“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging...“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.展开更多
Alzheimer's disease(AD),the leading cause of dementia,remains a formidable challenge to neurology.Despite decades of research focused on amyloid-β(Aβ)and tau pathologies,most clinical trials targeting these mole...Alzheimer's disease(AD),the leading cause of dementia,remains a formidable challenge to neurology.Despite decades of research focused on amyloid-β(Aβ)and tau pathologies,most clinical trials targeting these molecules failed,highlighting the need for alternative strategies[1].Recent attention has turned to neuroinflammation,particularly the role of microglia,the brain's resident immune cells[1].Microglia are central to AD progression.They can degrade Aβplaques and protect neurons,but may also exacerbate neurotoxicity through chronic inflammation[1].展开更多
Although posttraumatic stress disorder(PTSD)is on the rise,traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself.Traumatic experiences can be broadly class...Although posttraumatic stress disorder(PTSD)is on the rise,traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself.Traumatic experiences can be broadly classified into mental stress(MS)and traumatic brain injury(TBI),but the cellular mechanisms of MS-or TBI-induced PTSD remain unknown.Recent evidence has shown that the morphological remodeling of astrocytes accompanies and arguably contributes to fearful memories and stressrelated disorders.In this review,we summarize the roles of astrocytes in the pathogenesis of MS-PTSD and TBIPTSD.Astrocytes synthesize and secrete neurotrophic,proand anti-inflammatory factors and regulate the microenvironment of the nervous tissue through metabolic pathways,ionostatic control,and homeostatic clearance of neurotransmitters.Stress or trauma-associated impairment of these vital astrocytic functions contribute to the pathophysiological evolution of PTSD and may present therapeutic targets.展开更多
The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervo...The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man.The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured(in invertebrates)by septate junctions.展开更多
<strong>Background:</strong> Hydrolysis improves the sensitivity of drug detection for drug classes such as opiates/opioids and benzodiazepines, which are highly metabolized by glucuronidation and sulfatio...<strong>Background:</strong> Hydrolysis improves the sensitivity of drug detection for drug classes such as opiates/opioids and benzodiazepines, which are highly metabolized by glucuronidation and sulfation and should be implemented in analytical procedures to convert conjugated metabolites into the free or unbound form. This study was aimed to compare different enzymes to make an informed decision. <strong>Methods:</strong> In this study, the CEDIA Benzodiazepine assay was compared with the LC-MS-MS method using 150 positive urine samples and 50 negative urine samples. The samples were analysed without adding any enzyme and then by adding different enzymes to compare their performance.<strong> Results: </strong>The Kura <em>Escherichia coli</em> enzyme performed better than the Roche <em>Escherichia coli </em>enzyme which had 20% false-positive results. Kura BG-100 enzyme performed well but Kura B-One enzyme performed better The Kura B-One enzyme had only 11.5% false-positive results. When double the volume of Kura B-One enzyme was used to test to see if it will have any impact on reducing the number of false negatives, it performed worse. Kura Turbo enzyme behaved similarly to Kura BG-100. <strong>Conclusions: </strong>The <em>β</em>-glucuronidase enzymes comparison allowed us to identify the Kura B-One enzyme as the enzyme of choice for our operation because it reduces the false positives from 20% to 11.5% when compared with the Roche enzyme. It also improved the detection of oxazepam. The Kura B-One enzyme has a short incubation time for hydrolysis when used with the LC-MS-MS method. As a result, we improved the overall turn-around time and reduced the number of false positives that needed confirmation.展开更多
Worldwide,the incidence of major depressive disorder(MDD)is increasing annually,resulting in greater economic and social burdens.Moreover,the pathological mechanisms of MDD and the mechanisms underlying the effects of...Worldwide,the incidence of major depressive disorder(MDD)is increasing annually,resulting in greater economic and social burdens.Moreover,the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear,and additional diagnostic and therapeutic strategies for MDD still are needed.The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis,hypothalamicpituitary-adrenal(HPA)axis hypothesis,cytokine hypothesis,neuroplasticity hypothesis and systemic influence hypothesis,but these hypothesis cannot completely explain the pathological mechanism of MDD.Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD,thus in recent years,great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies,further revealing the disease features of MDD.Furthermore,some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention,some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms.In this work,we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD,preventive approaches and therapeutic medicines,as well as the related clinical trials.展开更多
Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system(CNS).Astroglia contribute to the pathophysiology of all neurological and neuropsych...Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system(CNS).Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome.Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions.Astroglia respond to external,non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure,molecular expression,and function.In addition,internally driven,cell autonomous changes of astroglial innate properties can lead to CNS pathologies.Astroglial pathophysiology is complex,with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder,disorder-stage,comorbidities,age,and sex.Here,we classify astroglial pathophysiology into(i)reactive astrogliosis,(ii)astroglial atrophy with loss of function,(iii)astroglial degeneration and death,and(iv)astrocytopathies characterised by aberrant forms that drive disease.We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders,including neurotrauma,stroke,neuroinfection,autoimmune attack and epilepsy,as well as neurodevelopmental,neurodegenerative,metabolic and neuropsychiatric disorders.Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.展开更多
Drug-facilitated sexual assault(DFSA)is a sexual act in which the victim is unable to give or rescind consent due to alcohol or drug intoxication,which involved the abuse of benzodiazepines around the world.Convention...Drug-facilitated sexual assault(DFSA)is a sexual act in which the victim is unable to give or rescind consent due to alcohol or drug intoxication,which involved the abuse of benzodiazepines around the world.Conventional techniques used for the analysis of benzodiazepines have the limitation of short detection time window due to the rapid metabolism of these drugs in body.This study aimed to investigate the characteristic changes of metabolites in the blood of rats after ingesting diazepam/clonazepam through a gas chromatography-mass spectrometry-based metabolomics method,allowing the indirect reveal of the rats ingested diazepam/clonazepam.First,we found that diazepam and clonazepam in the blood of rats could not be detected by liquid chromatography-tandem mass spectrometry after 48 h of ingestion.Then,orthogonal partial least squares discrimination analysis regression models were,respectively,constructed to determine whether the rats ingested diazepam/clonazepam after 48 h.The results showed that 5 metabolites were found to be associated with diazepam exposure,and 7 metabolites were found to be associated with clonazepam exposure,which may be characterization for the evaluation of digestion of diazepam and clonazepam in rat.展开更多
The hook effect is best explained by how the analyte signal generated from the assay is compromised due to either antibody excess or antigen excess.Reporting false negatives can also impact clinical decisions that may...The hook effect is best explained by how the analyte signal generated from the assay is compromised due to either antibody excess or antigen excess.Reporting false negatives can also impact clinical decisions that may have adverse effects on the patient.The clinical impact of the hook effect will lead to reporting either inaccurately low or false-negative results.Six different patient pools were tested using immunoassay screening methods and also the LC-MS/MS confirmation method.For the immunoassay screening method,50μL of each patient sample is pooled together for every 100 patient samples.If there is a sample with the hook effect,it would give a very low or a negative result when the pool is tested neat and it would give a positive result when the pool is tested in a 1∶100 dilution.The drugs tested included Cannabinoids,Benzodiazepines,Amphetamines,Ecstasy,EDP,Opiates,Heroin,Cocaine,Fentanyl,Oxycodone and a combined method for Buprenorphine/Norbuprenorphine.Patient Pool number 6 showed a positive Buprenorphine and Norbuprenorphine that was traced back to the sample with the hook effect based on the suggested protocol.The random and different patient pools were prepared by using a Gilson GX241 liquid handler.The neat result for Pool number 6 showed the immunoassay for Buprenorpone and Norpuprenorphine was“Not Detected”at 2.1μg/L while the LC-MS/MS result was 2,780μg/L(cut-off<10μg/L).However,the result for the 1 in 100 dilutions of the pool for the immunoassay was“Detected”at 37μg/L without multiplying by the dilution factor.The result for the LC-MS/MS was 2,970μg/L.The suggested protocol is practical and cost-effective to avoid the clinical impact of reporting either inaccurately low or false-negative results.Also,can be used for testing when suspected samples with the hook effect are investigated.展开更多
文摘“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.
基金supported by the National Natural Science Foundation of China(32170980)Guangdong Basic and Applied Basic Research Foundation(2022B1515020012)+7 种基金Shenzhen Fundamental Research Program(RCJC20231211090018040,ZDSYS20220606100801003)the 2023 Key Support Project of the Liaoning Provincial Department of Science and Technology([2023]61-7)the Ciberned(CB06/05/0076)the Spanish MICINN grant(PID2022-143020OB-I00)the Basque Government grant(IT1551-22)the Slovenian Research Agency grant J4-60077the Science and Technology Planning Project of Guangdong Province(2021B1212040006)the Sanming Project of Medicine in Shenzhen(SZSM202411023,SZSM202411013).
文摘Alzheimer's disease(AD),the leading cause of dementia,remains a formidable challenge to neurology.Despite decades of research focused on amyloid-β(Aβ)and tau pathologies,most clinical trials targeting these molecules failed,highlighting the need for alternative strategies[1].Recent attention has turned to neuroinflammation,particularly the role of microglia,the brain's resident immune cells[1].Microglia are central to AD progression.They can degrade Aβplaques and protect neurons,but may also exacerbate neurotoxicity through chronic inflammation[1].
基金This review was supported by the National Natural Science Foundation of China,(81871852)Shenyang Science and Technology Innovation Talents Project(RC210251)+3 种基金Liaoning Revitalization Talents Program(XLYC1807137)the Scientific Research Foundation for Returned Scholars of Education Ministry of China(20151098)Liaoning Thousand Talents Program(202078)the"Chunhui"Program of Education Ministry(2020703).
文摘Although posttraumatic stress disorder(PTSD)is on the rise,traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself.Traumatic experiences can be broadly classified into mental stress(MS)and traumatic brain injury(TBI),but the cellular mechanisms of MS-or TBI-induced PTSD remain unknown.Recent evidence has shown that the morphological remodeling of astrocytes accompanies and arguably contributes to fearful memories and stressrelated disorders.In this review,we summarize the roles of astrocytes in the pathogenesis of MS-PTSD and TBIPTSD.Astrocytes synthesize and secrete neurotrophic,proand anti-inflammatory factors and regulate the microenvironment of the nervous tissue through metabolic pathways,ionostatic control,and homeostatic clearance of neurotransmitters.Stress or trauma-associated impairment of these vital astrocytic functions contribute to the pathophysiological evolution of PTSD and may present therapeutic targets.
基金funding from European Regional Development Fund(project No 13.1.1-LMT-K-718-05-0005)under grant agreement with the Research Council of Lithuania(LMTLT)。
文摘The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man.The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured(in invertebrates)by septate junctions.
文摘<strong>Background:</strong> Hydrolysis improves the sensitivity of drug detection for drug classes such as opiates/opioids and benzodiazepines, which are highly metabolized by glucuronidation and sulfation and should be implemented in analytical procedures to convert conjugated metabolites into the free or unbound form. This study was aimed to compare different enzymes to make an informed decision. <strong>Methods:</strong> In this study, the CEDIA Benzodiazepine assay was compared with the LC-MS-MS method using 150 positive urine samples and 50 negative urine samples. The samples were analysed without adding any enzyme and then by adding different enzymes to compare their performance.<strong> Results: </strong>The Kura <em>Escherichia coli</em> enzyme performed better than the Roche <em>Escherichia coli </em>enzyme which had 20% false-positive results. Kura BG-100 enzyme performed well but Kura B-One enzyme performed better The Kura B-One enzyme had only 11.5% false-positive results. When double the volume of Kura B-One enzyme was used to test to see if it will have any impact on reducing the number of false negatives, it performed worse. Kura Turbo enzyme behaved similarly to Kura BG-100. <strong>Conclusions: </strong>The <em>β</em>-glucuronidase enzymes comparison allowed us to identify the Kura B-One enzyme as the enzyme of choice for our operation because it reduces the false positives from 20% to 11.5% when compared with the Roche enzyme. It also improved the detection of oxazepam. The Kura B-One enzyme has a short incubation time for hydrolysis when used with the LC-MS-MS method. As a result, we improved the overall turn-around time and reduced the number of false positives that needed confirmation.
基金supported by the National Natural Science Foundation of China,MX[grant number 32271038]and BL[grant number 81871852]Shenyang Science and Technology Innovation Talents Project,BL[grant number RC210251]+2 种基金‘ChunHui’Program of Education Ministry,BL[grant number 2020703]National Natural Science Foundation of China-Russian Science Foundation(NSFC-RSF),YT[grant number 82261138557]Sichuan Provincial Administration of Traditional Chinese Medicine,YT[grant number 2023zd024].
文摘Worldwide,the incidence of major depressive disorder(MDD)is increasing annually,resulting in greater economic and social burdens.Moreover,the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear,and additional diagnostic and therapeutic strategies for MDD still are needed.The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis,hypothalamicpituitary-adrenal(HPA)axis hypothesis,cytokine hypothesis,neuroplasticity hypothesis and systemic influence hypothesis,but these hypothesis cannot completely explain the pathological mechanism of MDD.Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD,thus in recent years,great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies,further revealing the disease features of MDD.Furthermore,some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention,some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms.In this work,we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD,preventive approaches and therapeutic medicines,as well as the related clinical trials.
基金grants from NSFC-RSF(82261138557)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202003)+3 种基金the Sichuan Science and Technology Program(2022YFH0006)Y.T.was supported by NSFC(82274668,82230127)Sichuan Provincial Administration of Traditional Chinese Medicine(2023zd024).Work in the M.V.S.laboratory is supported by National Institutes of Health(NS084030)by the Dr.Miriam and Sheldon G.Adelson Medical Foundation.
文摘Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system(CNS).Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome.Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions.Astroglia respond to external,non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure,molecular expression,and function.In addition,internally driven,cell autonomous changes of astroglial innate properties can lead to CNS pathologies.Astroglial pathophysiology is complex,with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder,disorder-stage,comorbidities,age,and sex.Here,we classify astroglial pathophysiology into(i)reactive astrogliosis,(ii)astroglial atrophy with loss of function,(iii)astroglial degeneration and death,and(iv)astrocytopathies characterised by aberrant forms that drive disease.We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders,including neurotrauma,stroke,neuroinfection,autoimmune attack and epilepsy,as well as neurodevelopmental,neurodegenerative,metabolic and neuropsychiatric disorders.Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.
基金The study was financially supported by the Project of the National Natural Sciences Foundation of China(81373239)The Innovation and Business Starting-oriented training program of College Students in Sichuan Province(C2020113713).
文摘Drug-facilitated sexual assault(DFSA)is a sexual act in which the victim is unable to give or rescind consent due to alcohol or drug intoxication,which involved the abuse of benzodiazepines around the world.Conventional techniques used for the analysis of benzodiazepines have the limitation of short detection time window due to the rapid metabolism of these drugs in body.This study aimed to investigate the characteristic changes of metabolites in the blood of rats after ingesting diazepam/clonazepam through a gas chromatography-mass spectrometry-based metabolomics method,allowing the indirect reveal of the rats ingested diazepam/clonazepam.First,we found that diazepam and clonazepam in the blood of rats could not be detected by liquid chromatography-tandem mass spectrometry after 48 h of ingestion.Then,orthogonal partial least squares discrimination analysis regression models were,respectively,constructed to determine whether the rats ingested diazepam/clonazepam after 48 h.The results showed that 5 metabolites were found to be associated with diazepam exposure,and 7 metabolites were found to be associated with clonazepam exposure,which may be characterization for the evaluation of digestion of diazepam and clonazepam in rat.
文摘The hook effect is best explained by how the analyte signal generated from the assay is compromised due to either antibody excess or antigen excess.Reporting false negatives can also impact clinical decisions that may have adverse effects on the patient.The clinical impact of the hook effect will lead to reporting either inaccurately low or false-negative results.Six different patient pools were tested using immunoassay screening methods and also the LC-MS/MS confirmation method.For the immunoassay screening method,50μL of each patient sample is pooled together for every 100 patient samples.If there is a sample with the hook effect,it would give a very low or a negative result when the pool is tested neat and it would give a positive result when the pool is tested in a 1∶100 dilution.The drugs tested included Cannabinoids,Benzodiazepines,Amphetamines,Ecstasy,EDP,Opiates,Heroin,Cocaine,Fentanyl,Oxycodone and a combined method for Buprenorphine/Norbuprenorphine.Patient Pool number 6 showed a positive Buprenorphine and Norbuprenorphine that was traced back to the sample with the hook effect based on the suggested protocol.The random and different patient pools were prepared by using a Gilson GX241 liquid handler.The neat result for Pool number 6 showed the immunoassay for Buprenorpone and Norpuprenorphine was“Not Detected”at 2.1μg/L while the LC-MS/MS result was 2,780μg/L(cut-off<10μg/L).However,the result for the 1 in 100 dilutions of the pool for the immunoassay was“Detected”at 37μg/L without multiplying by the dilution factor.The result for the LC-MS/MS was 2,970μg/L.The suggested protocol is practical and cost-effective to avoid the clinical impact of reporting either inaccurately low or false-negative results.Also,can be used for testing when suspected samples with the hook effect are investigated.
