To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging ...To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging were used in slice preparations of the anterior cingulate cortex （ACC） from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials （LFPs） and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation （LTP） and changes in LTP magnitude were also evaluated. We found that under naive conditions, the current sink was initially generated in layer Ⅵ, then spread to layer Ⅴ and finally confined to layers Ⅱ-Ⅲ. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers （Ⅴ-Ⅵ） to superficial layers （Ⅱ-Ⅲ） where intra- and extra- cortical inputs terminate. In the ACC slices from rats in an inflamed state （for 2 h） caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed,showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naive and saline controls. The change was more distinct in the superficial layers （Ⅱ-Ⅲ） than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers Ⅱ-Ⅲ by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation.展开更多
The α2δ-1 subunit of the voltage-gated Ca2＋ channel （VGCC） is a molecular target of gabapentin （GBP）, which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive...The α2δ-1 subunit of the voltage-gated Ca2＋ channel （VGCC） is a molecular target of gabapentin （GBP）, which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotrans- mitter release. We previously showed that GBP has an anti- allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated adminis- tration in a rat model of central post-stroke pain （CPSP） hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the c^2g-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor ~2^-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.展开更多
Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans.Human neuroimaging studies suggest that alcohol dependence and c...Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans.Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex（m PFC） interactions. However, whether acute administration of ethanol in the m PFC can modulate pain perception is unknown.Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the m PFC lowered the bilateral mechanical pain threshold for 48 h without influencing thermal pain sensitivity in adult rats.However, bilateral microinjections of artificial cerebrospinal fluid into the m PFC or bilateral microinjections of ethanol into the dorsolateral PFC（also termed as motor cortex area 1 in Paxinos and Watson＇s atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005） failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol didnot change the expression of either pro-apoptotic（caspase-3 and Bax） or anti-apoptotic（Bcl-2） proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether c-aminobutyric acid A（GABA_A） receptors are involved in mediating the ethanol effects, muscimol, a selective GABA_Areceptor agonist, or bicuculline, a selective GABA_A receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral m PFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABA_A receptors in the m PFC of rats.展开更多
Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a...Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a new template bearing N-phenylbenzenesulfonamide（PBSA） structure was designed to enhance the interactions with HIV-1 RT.In this manuscript,a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity.The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC_（50） values ranging of 0.105-14.531 μmol/L.In particular,compound 13 f not only has high anti-HIV-1 activity（0.108 μmol/L）,but also possesses low toxicity with a Tl value of 1816.6.Furthermore,the major interactions of the inhibitor 13 f with HIV-1 RT were also investigated using the molecular modelling.Our discovered structure-activity relationships（SARs） of these analogues may serve as an important clue for further optimizations.展开更多
Dear Editor.Empathy for distress refers to the highly evolutionarilyconserved ability of humans and other social animals to feel,recognize,and understand others’painful conditions(pain,fear,and catastrophe)[1,2]and e...Dear Editor.Empathy for distress refers to the highly evolutionarilyconserved ability of humans and other social animals to feel,recognize,and understand others’painful conditions(pain,fear,and catastrophe)[1,2]and even benefit others by releasing distress through sharing,caring,and cooperation[1].In the past decade,several types of lower empathic response have been gradually identified and characterized in laboratory rodents(rats and mice),referred to as empathic contagious pain[3-5],observational fear learning[2],and contagious itch[6].展开更多
Background and Aims: Spontaneous bacterial peritonitis(SBP) is one of the leading causes of death in patients withliver cirrhosis. We aimed to establish a prognostic model toevaluate the 1-year survival of cirrhosis p...Background and Aims: Spontaneous bacterial peritonitis(SBP) is one of the leading causes of death in patients withliver cirrhosis. We aimed to establish a prognostic model toevaluate the 1-year survival of cirrhosis patients after thefirst episode of SBP. Methods: A prognostic model was developedbased on a retrospective derivation cohort of 309cirrhosis patients with first-ever SBP and was validated in aseparate validation cohort of 141 patients. We used Uno’sconcordance, calibration curve, and decision curve (DCA)analysis to evaluate the discrimination, calibration, and clinicalnet benefit of the model. Results: A total of 59 (19.1%)patients in the derivation cohort and 42 (29.8%) patientsin the validation cohort died over the course of 1 year. Aprognostic model in nomogram form was developed withpredictors including age [hazard ratio (HR): 1.25;95% confidenceinterval (CI): 0.92–1.71], total serum bilirubin (HR:1.66;95% CI: 1.28–2.14), serum sodium (HR: 0.94;95%CI: 0.90–0.98), history of hypertension (HR: 2.52;95% CI:1.44–4.41) and hepatic encephalopathy (HR: 2.06;95%CI: 1.13–3.73). The nomogram had a higher concordance(0.79) compared with the model end-stage liver disease(0.67) or Child-Turcotte-Pugh (0.71) score. The nomogramalso showed acceptable calibration (calibration slope, 1.12;Bier score, 0.15±0.21) and optimal clinical net benefit in thevalidation cohort. Conclusions: This prediction model developedbased on characteristics of first-ever SBP patientsmay benefit the prediction of patients’ 1-year survival.展开更多
Non-human primates such as Chinese rhesus macaques are the favorable models for preclinical study of potential therapeutic drugs,vaccines and mechanisms of human diseases.Little is known about the normal levels of leu...Non-human primates such as Chinese rhesus macaques are the favorable models for preclinical study of potential therapeutic drugs,vaccines and mechanisms of human diseases.Little is known about the normal levels of leukocyte subpopulations of Chinese rhesus macaques.To obtain these data,100 blood samples from Chinese rhesus macaques were collected.The normal range of major leukocyte subpopulations,such as T lymphocytes,B lymphocytes,monocytes,myeloid dendritic cells(mDCs)and plasmacytoid dendritic cells(pDCs),were quantitatively analyzed by flow cytometry through BD trucount tubes.The influence of age and sex on the cell counts of leukocyte subpopulations was analyzed.The counts of CD3^(+)T cells,CD3+CD4^(+)T cells,CD3+CD8^(+)T cells and B cells decreased with age,but those of monocytes,mDCs and pDCs had no significant correlation with age.Significant differences existed in the cell counts of most leukocyte subpopulations between the male and female groups except pDCs.Furthermore the values of the females were higher than those of the males.The study provided basic information about the leukocyte subpopulations of Chinese rhesus macaques,and it may be valuable for immunobiological study of Chinese rhesus macaques.展开更多
The human microbiome has become a new frontier of life sciences and plays a crucial role in determining individual and population health.Over thousands of years of medical practice,practitioners of traditional Chinese...The human microbiome has become a new frontier of life sciences and plays a crucial role in determining individual and population health.Over thousands of years of medical practice,practitioners of traditional Chinese medicine(TCM)developed an understanding of the importance and activity of commensal microorganisms without access to modern technology.In this review,we examine the theoretical similarities between modern studies of the human microbiome and TCM,and propose feasible strategies to integrate the 2 fields.Advances in our understanding of the human microbiome will also help to modernize the practice of TCM,thereby providing a basis for bridging the gap between modern medicine and TCM.展开更多
基金supported by grants from the National Basic Research Development ProgramMinistry of Science and Technology of China(2013CB835100+3 种基金2013BAI04B04)the National Natural Science Foundation of China(8107089981171049)a Military Project of China(AWS12J004)
文摘To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging were used in slice preparations of the anterior cingulate cortex （ACC） from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials （LFPs） and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation （LTP） and changes in LTP magnitude were also evaluated. We found that under naive conditions, the current sink was initially generated in layer Ⅵ, then spread to layer Ⅴ and finally confined to layers Ⅱ-Ⅲ. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers （Ⅴ-Ⅵ） to superficial layers （Ⅱ-Ⅲ） where intra- and extra- cortical inputs terminate. In the ACC slices from rats in an inflamed state （for 2 h） caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed,showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naive and saline controls. The change was more distinct in the superficial layers （Ⅱ-Ⅲ） than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers Ⅱ-Ⅲ by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation.
基金supported by the National Natural Science Foundation of China(81171049)the National Basic Research Development Program of China(2011CB504100 and2013CB835100)+1 种基金the National Key Technology R&D Program of China(2013BAI04B04)the Twelfth Five-Year Project of China(AWS12J004)
文摘The α2δ-1 subunit of the voltage-gated Ca2＋ channel （VGCC） is a molecular target of gabapentin （GBP）, which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotrans- mitter release. We previously showed that GBP has an anti- allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated adminis- tration in a rat model of central post-stroke pain （CPSP） hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the c^2g-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor ~2^-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.
基金supported by grants from the National Basic Research Development Program of China (2013CB835103)the National Natural Science Foundation of China (81571072 and 31600855)
文摘Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans.Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex（m PFC） interactions. However, whether acute administration of ethanol in the m PFC can modulate pain perception is unknown.Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the m PFC lowered the bilateral mechanical pain threshold for 48 h without influencing thermal pain sensitivity in adult rats.However, bilateral microinjections of artificial cerebrospinal fluid into the m PFC or bilateral microinjections of ethanol into the dorsolateral PFC（also termed as motor cortex area 1 in Paxinos and Watson＇s atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005） failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol didnot change the expression of either pro-apoptotic（caspase-3 and Bax） or anti-apoptotic（Bcl-2） proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether c-aminobutyric acid A（GABA_A） receptors are involved in mediating the ethanol effects, muscimol, a selective GABA_Areceptor agonist, or bicuculline, a selective GABA_A receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral m PFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABA_A receptors in the m PFC of rats.
基金supported in part by grants from the National Natural Science Foundation of China(No.81402788)the Ph.D. Start-up Fund of Natural Science Foundation of Liaoning Province, China(No.20141115)
文摘Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a new template bearing N-phenylbenzenesulfonamide（PBSA） structure was designed to enhance the interactions with HIV-1 RT.In this manuscript,a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity.The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC_（50） values ranging of 0.105-14.531 μmol/L.In particular,compound 13 f not only has high anti-HIV-1 activity（0.108 μmol/L）,but also possesses low toxicity with a Tl value of 1816.6.Furthermore,the major interactions of the inhibitor 13 f with HIV-1 RT were also investigated using the molecular modelling.Our discovered structure-activity relationships（SARs） of these analogues may serve as an important clue for further optimizations.
基金grants from the National Natural Science Foundation of China(81571072 and 31600855)the Military Laboratory Animal Project(SYDW[2017]14 and SYDW[2018]07)。
文摘Dear Editor.Empathy for distress refers to the highly evolutionarilyconserved ability of humans and other social animals to feel,recognize,and understand others’painful conditions(pain,fear,and catastrophe)[1,2]and even benefit others by releasing distress through sharing,caring,and cooperation[1].In the past decade,several types of lower empathic response have been gradually identified and characterized in laboratory rodents(rats and mice),referred to as empathic contagious pain[3-5],observational fear learning[2],and contagious itch[6].
基金The work was supported by the Capital’s Funds for Health Improvement and Research(No.2020-2-2172)Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support(No.ZYLX202127)the Fund of Beijing Science&Technology Development of TCM(No.JJ2018-44).
文摘Background and Aims: Spontaneous bacterial peritonitis(SBP) is one of the leading causes of death in patients withliver cirrhosis. We aimed to establish a prognostic model toevaluate the 1-year survival of cirrhosis patients after thefirst episode of SBP. Methods: A prognostic model was developedbased on a retrospective derivation cohort of 309cirrhosis patients with first-ever SBP and was validated in aseparate validation cohort of 141 patients. We used Uno’sconcordance, calibration curve, and decision curve (DCA)analysis to evaluate the discrimination, calibration, and clinicalnet benefit of the model. Results: A total of 59 (19.1%)patients in the derivation cohort and 42 (29.8%) patientsin the validation cohort died over the course of 1 year. Aprognostic model in nomogram form was developed withpredictors including age [hazard ratio (HR): 1.25;95% confidenceinterval (CI): 0.92–1.71], total serum bilirubin (HR:1.66;95% CI: 1.28–2.14), serum sodium (HR: 0.94;95%CI: 0.90–0.98), history of hypertension (HR: 2.52;95% CI:1.44–4.41) and hepatic encephalopathy (HR: 2.06;95%CI: 1.13–3.73). The nomogram had a higher concordance(0.79) compared with the model end-stage liver disease(0.67) or Child-Turcotte-Pugh (0.71) score. The nomogramalso showed acceptable calibration (calibration slope, 1.12;Bier score, 0.15±0.21) and optimal clinical net benefit in thevalidation cohort. Conclusions: This prediction model developedbased on characteristics of first-ever SBP patientsmay benefit the prediction of patients’ 1-year survival.
基金This work was supported in part by grants from Scientific and Technological Projects of China(2008ZX10001-002,2008ZX10001-015,2008ZX10005-005,2009ZX09501-029)Yunnan(2006PT08)+2 种基金973 Program(2006CB504208,2009CB522306)the NSFC(30471605,30671960,U0832601,30872317)CAS(KSCX1-YW-R-15,KSCX2-YW-R-185),and“Western Light”Projects.
文摘Non-human primates such as Chinese rhesus macaques are the favorable models for preclinical study of potential therapeutic drugs,vaccines and mechanisms of human diseases.Little is known about the normal levels of leukocyte subpopulations of Chinese rhesus macaques.To obtain these data,100 blood samples from Chinese rhesus macaques were collected.The normal range of major leukocyte subpopulations,such as T lymphocytes,B lymphocytes,monocytes,myeloid dendritic cells(mDCs)and plasmacytoid dendritic cells(pDCs),were quantitatively analyzed by flow cytometry through BD trucount tubes.The influence of age and sex on the cell counts of leukocyte subpopulations was analyzed.The counts of CD3^(+)T cells,CD3+CD4^(+)T cells,CD3+CD8^(+)T cells and B cells decreased with age,but those of monocytes,mDCs and pDCs had no significant correlation with age.Significant differences existed in the cell counts of most leukocyte subpopulations between the male and female groups except pDCs.Furthermore the values of the females were higher than those of the males.The study provided basic information about the leukocyte subpopulations of Chinese rhesus macaques,and it may be valuable for immunobiological study of Chinese rhesus macaques.
基金supported by the National Natural Science Foundation of China(No.816220108030,No.81603411,No.81573814)China Postdoctoral Science Foundation No.2018M630465.
文摘The human microbiome has become a new frontier of life sciences and plays a crucial role in determining individual and population health.Over thousands of years of medical practice,practitioners of traditional Chinese medicine(TCM)developed an understanding of the importance and activity of commensal microorganisms without access to modern technology.In this review,we examine the theoretical similarities between modern studies of the human microbiome and TCM,and propose feasible strategies to integrate the 2 fields.Advances in our understanding of the human microbiome will also help to modernize the practice of TCM,thereby providing a basis for bridging the gap between modern medicine and TCM.
