Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder resulting from a selective loss of dopaminergic neurons. The pathogenesis of PD remains incompletely understood, but increasing evidence f...Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder resulting from a selective loss of dopaminergic neurons. The pathogenesis of PD remains incompletely understood, but increasing evidence from human and animal studies has suggested that oxidative damage contributes to the neuronal loss in PD. In this study, we used rotenone (a mitochondrial complex I inhibitor) based cell and Drosophila models that resemble some key pathological features of PD to test whether curcumin, a potent antioxidant compound, derived from the curry spice turmeric, could protect against rotenone-induced neuronal toxicity. We found that curcumin reduced rotenone induced cell death in SH-SY5Y human neuroblastoma cells and alleviated PD-like symptoms in drosophila via reducing the intracellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting the caspase-3/caspase-9 activity. These results suggest that curcumin is a promising therapeutic compound for PD.展开更多
During the continuing evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November of that year.Along ...During the continuing evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November of that year.Along with its sublineages,it has maintained a prominent role ever since.The Nsp5 main protease(Mpro)of the Omicron virus is characterized by a single dominant mutation,P132H.Here we determined the X-ray crystal structures of the P132H mutant(or O-Mpro)as a free enzyme and in complex with the Mpro inhibitor,the alpha-ketoamide 13b-K,and we conducted enzymological,biophysical,as well as theoretical studies to characterize the O-Mpro.We found that O-Mpro has a similar overall structure and binding with 13b-K;however,it displays lower enzymatic activity and lower thermal stability compared to the WT-Mpro(with“WT”referring to the prototype strain).Intriguingly,the imidazole ring of His132 and the carboxylate plane of Glu240 are in a stacked configuration in the X-ray structures determined here.Empirical folding free energy calculations suggest that the O-Mpro dimer is destabilized relative to the WT-Mpro due to less favorable van der Waals interactions and backbone conformations in the individual protomers.All-atom continuous constant-pH molecular dynamics(MD)simulations reveal that His132 and Glu240 display coupled titration.At pH 7,His132 is predominantly neutral and in a stacked configuration with respect to Glu240 which is charged.In order to examine whether the Omicron mutation eases the emergence of further Mpro mutations,we also analyzed the P132H+T169S double mutant,which is characteristic of the BA.1.1.2 lineage.However,we found little evidence of a correlation between the two mutation sites.展开更多
The constitutive androstane receptor （CAR, NRll3） plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target gen...The constitutive androstane receptor （CAR, NRll3） plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent （indirect） mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mecha- nisms yet to be fully understood. Accumulating evi- dence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be func- tionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our under- standing of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation.展开更多
Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide vari...Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.展开更多
We examined persistence in seven common preventive health practices for a nationally representative sample of Medicare beneficiaries over 4-year observation periods. Six panels from the 1997-2005 Medicare Current Bene...We examined persistence in seven common preventive health practices for a nationally representative sample of Medicare beneficiaries over 4-year observation periods. Six panels from the 1997-2005 Medicare Current Beneficiary Survey (MCBS) were used resulting in 13,913 unique individuals with ages ranging from below 65 (disabled) to over 80 years old. Persistence in behavior was defined as the proportion of the observation period beneficiaries participated in each activity. We estimated behavioral persistence as a function of baseline demographic, socioeconomic, and health characteristics using multivariate regression analysis. Beneficiaries were most persistent in smoking abstinence (81% reported not smoking) and least persistent with routine exercise (47% reporting none). From multivariate regression results, there was greater persistence among beneficiaries who were married when compared to those living alone (p 300% FPL compared to <100% FPL all p < 0.01). Increasing age (greater than 80 compared to 65 - 69) was associated with increased compliance in influenza vaccination and smoking cessation (p < 0.01) while negatively associated with weekly exercise and cancer screenings (p < 0.01). Medicare beneficiaries are inconsistently persistent with common preventive health practices.展开更多
Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leu...Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.展开更多
Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed.The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has...Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed.The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme.The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor(CAR) and pregnane X receptor(PXR) in the liver.In addition to CYP2B6,these receptors also mediate the inductive expression of CYP3A4,and a number of important phase II enzymes and drug transporters.CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide,anesthetics propofol and ketamine,synthetic opioids pethidine and methadone,and the antiretrovirals nevirapine and efavirenz,among others.Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs.These variances arise from a number of sources including genetic polymorphism,and xenobiotic intervention.In this review,we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions.展开更多
文摘Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder resulting from a selective loss of dopaminergic neurons. The pathogenesis of PD remains incompletely understood, but increasing evidence from human and animal studies has suggested that oxidative damage contributes to the neuronal loss in PD. In this study, we used rotenone (a mitochondrial complex I inhibitor) based cell and Drosophila models that resemble some key pathological features of PD to test whether curcumin, a potent antioxidant compound, derived from the curry spice turmeric, could protect against rotenone-induced neuronal toxicity. We found that curcumin reduced rotenone induced cell death in SH-SY5Y human neuroblastoma cells and alleviated PD-like symptoms in drosophila via reducing the intracellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting the caspase-3/caspase-9 activity. These results suggest that curcumin is a promising therapeutic compound for PD.
基金Financial support from the German Center for Infection Research(DZIFproject FF 01.905,to R.H.)+1 种基金the National Institutes of Health(R35GM148261 to J.S.)is gratefully acknowledged.R.H.is also supported by the Government of Schleswig-Holstein through its StructureExcellence Fund as well as by a close partnership between the Possehl Foundation(Lübeck)and the University of Lübeck.
文摘During the continuing evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November of that year.Along with its sublineages,it has maintained a prominent role ever since.The Nsp5 main protease(Mpro)of the Omicron virus is characterized by a single dominant mutation,P132H.Here we determined the X-ray crystal structures of the P132H mutant(or O-Mpro)as a free enzyme and in complex with the Mpro inhibitor,the alpha-ketoamide 13b-K,and we conducted enzymological,biophysical,as well as theoretical studies to characterize the O-Mpro.We found that O-Mpro has a similar overall structure and binding with 13b-K;however,it displays lower enzymatic activity and lower thermal stability compared to the WT-Mpro(with“WT”referring to the prototype strain).Intriguingly,the imidazole ring of His132 and the carboxylate plane of Glu240 are in a stacked configuration in the X-ray structures determined here.Empirical folding free energy calculations suggest that the O-Mpro dimer is destabilized relative to the WT-Mpro due to less favorable van der Waals interactions and backbone conformations in the individual protomers.All-atom continuous constant-pH molecular dynamics(MD)simulations reveal that His132 and Glu240 display coupled titration.At pH 7,His132 is predominantly neutral and in a stacked configuration with respect to Glu240 which is charged.In order to examine whether the Omicron mutation eases the emergence of further Mpro mutations,we also analyzed the P132H+T169S double mutant,which is characteristic of the BA.1.1.2 lineage.However,we found little evidence of a correlation between the two mutation sites.
文摘The constitutive androstane receptor （CAR, NRll3） plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent （indirect） mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mecha- nisms yet to be fully understood. Accumulating evi- dence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be func- tionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our under- standing of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation.
文摘Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.
文摘We examined persistence in seven common preventive health practices for a nationally representative sample of Medicare beneficiaries over 4-year observation periods. Six panels from the 1997-2005 Medicare Current Beneficiary Survey (MCBS) were used resulting in 13,913 unique individuals with ages ranging from below 65 (disabled) to over 80 years old. Persistence in behavior was defined as the proportion of the observation period beneficiaries participated in each activity. We estimated behavioral persistence as a function of baseline demographic, socioeconomic, and health characteristics using multivariate regression analysis. Beneficiaries were most persistent in smoking abstinence (81% reported not smoking) and least persistent with routine exercise (47% reporting none). From multivariate regression results, there was greater persistence among beneficiaries who were married when compared to those living alone (p 300% FPL compared to <100% FPL all p < 0.01). Increasing age (greater than 80 compared to 65 - 69) was associated with increased compliance in influenza vaccination and smoking cessation (p < 0.01) while negatively associated with weekly exercise and cancer screenings (p < 0.01). Medicare beneficiaries are inconsistently persistent with common preventive health practices.
文摘Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.
基金supported by research grants from the U.S. National Institute of Health (DK061652 and GM107058)
文摘Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed.The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme.The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor(CAR) and pregnane X receptor(PXR) in the liver.In addition to CYP2B6,these receptors also mediate the inductive expression of CYP3A4,and a number of important phase II enzymes and drug transporters.CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide,anesthetics propofol and ketamine,synthetic opioids pethidine and methadone,and the antiretrovirals nevirapine and efavirenz,among others.Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs.These variances arise from a number of sources including genetic polymorphism,and xenobiotic intervention.In this review,we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions.
