This work was aimed to establish a quality control method for evaluating the effects on glucose and lipids of the fruiting body of Isaria cicadae Miquel from strain Ic-17-7(Ic-17-7fb) using a rat model of type 2 diabe...This work was aimed to establish a quality control method for evaluating the effects on glucose and lipids of the fruiting body of Isaria cicadae Miquel from strain Ic-17-7(Ic-17-7fb) using a rat model of type 2 diabetes(T2DM). Random amplified polymorphic DNA, sequence-characterized amplified region, and high-performance liquid chromatography(HPLC) were used for the quality control of Ic-17-7fb. The pharmacological effects on streptozocin(STZ)-induced high fat diet(HFD)-fed Albino Wistar rats were evaluated. The rats underwent the following treatments: control, metformin, Ic-17-7fb(0.166 and 0.5 g·kg;) or without treatment. The fasting blood glucose(FBG), blood glucose, total cholesterol(TC), triglyceride(TG), high-density lipoprotein(HDL-c), and low-density lipoprotein(LDL-c) were measured. Ic-17-7fb amplified a single specific band by S11-2-F3 and S11-2-R3 primers. An HPLC-based quality and quantity method was established for industrial application. The contents of adenosine and N;-(2-hydroxyethyl) adenosine(HEA) of the cultivated Ic-17-7fb were analyzed. All of the validation lots of cultured Ic-17-7fb passed the quantity control of the training set(0.90 mg·g;of adenosine and 0.89 mg·g;of HEA). After two weeks of administration, the average FBG was 4.89 ± 0.42(control), 26.10 ± 5.77(model), 23.63 ± 6.15(metformin), 17.96 ± 9.36(Ic-17-7fb for 0.166 g·kg;), and 19.69 ±8.71 mmol·L;(Ic-17-7fb for 0.5 g·kg;). The FBG of Ic-17-7fb(0.166 g·kg;) treatment significantly reduced by 31.19%, compared with the model after two weeks of administration(P < 0.01). Metformin, Ic-17-7fb(0.166 g·kg;), and Ic-17-7fb(0.5 g·kg;) reduced TC, TG, HDL-c, and LDL-c compared with the T2DM model treatment at the 6 th week of treatment(P < 0.05). This study established the first quality standard for Ic-17-7fb, which can be effectively applied in the treatment of T2DM. The reliable quality control method and pharmacological effect will broaden its application space.展开更多
Recent insights collectively suggest the important roles of lysyl oxidase(LysOX)in the pathological processes of several acute and chronic neurological diseases,but the molecular regulatory mechanisms remain elusive.H...Recent insights collectively suggest the important roles of lysyl oxidase(LysOX)in the pathological processes of several acute and chronic neurological diseases,but the molecular regulatory mechanisms remain elusive.Herein,we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons.Mechanistically,LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase(ERK)-dependent 5-lipoxygenase(Alox5)signaling.In addition,overexpression of LysOX via adeno-associated viral vector(AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage.Our studies show that pharmacological inhibition of LysOX withβ-aminopropionitrile(BAPN)significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage,while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers.These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage.Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.展开更多
Individual variability in drug response(IVDR)can be a major cause of adverse drug reactions(ADRs)and prolonged therapy,resulting in a substantial health and economic burden.Despite extensive research in pharmacogenomi...Individual variability in drug response(IVDR)can be a major cause of adverse drug reactions(ADRs)and prolonged therapy,resulting in a substantial health and economic burden.Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics(PK)and pharmacodynamics(PD),genetic diversity explains only a limited proportion of IVDR.The role of gut microbiota,also known as the second genome,and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies.Consequently,the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs.This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases,including cancer,cardiovascular diseases(CVDs),endocrine diseases,and others.We summarise how microbiota,directly and indirectly,modify the absorption,distribution,metabolism,and excretion(ADME)of drugs.Conversely,drugs can also modulate the composition and function of gut microbiota,leading to changes in microbial metabolism and immune response.We also discuss the practical challenges,strategies,and opportunities in this field,emphasizing the critical need to develop an innovative approach to multi-omics,integrate various data types,including human and microbiota genomic data,as well as translate lab data into clinical practice.To sum up,pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes,and further research in this field is imperative to unlock its full potential for precision medicine.展开更多
To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma(NSCLC),we performed a two-cohort of genome-wide association studies(GWAS),including 34 for W...To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma(NSCLC),we performed a two-cohort of genome-wide association studies(GWAS),including 34 for WES-based and 433 for microarray-based analyses,as well as two independent validation cohorts.After integrating the results of two studies,the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples,and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments.We found that a total of 68 variations were significant at P<1×10^(-3)in cohort 1 discovery stage,of which 3 SNPs were verified in 262 independent samples.A total of541 SNPs were significant at P<1×10^(-4)in cohort 2 discovery stage,of which 8 SNPs were verified in 347 independent samples.Comparing the validated SNPs in two GWAS,ADCY1 gene was verified in both independent studies.The results of fine-mapping showed that the G allele carriers of ADCY1rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy.In conclusion,our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.展开更多
Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provide...Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.展开更多
Patients with coronavirus disease 2019 (COVID-19) often succumb to neurological manifestations such as loss of smell, headache, disturbed consciousness, seizure, and stroke. In a recent paper published in Nature, Yang...Patients with coronavirus disease 2019 (COVID-19) often succumb to neurological manifestations such as loss of smell, headache, disturbed consciousness, seizure, and stroke. In a recent paper published in Nature, Yang et al.[1] reported substantial cellular perturbations in the choroid plexus and cortex, notably an infiltration of peripheral T cells into the parenchyma and microglial activation and astrogliosis with distinct transcriptional profiles. These findings provide a complex view of the cellular and molecular processes underlying COVID-19-related neurological abnormalities.展开更多
基金supported by China Spark Program (No.2015GA700011)。
文摘This work was aimed to establish a quality control method for evaluating the effects on glucose and lipids of the fruiting body of Isaria cicadae Miquel from strain Ic-17-7(Ic-17-7fb) using a rat model of type 2 diabetes(T2DM). Random amplified polymorphic DNA, sequence-characterized amplified region, and high-performance liquid chromatography(HPLC) were used for the quality control of Ic-17-7fb. The pharmacological effects on streptozocin(STZ)-induced high fat diet(HFD)-fed Albino Wistar rats were evaluated. The rats underwent the following treatments: control, metformin, Ic-17-7fb(0.166 and 0.5 g·kg;) or without treatment. The fasting blood glucose(FBG), blood glucose, total cholesterol(TC), triglyceride(TG), high-density lipoprotein(HDL-c), and low-density lipoprotein(LDL-c) were measured. Ic-17-7fb amplified a single specific band by S11-2-F3 and S11-2-R3 primers. An HPLC-based quality and quantity method was established for industrial application. The contents of adenosine and N;-(2-hydroxyethyl) adenosine(HEA) of the cultivated Ic-17-7fb were analyzed. All of the validation lots of cultured Ic-17-7fb passed the quantity control of the training set(0.90 mg·g;of adenosine and 0.89 mg·g;of HEA). After two weeks of administration, the average FBG was 4.89 ± 0.42(control), 26.10 ± 5.77(model), 23.63 ± 6.15(metformin), 17.96 ± 9.36(Ic-17-7fb for 0.166 g·kg;), and 19.69 ±8.71 mmol·L;(Ic-17-7fb for 0.5 g·kg;). The FBG of Ic-17-7fb(0.166 g·kg;) treatment significantly reduced by 31.19%, compared with the model after two weeks of administration(P < 0.01). Metformin, Ic-17-7fb(0.166 g·kg;), and Ic-17-7fb(0.5 g·kg;) reduced TC, TG, HDL-c, and LDL-c compared with the T2DM model treatment at the 6 th week of treatment(P < 0.05). This study established the first quality standard for Ic-17-7fb, which can be effectively applied in the treatment of T2DM. The reliable quality control method and pharmacological effect will broaden its application space.
基金supported by the National Natural Science Foundation of China (No. 81974502 and 81671293)the Natural Science Foundation of Hunan Province (No. 2020JJ3061, China)the Hunan Provincial Department of Education Innovation Platform Open Fund Project (No. 17K100, China)
文摘Recent insights collectively suggest the important roles of lysyl oxidase(LysOX)in the pathological processes of several acute and chronic neurological diseases,but the molecular regulatory mechanisms remain elusive.Herein,we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons.Mechanistically,LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase(ERK)-dependent 5-lipoxygenase(Alox5)signaling.In addition,overexpression of LysOX via adeno-associated viral vector(AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage.Our studies show that pharmacological inhibition of LysOX withβ-aminopropionitrile(BAPN)significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage,while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers.These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage.Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.
基金the National Key Research and Development Program(No.2021YFA1301200)the National Scientific Foundation of China(No.82373961,82073945,82373960,and 81974513)the Natural Science Foundation of Hunan Province(grant2022JJ80113,2022JJ80097).
文摘Individual variability in drug response(IVDR)can be a major cause of adverse drug reactions(ADRs)and prolonged therapy,resulting in a substantial health and economic burden.Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics(PK)and pharmacodynamics(PD),genetic diversity explains only a limited proportion of IVDR.The role of gut microbiota,also known as the second genome,and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies.Consequently,the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs.This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases,including cancer,cardiovascular diseases(CVDs),endocrine diseases,and others.We summarise how microbiota,directly and indirectly,modify the absorption,distribution,metabolism,and excretion(ADME)of drugs.Conversely,drugs can also modulate the composition and function of gut microbiota,leading to changes in microbial metabolism and immune response.We also discuss the practical challenges,strategies,and opportunities in this field,emphasizing the critical need to develop an innovative approach to multi-omics,integrate various data types,including human and microbiota genomic data,as well as translate lab data into clinical practice.To sum up,pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes,and further research in this field is imperative to unlock its full potential for precision medicine.
基金supported by the National Key Research and Development Programs(2016YFC1306900 and 2017ZX09304014,China)National Natural Science Foundation of China(81573508,81874327,81773823,81803640 and 82073943,China)+3 种基金Fundamental Research Funds for the Central Universities of Central South University(2018zzts251,China)The StrategyOriented Special Project of Central South University in China(ZLXD2017003)Youth Science Foundation of Xiangya Hospital,Central South University(2017Q02,China)Hunan Cancer Hospital Climb Plan(YF2020011,China)。
文摘To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma(NSCLC),we performed a two-cohort of genome-wide association studies(GWAS),including 34 for WES-based and 433 for microarray-based analyses,as well as two independent validation cohorts.After integrating the results of two studies,the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples,and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments.We found that a total of 68 variations were significant at P<1×10^(-3)in cohort 1 discovery stage,of which 3 SNPs were verified in 262 independent samples.A total of541 SNPs were significant at P<1×10^(-4)in cohort 2 discovery stage,of which 8 SNPs were verified in 347 independent samples.Comparing the validated SNPs in two GWAS,ADCY1 gene was verified in both independent studies.The results of fine-mapping showed that the G allele carriers of ADCY1rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy.In conclusion,our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
基金funded by the National Natural Science Foundation of China(No.81974502 and 81671293)Natural Science Foundation of Hunan Province(No.2020JJ3061).
文摘Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.
基金supported by the National Natural Science Foundation of China(81671293 and 81974502)Natural Science Foundation of Hunan Province(2020JJ3061)。
文摘Patients with coronavirus disease 2019 (COVID-19) often succumb to neurological manifestations such as loss of smell, headache, disturbed consciousness, seizure, and stroke. In a recent paper published in Nature, Yang et al.[1] reported substantial cellular perturbations in the choroid plexus and cortex, notably an infiltration of peripheral T cells into the parenchyma and microglial activation and astrogliosis with distinct transcriptional profiles. These findings provide a complex view of the cellular and molecular processes underlying COVID-19-related neurological abnormalities.
