Ying Xu, Jian Tang, Binbin Yuan, Xuemei Luo, Pei Liang, Ning Liu, Danjiang Dong, Lu Jin, Weihong Ge, Qin Gu
To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.
{"title":"A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime-avibactam in a case series of critically ill patients with augmented renal clearance.","authors":"Ying Xu, Jian Tang, Binbin Yuan, Xuemei Luo, Pei Liang, Ning Liu, Danjiang Dong, Lu Jin, Weihong Ge, Qin Gu","doi":"10.1002/prp2.1163","DOIUrl":"10.1002/prp2.1163","url":null,"abstract":"<p><p>To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/C<sub>T</sub> ratio of AVI >1 (equivalent to 100% fT > C<sub>T</sub> 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040283","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}
Iris Lim, Taishi Masutani, Hikaru Hashitani, Russ Chess-Williams, Donna Sellers
The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 μM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 μM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 μM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 μM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.
{"title":"Inhibition of PDE-4 isoenzyme attenuates frequency and overall contractility of agonist-evoked ureteral phasic contractions.","authors":"Iris Lim, Taishi Masutani, Hikaru Hashitani, Russ Chess-Williams, Donna Sellers","doi":"10.1002/prp2.1175","DOIUrl":"10.1002/prp2.1175","url":null,"abstract":"<p><p>The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 μM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 μM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 μM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 μM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.</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/PMC10858371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139712810","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}
Tereza Tykvartova, Matus Miklovic, Martin Kotrc, Petra Skaroupkova, Ludmila Kazdova, Jaroslava Trnovska, Vojtech Skop, Michal Kolar, Jiri Novotny, Vojtech Melenovsky
While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.
{"title":"The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload.","authors":"Tereza Tykvartova, Matus Miklovic, Martin Kotrc, Petra Skaroupkova, Ludmila Kazdova, Jaroslava Trnovska, Vojtech Skop, Michal Kolar, Jiri Novotny, Vojtech Melenovsky","doi":"10.1002/prp2.1172","DOIUrl":"10.1002/prp2.1172","url":null,"abstract":"<p><p>While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139569509","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}
Human organs-on-chips (organ chips) are small microfluidic devices that allow human cells to perform complex organ-level functions in vitro by recreating multi-cellular and multi-tissue structures and applying in vivo-like biomechanical cues. Human Organ Chips are being used for drug discovery and toxicology testing as an alternative to animal models which are ethically challenging and often do not predict clinical efficacy or toxicity. In this mini-review, we summarize our presentation that reviewed the state of the art relating to these microfluidic culture devices designed to mimic specific human organ structures and functions, and the application of Organ Chips to regenerative pharmacology.
{"title":"Human organ chips for regenerative pharmacology.","authors":"Girija Goyal, Chaitra Belgur, Donald E Ingber","doi":"10.1002/prp2.1159","DOIUrl":"10.1002/prp2.1159","url":null,"abstract":"<p><p>Human organs-on-chips (organ chips) are small microfluidic devices that allow human cells to perform complex organ-level functions in vitro by recreating multi-cellular and multi-tissue structures and applying in vivo-like biomechanical cues. Human Organ Chips are being used for drug discovery and toxicology testing as an alternative to animal models which are ethically challenging and often do not predict clinical efficacy or toxicity. In this mini-review, we summarize our presentation that reviewed the state of the art relating to these microfluidic culture devices designed to mimic specific human organ structures and functions, and the application of Organ Chips to regenerative pharmacology.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040285","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}
TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.
{"title":"The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity.","authors":"Wen-Dong Xu, Shui-Zheng Lai, Jia Zhao, Shi-Jie Wei, Xue-Ying Fang, Yi-Yi Liu, Xiang-Lu Rong, Jiao Guo","doi":"10.1002/prp2.1160","DOIUrl":"10.1002/prp2.1160","url":null,"abstract":"<p><p>TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139088003","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}
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.
{"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":2.9,"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}
Seungmin Ham, Saori Mukaida, Masaaki Sato, Peter Keov, Tore Bengtsson, Sebastian Furness, Nicholas D Holliday, Bronwyn A Evans, Roger J Summers, Dana S Hutchinson
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.
{"title":"Role of G protein-coupled receptor kinases (GRKs) in β<sub>2</sub> -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 β<sub>2</sub> -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 β<sub>2</sub> -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 β<sub>2</sub> -ARs were generated and receptor affinity for [<sup>3</sup> H]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β<sub>2</sub> -AR agonists, cAMP accumulation, GLUT4 translocation, [<sup>3</sup> H]-2-deoxyglucose uptake, and β<sub>2</sub> -AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β<sub>2</sub> -AR and β-arrestin2 or between β<sub>2</sub> -AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β<sub>2</sub> -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 β<sub>2</sub> -AR agonists occurred in CHO-GLUT4myc cells expressing β<sub>2</sub> -ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type β<sub>2</sub> -AR. However, β<sub>2</sub> -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 β<sub>2</sub> -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}
Monkeypox (mpox), a virus belonging to the orthopoxvirus family, can cause a zoonotic infectious disease with morbidity and cosmetic complications. Therefore, effective antiviral drugs with appropriate safety profiles are important for the treatment of patients with mpox. To date, there is no FDA-approved drug for the treatment of mpox. However, tecovirimat, brincidofovir, and cidofovir are the candidate therapies for the management of mpox. Given the safety concerns following the use of these medications, we aimed to review evidence on the clinical considerations of mpox antiviral medications that will be useful to guide clinicians in the treatment approach. Based on the current evidence, tecovirimat has favorable clinical efficacy, safety, and side effect profile and it can be considered as first-line treatment for mpox.
{"title":"Clinical considerations on monkeypox antiviral medications: An overview.","authors":"Fariba Pourkarim, Taher Entezari-Maleki","doi":"10.1002/prp2.1164","DOIUrl":"10.1002/prp2.1164","url":null,"abstract":"<p><p>Monkeypox (mpox), a virus belonging to the orthopoxvirus family, can cause a zoonotic infectious disease with morbidity and cosmetic complications. Therefore, effective antiviral drugs with appropriate safety profiles are important for the treatment of patients with mpox. To date, there is no FDA-approved drug for the treatment of mpox. However, tecovirimat, brincidofovir, and cidofovir are the candidate therapies for the management of mpox. Given the safety concerns following the use of these medications, we aimed to review evidence on the clinical considerations of mpox antiviral medications that will be useful to guide clinicians in the treatment approach. Based on the current evidence, tecovirimat has favorable clinical efficacy, safety, and side effect profile and it can be considered as first-line treatment for mpox.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040284","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}
Periodontal ligament stem cells (PDLSCs) are important mesenchymal stem cells contributing to regenerating lost periodontal tissues and repairing bone defects. Studies on the molecular mechanism affecting the osteogenic differentiation of PDLSCs are necessary. Scopolamine (SCO) is known as a regulator of neural cell damage. The focus of the current study is on unveiling the role of SCO-mediated molecular mechanism in the osteogenic differentiation of PDLSCs. Through CCK-8 assay and LDH detection, we confirmed that SCO enhanced the viability of PDLSCs. Moreover, we determined that SCO induced the PDLSCs osteogenic differentiation, according to data of ALP activity measurement and ARS staining. Mechanistically, we performed western blot and identified that SCO could promote the lactylation of runt-related transcription factor 2 (RUNX2). We also found through rescue assays that knockdown of RUNX2 could reverse the effect of SCO treatment on the osteogenic differentiation of PDLSCs. Further mechanism investigation revealed that lactylation of RUNX2 at K176 site enhances the protein stability of RUNX2 through deubiquitination. Collectively, our present study unveils that SCO stabilizes RUNX2 to promote the osteogenic differentiation of PDLSCs through the lactylation modification of RUNX2.
{"title":"Scopolamine regulates the osteogenic differentiation of human periodontal ligament stem cells through lactylation modification of RUNX2 protein.","authors":"Ying Wu, Pan Gong","doi":"10.1002/prp2.1169","DOIUrl":"10.1002/prp2.1169","url":null,"abstract":"<p><p>Periodontal ligament stem cells (PDLSCs) are important mesenchymal stem cells contributing to regenerating lost periodontal tissues and repairing bone defects. Studies on the molecular mechanism affecting the osteogenic differentiation of PDLSCs are necessary. Scopolamine (SCO) is known as a regulator of neural cell damage. The focus of the current study is on unveiling the role of SCO-mediated molecular mechanism in the osteogenic differentiation of PDLSCs. Through CCK-8 assay and LDH detection, we confirmed that SCO enhanced the viability of PDLSCs. Moreover, we determined that SCO induced the PDLSCs osteogenic differentiation, according to data of ALP activity measurement and ARS staining. Mechanistically, we performed western blot and identified that SCO could promote the lactylation of runt-related transcription factor 2 (RUNX2). We also found through rescue assays that knockdown of RUNX2 could reverse the effect of SCO treatment on the osteogenic differentiation of PDLSCs. Further mechanism investigation revealed that lactylation of RUNX2 at K176 site enhances the protein stability of RUNX2 through deubiquitination. Collectively, our present study unveils that SCO stabilizes RUNX2 to promote the osteogenic differentiation of PDLSCs through the lactylation modification of RUNX2.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10804664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521603","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}
Kartheek Sooda, Simon J. Allison, Farideh A. Javid
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.
{"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 CB<sub>1</sub> and CB<sub>2</sub> 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 CB<sub>1</sub> or CB<sub>2</sub> receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB<sub>1</sub> 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}