Pharmacology Research & Perspectives最新文献

{"title":"Decreased hepatic enzymes reflect the decreased vitamin B6 levels in Parkinson's disease patients.","authors":"Kensuke Ikenaka, Yuta Kajiyama, César Aguirre, Chi-Jing Choong, Seira Taniguchi, Junko Doi, Nan Wang, Takahiro Ajiki, Kotaro Ogawa, Keita Kakuda, Yasuyoshi Kimura, Hideki Mochizuki","doi":"10.1002/prp2.1174","DOIUrl":"10.1002/prp2.1174","url":null,"abstract":"<p><p>The study aims to investigate the vitamin B6 levels in Parkinson's disease (PD) patients and their association with liver enzymes and evaluate how much dysregulation is associated with levodopa dose. Furthermore, to evaluate the effect of Opicapone, a catechol-o-methyl-transferase inhibitor, on vitamin B6 levels by monitoring the AST and ALT levels in patients treated with Levodopa-Carbidopa Intestinal Gel Infusion (LCIG). For these aims, serum vitamin B6 levels were measured (PD, n = 72 and controls, n = 31). The vitamin B6 level was compared with the total levodopa dose, clinical parameters, and blood homocysteine, albumin, and hemoglobin levels in PD patients. Correlations between vitamin B6 levels and AST and ALT levels, as well as the ratio ALT/AST, were analyzed. Changes in the AST and ALT levels and ALT/AST were analyzed in the patients treated with LCIG before and after the therapy (n = 24) and in the patients treated with LCIG + Opicapone before and after Opicapone treatment (n = 12). We found vitamin B6 levels were significantly lower in PD patients. Total levodopa dose and albumin levels were independently associated with vitamin B6 levels. Decreased vitamin B6 levels appeared as lower AST and ALT levels and ALT/AS. Treatment with LCIG decreased the AST and ALT levels and ALT/AST. Adjunctive therapy with Opicapone to LCIG ameliorated the decreased ALT and ALT/AST. We conclude that the ALT and ALT/AST can be useful parameters for monitoring vitamin B6 levels and Opicapone can ameliorate the dysregulated vitamin B6 in PD patients.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of G protein-coupled receptor kinases (GRKs) in β₂ -adrenoceptor-mediated glucose uptake.","authors":"Seungmin Ham, Saori Mukaida, Masaaki Sato, Peter Keov, Tore Bengtsson, Sebastian Furness, Nicholas D Holliday, Bronwyn A Evans, Roger J Summers, Dana S Hutchinson","doi":"10.1002/prp2.1176","DOIUrl":"10.1002/prp2.1176","url":null,"abstract":"<p><p>Truncation of the C-terminal tail of the β₂ -AR, transfection of βARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β₂ -AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant β₂ -ARs were generated and receptor affinity for [³ H]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β₂ -AR agonists, cAMP accumulation, GLUT4 translocation, [³ H]-2-deoxyglucose uptake, and β₂ -AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β₂ -AR and β-arrestin2 or between β₂ -AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β₂ -AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to β₂ -AR agonists occurred in CHO-GLUT4myc cells expressing β₂ -ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type β₂ -AR. However, β₂ -ARs lacking phosphorylation sites failed to recruit β-arrestin2 and did not internalize. GRK2 knock-down or GRK2 inhibitors decreased isoprenaline-stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the β₂ -AR is not associated with isoprenaline- or BRL37344-stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock-down or GRK2 inhibition reduces isoprenaline-stimulated glucose uptake.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10853676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139707430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the cytotoxicity induced by cannabinoids on human ovarian carcinoma cells","authors":"Kartheek Sooda, Simon J. Allison, Farideh A. Javid","doi":"10.1002/prp2.1152","DOIUrl":"https://doi.org/10.1002/prp2.1152","url":null,"abstract":"Cannabinoids have been shown to induce anti-tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti-tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non-carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB₁ and CB₂ receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB₁ or CB₂ receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB₁ receptor activity in cisplatin-resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138714382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-created in vivo pharmacology practical classes using the novel organism Lumbriculus variegatus","authors":"Julanta J. Carriere, Nia A. Davies, Margaret R. Cunningham, Melisa J. Wallace, Aidan Seeley","doi":"10.1002/prp2.1158","DOIUrl":"https://doi.org/10.1002/prp2.1158","url":null,"abstract":"Co-creation within higher education emphasizes learner empowerment to promote collaboration between the students and staff, enabling students to become active participants in their learning process and the construction of resources with academic staff. Concurrently, a diminishing number of higher education institutions offer in vivo practical classes, resulting in an in vivo skills shortage. To address this, and to actively engage students in their own learning, we describe the co-creation of a student-led drug trial using <i>Lumbriculus variegatus</i>. Under blinded conditions, final-year undergraduate biomedical science students, under the tutelage of academic staff and fellow students, were involved in the co-creation of an in vivo practical class to determine the effects of histamine and histamine receptor inverse agonists mepyramine and loratadine. Throughout this process, undergraduate- and masters-level students played key roles in every aspect of practical delivery and data analysis. Herein, students demonstrated the test compounds, both in isolation and in combination, resulted in reduced stereotypical movements of <i>L. variegatus</i> (<i>p</i> &lt; .05, <i>n</i> ≥ 6). 15% of students in the class responded to a feedback survey (<i>n</i> = 8) after the class. Students reported the class provided “<i>real life</i>” insights into in vivo research and enabled the development of hands-on skills which would be useful in applying in their future careers. All students reported that they enjoyed the class with 25% (<i>n</i> = 2) reporting concerns about animal use in research, enabling useful discussions about animals in research. Moreover, these student-led in vivo trials add to the pharmacological knowledge of <i>L. variegatus</i> promoting education-led research.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138554935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating signaling bias for synthetic cannabinoid receptor agonists at the cannabinoid CB₂ receptor.","authors":"Monica Patel, Natasha L Grimsey, Samuel D Banister, David B Finlay, Michelle Glass","doi":"10.1002/prp2.1157","DOIUrl":"10.1002/prp2.1157","url":null,"abstract":"<p><p>The rapid structural evolution and emergence of novel synthetic cannabinoid receptor agonists (SCRAs) in the recreational market remains a key public health concern. Despite representing one of the largest classes of new psychoactive substances, pharmacological data on new SCRAs is limited, particularly at the cannabinoid CB₂ receptor (CB₂ ). Hence, the current study aimed to characterize the molecular pharmacology of a structurally diverse panel of SCRAs at CB₂ , including 4-cyano MPP-BUT7AICA, 4F-MDMB-BUTINACA, AMB-FUBINACA, JWH-018, MDMB-4en-PINACA, and XLR-11. The activity of SCRAs was assessed in a battery of in vitro assays in CB₂ -expressing HEK 293 cells: G protein activation (Gα_i3 and Gα_oB ), phosphorylation of ERK1/2, and β-arrestin 1/2 translocation. The activity profiles of the ligands were further evaluated using the operational analysis to identify ligand bias. All SCRAs activated the CB₂ signaling pathways in a concentration-dependent manner, although with varying potencies and efficacies. Despite the detection of numerous instances of statistically significant bias, compound activities generally appeared only subtly distinct in comparison with the reference ligand, CP55940. In contrast, the phytocannabinoid THC exhibited an activity profile distinct from the SCRAs; most notably in the translocation of β-arrestins. These findings demonstrate that CB₂ is able to accommodate a structurally diverse array of SCRAs to generate canonical agonist activity. Further research is required to elucidate whether the activation of CB₂ contributes to the toxicity of these compounds.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10685394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental pharmacology in precision medicine.","authors":"Alicja Urbaniak, Kenneth E Thummel, Ayoade N Alade, Allan E Rettie, Bhagwat Prasad, Amedeo De Nicolò, Jennifer H Martin, David N Sheppard, Michael F Jarvis","doi":"10.1002/prp2.1147","DOIUrl":"10.1002/prp2.1147","url":null,"abstract":"","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time to treat the climate and nature crisis as one indivisible global health emergency.","authors":"Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski","doi":"10.1002/prp2.1156","DOIUrl":"10.1002/prp2.1156","url":null,"abstract":"","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138299822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of an escape room based on general pharmacokinetics: Students' perceptions of its motivational climate.","authors":"Anneke van Houwelingen, Freija Ter Heegde, Wendy Boschloo, Leonie Piek, Theo Wubbels","doi":"10.1002/prp2.1155","DOIUrl":"10.1002/prp2.1155","url":null,"abstract":"<p><p>We designed an escape room based on the basic principles of pharmacokinetics for undergraduate bachelor students and explored its effect on students' perceived motivational climate and usefulness as a formative assessment via a mixed-method design. The effect on students' perceptions of the motivational climate was measured using pre- and post-test measurements of the MUSIC® inventory. Students' experiences with the escape room and suggestions for improvement were collected by open-ended survey questions. Forty-one students initially joined the study while 28 students completed both the pre- and post-test MUSIC® inventory. Data from the MUSIC® inventory revealed the effect of playing the escape room on students' situational interest was positive with medium to large effect (Cohen's d_av  = 0.63). Data from the open-ended questions confirmed the outcome of the MUSIC® inventory. While there was a positive effect on situational interest, students found the escape room not very useful as a tool for formative assessment. Further research should include a control group and focus on the effect of the escape room on academic success and work toward increasing the capacity of the escape room for large-scale courses.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review of knowledge, attitude and practice of pharmacogenomics in pediatric oncology patients.","authors":"Claire Moore, Smaro Lazarakis, Tayla Stenta, Marliese Alexander, Rachel Phan Nguyen, David A Elliott, Rachel Conyers","doi":"10.1002/prp2.1150","DOIUrl":"10.1002/prp2.1150","url":null,"abstract":"<p><p>Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10682497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138445694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative analysis of the UDP-glucuronosyltransferase transcriptome in human tissues.","authors":"Lucas Zhou, Abelardo D Montalvo, Joseph M Collins, Danxin Wang","doi":"10.1002/prp2.1154","DOIUrl":"10.1002/prp2.1154","url":null,"abstract":"<p><p>UDP-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that play important roles in the detoxification of endogenous and exogenous substrates. The 22 human UGTs belong to four families (UGT1, UGT2, UGT3, and UGT8) and differ in their expression, substrate specificity, UDP-sugar preference, and physiological functions. Differential expression/activity of the UGTs contributes to interperson variability in drug responses and toxicity, hormone homeostasis, and disease/cancer risks. However, in normal tissues, the tissue-specific expression profiles and transcriptional regulation of the UGTs are still not fully understood. In this study, we comprehensively analyzed the transcriptome of 22 UGTs in 54 human tissues/regions using RNAseq data from GTEx. We then validated the findings in the liver and small intestine samples using real-time PCR. Our results showed large interindividual variability across tissues in the expression of each UGT and the overall composition of UGT pools, consisting of different UGTs and their splice isoforms. Our results also revealed coexpression of the UGTs, Cytochrome P450s, and many transcription factors in the liver, suggesting potential coregulation or functional coordination. Our results provide the groundwork for future studies to detail further the regulation of the expression and activity of the UGTs.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}