-02DOI: 10.14218/jerp.2021.00030
Tom Seymour, Jinwei Zhang
The leading cause of dementia is Alzheimer’s disease (AD), which affects millions worldwide. Aging populations can foretell the worsening burden of the disease in the future. AD is characterised by the following hallmark pathologies: amyloid-β over-production and deposition, abnormal hyperphosphorylation of tau leading to the formation of neurofibrillary tangles, and neuroinflammation. Many potential treatments fail in clinical trials, suggesting that present theories are outdated or lead to therapeutic dead-ends. A gum disease-causing species of bacteria, Porphyromonas gingivalis, is being increasingly linked with AD, given the ubiquity of gum disease amongst older populations, and studies have revealed that the bacteria causes and exacerbates AD pathology both in vitro and in vivo. P. gingivalis produce many neurotoxic molecules, including gingipain enzymes, lipopolysaccharide and phosphoglycerol dihydroceramides, and all of these have been shown to affect AD pathologies. Numerous mechanisms by which these neurotoxic species reach the brain have been proposed, and one of these is the bacteria’s use of outer membrane vesicles. This review presents the present evidence of the effects of P. gingivalis and its outer membrane vesicles, gingipains, lipopolysaccharide and phosphoglycerol dihydroceramides, on neurodegeneration in neuronal cultures, mice models and post-mortem studies, and determines how this evidence can be used to develop new treatments for AD.
{"title":"Porphyromonas Gingivalis in the Pathogenesis of Alzheimer’s Disease and Its Therapeutic Target","authors":"Tom Seymour, Jinwei Zhang","doi":"10.14218/jerp.2021.00030","DOIUrl":"https://doi.org/10.14218/jerp.2021.00030","url":null,"abstract":"The leading cause of dementia is Alzheimer’s disease (AD), which affects millions worldwide. Aging populations can foretell the worsening burden of the disease in the future. AD is characterised by the following hallmark pathologies: amyloid-β over-production and deposition, abnormal hyperphosphorylation of tau leading to the formation of neurofibrillary tangles, and neuroinflammation. Many potential treatments fail in clinical trials, suggesting that present theories are outdated or lead to therapeutic dead-ends. A gum disease-causing species of bacteria, Porphyromonas gingivalis, is being increasingly linked with AD, given the ubiquity of gum disease amongst older populations, and studies have revealed that the bacteria causes and exacerbates AD pathology both in vitro and in vivo. P. gingivalis produce many neurotoxic molecules, including gingipain enzymes, lipopolysaccharide and phosphoglycerol dihydroceramides, and all of these have been shown to affect AD pathologies. Numerous mechanisms by which these neurotoxic species reach the brain have been proposed, and one of these is the bacteria’s use of outer membrane vesicles. This review presents the present evidence of the effects of P. gingivalis and its outer membrane vesicles, gingipains, lipopolysaccharide and phosphoglycerol dihydroceramides, on neurodegeneration in neuronal cultures, mice models and post-mortem studies, and determines how this evidence can be used to develop new treatments for AD.","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45792026","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 : 2021-10-14DOI: 10.14218/jerp.2021.00032
Jason Y Tang,Igor F. Tsigelny,Jerry P. Greenberg,Mark A. Miller,Valentina L. Kouznetsova
Severe acute respiratory syndrome coronavirus (SARS-CoV) 2 infection has caused millions of deaths worldwide, pushing the urgent need for an efficient treatment. Nonstructural protein 15 (NSP15) is a promising target due to its importance for SARS-CoV-2’s evasion of the host’s innate immune response.
{"title":"Potential SARS-CoV-2 Nonstructural Protein 15 Inhibitors: Repurposing FDA-Approved Drugs","authors":"Jason Y Tang,Igor F. Tsigelny,Jerry P. Greenberg,Mark A. Miller,Valentina L. Kouznetsova","doi":"10.14218/jerp.2021.00032","DOIUrl":"https://doi.org/10.14218/jerp.2021.00032","url":null,"abstract":"Severe acute respiratory syndrome coronavirus (SARS-CoV) 2 infection has caused millions of deaths worldwide, pushing the urgent need for an efficient treatment. Nonstructural protein 15 (NSP15) is a promising target due to its importance for SARS-CoV-2’s evasion of the host’s innate immune response.","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":"18 4","pages":"000-000"},"PeriodicalIF":0.0,"publicationDate":"2021-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138527498","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 : 2021-09-30DOI: 10.14218/jerp.2021.00024
Sandrine Charles,Aude Ratier,Christelle Lopes
This paper gives the full analytical solution of the generic set of ordinary differential equations that define one-compartment toxicokinetic models. These models describe the uptake and elimination processes that occur within living organisms when exposed to chemical substances. The models solved in this paper consider living organisms as a unique compartment, into which a parent compound enters via several possible exposure routes and from which it is eliminated as well as its potential metabolites. Benefiting from generic solutions of one-compartment toxicokinetic models is particularly useful when fitting them to experimental data, facilitating the writing of the inference algorithms leading to parameter estimates. Additionally, these models are of crucial interest in environmental risk assessment for the calculation of bioaccumulation metrics as required by regulators in support of decision-making when they evaluate dossiers for marketing authorisation of active substances.
{"title":"Generic Solving of One-compartment Toxicokinetic Models","authors":"Sandrine Charles,Aude Ratier,Christelle Lopes","doi":"10.14218/jerp.2021.00024","DOIUrl":"https://doi.org/10.14218/jerp.2021.00024","url":null,"abstract":"This paper gives the full analytical solution of the generic set of ordinary differential equations that define one-compartment toxicokinetic models. These models describe the uptake and elimination processes that occur within living organisms when exposed to chemical substances. The models solved in this paper consider living organisms as a unique compartment, into which a parent compound enters via several possible exposure routes and from which it is eliminated as well as its potential metabolites. Benefiting from generic solutions of one-compartment toxicokinetic models is particularly useful when fitting them to experimental data, facilitating the writing of the inference algorithms leading to parameter estimates. Additionally, these models are of crucial interest in environmental risk assessment for the calculation of bioaccumulation metrics as required by regulators in support of decision-making when they evaluate dossiers for marketing authorisation of active substances.","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":"1 1","pages":"000-000"},"PeriodicalIF":0.0,"publicationDate":"2021-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138527494","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 : 2021-09-09DOI: 10.14218/jerp.2021.00016
Xin Zou, Hailong Yin, Lei Shi, Hai-ping Li, Mengheng Wang, Wanci Song, Yang Luo, Wei-Liang Chen, Hezhen Wu, Yan-fang Yang, Junfeng Zan, Yan-wen Liu, Hanxiong Dan, Q. Yin, Pengtao You
Depression is a severe and recurrent mental disease and contributes to the global disease burden. However, there are limited effective treatments for depression. This study evaluated the effect of a compound Gaoziban tablet (CGZBT) on depression and explored its potential mechanisms that underlie its action in rats.
{"title":"Treatment with Gaoziban Tablet Ameliorates Depression by Promoting GSK-3β Phosphorylation to Enhance the Wnt/β-catenin Activation in the Hippocampus of Rats","authors":"Xin Zou, Hailong Yin, Lei Shi, Hai-ping Li, Mengheng Wang, Wanci Song, Yang Luo, Wei-Liang Chen, Hezhen Wu, Yan-fang Yang, Junfeng Zan, Yan-wen Liu, Hanxiong Dan, Q. Yin, Pengtao You","doi":"10.14218/jerp.2021.00016","DOIUrl":"https://doi.org/10.14218/jerp.2021.00016","url":null,"abstract":"Depression is a severe and recurrent mental disease and contributes to the global disease burden. However, there are limited effective treatments for depression. This study evaluated the effect of a compound Gaoziban tablet (CGZBT) on depression and explored its potential mechanisms that underlie its action in rats.","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44250776","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 : 2021-08-11DOI: 10.33774/chemrxiv-2021-ht9sx
Jason X Tang, I. Tsigelny, J. Greenberg, Mark R. Miller, V. Kouznetsova
Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths worldwide, pushing the urgent need for an efficient treatment. Nonstructural protein 15 (NSP15) is a promising target due to its importance for SARS-CoV-2’s evasion of the host’s innate immune response. Methods: Using the crystal structure of SARS-CoV-2 NSP15 endoribonuclease, we developed a pharmacophore model of the functional centers in the NSP15 inhibitor’s binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. The conformations of these compounds underwent 3D fingerprint similarity clustering, and possible conformers were docked to the NSP15 binding pocket. We also simulated docking of random compounds to the NSP15 binding pocket for comparison. Results: This search identified 170 compounds as potential inhibitors of SARS-CoV-2 NSP15. The mean free energy of docking for the group of potential inhibitors were significantly lower than for the group of random compounds. Twenty-one of the compounds identified as potential NSP15 inhibitors were antiviral compounds used in the inhibition of a range of viruses, including MERS, SARS-CoV, and even SARS-CoV-2. Eight of the selected antiviral compounds in cluster A are pyrimidine analogues, six of which are currently used in a clinical setting. Four tyrosine kinase inhibitors were identified with potential SARS-CoV-2 inhibition, which is consistent with previous studies showing some kinase inhibitors acting as antiviral drugs. Conclusions: We recommended testing of these 21 selected antiviral compounds for the treatment of COVID-19.
{"title":"Potential SARS-CoV-2 Nonstructural Protein 15 (NSP15) Inhibitors: Repurposing FDA-Approved Drugs","authors":"Jason X Tang, I. Tsigelny, J. Greenberg, Mark R. Miller, V. Kouznetsova","doi":"10.33774/chemrxiv-2021-ht9sx","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-ht9sx","url":null,"abstract":"Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths worldwide, pushing the urgent need for an efficient treatment. Nonstructural protein 15 (NSP15) is a promising target due to its importance for SARS-CoV-2’s evasion of the host’s innate immune response. Methods: Using the crystal structure of SARS-CoV-2 NSP15 endoribonuclease, we developed a pharmacophore model of the functional centers in the NSP15 inhibitor’s binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. The conformations of these compounds underwent 3D fingerprint similarity clustering, and possible conformers were docked to the NSP15 binding pocket. We also simulated docking of random compounds to the NSP15 binding pocket for comparison. Results: This search identified 170 compounds as potential inhibitors of SARS-CoV-2 NSP15. The mean free energy of docking for the group of potential inhibitors were significantly lower than for the group of random compounds. Twenty-one of the compounds identified as potential NSP15 inhibitors were antiviral compounds used in the inhibition of a range of viruses, including MERS, SARS-CoV, and even SARS-CoV-2. Eight of the selected antiviral compounds in cluster A are pyrimidine analogues, six of which are currently used in a clinical setting. Four tyrosine kinase inhibitors were identified with potential SARS-CoV-2 inhibition, which is consistent with previous studies showing some kinase inhibitors acting as antiviral drugs. Conclusions: We recommended testing of these 21 selected antiviral compounds for the treatment of COVID-19.","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47004033","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 : 2021-07-30DOI: 10.14218/jerp.2021.00011
Yan Liu, L. Xiong, Yanyu Wang, Maohui Luo, Longfei Zhang, Yongqing Zhang
QingFeiPaiDu decoction (QFPDD) treatment benefits patients with coronavirus disease 2019 (COVID-19). This study aims to elucidate the mechanisms that underlie the anti-inflammatory effects of QFPDD.
{"title":"Network Pharmacology Elucidates the Anti-Inflammatory Mechanisms of QingFeiPaiDu Decoction for Treatment of COVID-19","authors":"Yan Liu, L. Xiong, Yanyu Wang, Maohui Luo, Longfei Zhang, Yongqing Zhang","doi":"10.14218/jerp.2021.00011","DOIUrl":"https://doi.org/10.14218/jerp.2021.00011","url":null,"abstract":"QingFeiPaiDu decoction (QFPDD) treatment benefits patients with coronavirus disease 2019 (COVID-19). This study aims to elucidate the mechanisms that underlie the anti-inflammatory effects of QFPDD.","PeriodicalId":73746,"journal":{"name":"Journal of exploratory research in pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48595875","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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