Hypothalamic Corticotropin-releasing factor (CRF) directly activates the hypothalamic pituitary adrenal axis (HPA axis) during the surgical trauma induced stress response. Electroacupuncture (EA) has been demonstrated...Hypothalamic Corticotropin-releasing factor (CRF) directly activates the hypothalamic pituitary adrenal axis (HPA axis) during the surgical trauma induced stress response. Electroacupuncture (EA) has been demonstrated to have stress relieving effects in breast surgery, colorectal surgery, prostatectomy and craniotomy. This study was aimed to investigate the hypothesis that EA could regulate hypothalamic CRF in surgical trauma rats. In experiment one, Sprague-Dawley (SD) male rats were divided into intact, model (10% partial hepatectomy), sham EA and EA group. Rats from the Sham EA and EA group were stimulated at ST36-Zusanli and SP6-Sanyiniiao acupoints twice, 24 hours before the surgery and immediately after the surgery. Expressions of hypothalamic CRF and CRFR, GABA receptors, glutamate decarboxylase (GAD), serum adrenocorticotropic hormone (ACTH) and Corticosterone (CORT) were observed at 2, 4, 8 and 24 h after the surgery by radioimmunoassay (RIA), western blot, real-time PCR and immunohistochemistry. In the experiment two, SD male rats were divided into the intact, model, model + vehicle, model + L-838,417 EA and EA + L838,417 group. It was found that hypothalamus CRF, serum ACTH and CORT levels were increased in model group compared with the intact group, and those in the EA group decreased in comparison with the model group. Compared with the model group, hypothalamus-aminobutyric acid (GABA) receptor Aα3 mRNA and protein expressions of the EA group raised strikingly. In conclusion, EA alleviated surgical stress response by improving the GABA synthesis in hypothalamus, thus enhancing GABA receptors’ inhibitory regulation of the HPA axis dysfunction in rats with acute surgical trauma.展开更多
Neuroinflammation is implicated in the pathophysiology of depression.The reduction of hippocampal volume in depression remains controversial because of interindividual variability in clinical studies.Herein,we studied...Neuroinflammation is implicated in the pathophysiology of depression.The reduction of hippocampal volume in depression remains controversial because of interindividual variability in clinical studies.Herein,we studied the effects of clomipramine,a tricyclic antidepressant(TCA)that modulates serotonin and norepinephrine uptake,on chronic mild unpredictable stress(CMS)-induced depressive-like behaviors,hippocampal neuroinflammation,and hippocampal volume.展开更多
Neuroinflammation is implicated in the pathophysiology of depression. The reduction of hippocampal volume indepression remains controversial because of interindividual variability in clinical studies. Herein, we studi...Neuroinflammation is implicated in the pathophysiology of depression. The reduction of hippocampal volume indepression remains controversial because of interindividual variability in clinical studies. Herein, we studied theeffects of clomipramine, a tricyclic antidepressant (TCA) that modulates serotonin and norepinephrine uptake, onchronic mild unpredictable stress (CMS) induced depressive-like behaviors, hippocampal neuroinflammation, and hippocampal volume. Using a rat model of CMS induced depression, we administered clomipramine every day for4 weeks, starting 8 weeks after the beginning of the CMS procedure. Behavioral changes were measured by forcedswim test, open field test, and elevated plus maze. Neuroinflammation in the hippocampus was assessed byimmunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction. Hippocampal volumeswere dynamically measured using T2- weighted imaging with 7T structural magnetic resonance imaging.展开更多
Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similari...Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic pain.At present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be achieved.Hence,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs.Herein,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root ganglion.The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to CIBP.The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.展开更多
Studies have demonstrated that a functional network of meningeal lymphatic vessels exists in the brain.However,it is unknown whether lymphatic vessels could also extend deep into the brain parenchyma and whether the v...Studies have demonstrated that a functional network of meningeal lymphatic vessels exists in the brain.However,it is unknown whether lymphatic vessels could also extend deep into the brain parenchyma and whether the vessels could be regulated by stressful life events.We used tissue clearing techniques,immunostaining,light-sheet whole-brain imaging,confocal imaging in thick brain sections and flow cytometry to demonstrate the existence of lymphatic vessels deep in the brain parenchyma.Chronic unpredictable mild stress or chronic corticosterone treatment was used to examine the regulation of brain lymphatic vessels by stressful events.Western blotting and coimmunoprecipitation were used to provide mechanistic insights.We demonstrated the existence of lymphatic vessels deep in the brain parenchyma and characterized their features in the cortex,cerebellum,hippocampus,midbrain,and brainstem.Furthermore,we showed that deep brain lymphatic vessels can be regulated by stressful life events.Chronic stress reduced the length and areas of lymphatic vessels in the hippocampus and thalamus but increased the diameter of lymphatic vessels in the amygdala.No changes were observed in prefrontal cortex,lateral habenula,or dorsal raphe nucleus.Chronic corticosterone treatment reduced lymphatic endothelial cell markers in the hippocampus.Mechanistically,chronic stress might reduce hippocampal lymphatic vessels by down-regulating vascular endothelial growth factor C receptors and up-regulating vascular endothelial growth factor C neutralization mechanisms.Our results provide new insights into the characteristic features of deep brain lymphatic vessels,as well as their regulation by stressful life events.展开更多
The purpose of the present study was to investigate whether catalpol exhibited neuro-protective effects in chronic unpredictable mild stress(CUMS)mice through oxidative stress-mediated nucleotide-binding oligomerizati...The purpose of the present study was to investigate whether catalpol exhibited neuro-protective effects in chronic unpredictable mild stress(CUMS)mice through oxidative stress-mediated nucleotide-binding oligomerization domain,leucine-rich repeat,and pyrin-domain-containing 3(NLRP3)inflammasome and neuroinflammation.展开更多
The hypothalamic–pituitary–adrenal(HPA) axis is a critical component of the neuroendocrine system,playing a central role in regulating the body's stress response and modulating various physiological processes. D...The hypothalamic–pituitary–adrenal(HPA) axis is a critical component of the neuroendocrine system,playing a central role in regulating the body's stress response and modulating various physiological processes. Dysregulation of HPA axis function disrupts the neuroendocrine equilibrium, resulting in impaired physiological functions. Acupuncture is recognized as a non-pharmacological type of therapy which has been confirmed to play an important role in modulating the HPA axis and thus favorably targets diseases with abnormal activation of the HPA axis. With numerous studies reporting the promising efficacy of acupuncture for neuroendocrine disorders, a comprehensive review in terms of the underlying molecular mechanism for acupuncture, especially in regulating the HPA axis, is currently in need. This review fills the need and summarizes recent breakthroughs, from the basic principles and the pathological changes of HPA axis dysfunction, to the molecular mechanisms by which acupuncture regulates the HPA axis. These mechanisms include the modulation of multiple neurotransmitters and their receptors, neuropeptides and their receptors, and microRNAs in the paraventricular nucleus,hippocampus, amygdala and pituitary gland, which alleviate the hyperfunctioning of the HPA axis.This review comprehensively summarizes the mechanism of acupuncture in regulating HPA axis dysfunction for the first time, providing new targets and prospects for further exploration of acupuncture.展开更多
The present study was designed to investigate the mechanisms by which P2X7 receptors(P2X7Rs)mediate the activation of vasopressinergic neurons thereby increasing sympathetic hyperactivity in the paraventricular nucleu...The present study was designed to investigate the mechanisms by which P2X7 receptors(P2X7Rs)mediate the activation of vasopressinergic neurons thereby increasing sympathetic hyperactivity in the paraventricular nucleus(PVN) of the hypothalamus of rats with acute myocardial ischemia(AMI). The left anterior descending branch of the coronary artery was ligated to induce AMI in rats. The rats were pretreated with BBG(brilliant blue G, a P2X7R antagonist), nelivaptan(a vasopressin V1b receptor antagonist), or diphenyleneiodonium(DPI) [an nicotinamide adenine dinucleotide phosphate(NADPH)oxidase inhibitor]. Hemodynamic parameters of the heart were monitored. Myocardial injury and cardiomyocyte apoptosis were assessed. In the PVN of AMI rats, P2X7R mediated microglial activation, while reactive oxygen species(ROS) and NADPH oxidase 2(NOX2) were higher than in the sham group. Intraperitoneal injection of BBG effectively reduced ROS production and vasopressin expression in the PVN of AMI rats. Moreover, both BBG and DPI pretreatment effectively reduced sympathetic hyperactivity and ameliorated AMI injury, as represented by reduced inflammation and apoptosis of cardiomyocytes.Furthermore, microinjection of nelivaptan into the PVN improved cardiac function and reduced the norepinephrine(AE) levels in AMI rats. Collectively, the results suggest that, within the PVN of AMI rats, P2X7R upregulation mediates microglial activation and the overproduction of ROS, which in turn activates vasopressinergic neuron V1b receptors and sympathetic hyperactivity, hence aggravating myocardial injury in the AMI setting.展开更多
Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high...Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a highfat diet, we found that:(1) the acute thermal pain sensory threshold did not change in obese mice;(2) the model obese mice had fewer nociceptive responses in formalininduced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation;(3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice,indicating the dysmodulation of topical leptin–leptin receptor signaling in these mice; and(4) leptin–leptin receptor signaling-deficient mice(ob/ob and db/db) or leptin–leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wildtype mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin–leptin receptor pathway could be a peripheral target against acute inflammatory pain.展开更多
文摘Hypothalamic Corticotropin-releasing factor (CRF) directly activates the hypothalamic pituitary adrenal axis (HPA axis) during the surgical trauma induced stress response. Electroacupuncture (EA) has been demonstrated to have stress relieving effects in breast surgery, colorectal surgery, prostatectomy and craniotomy. This study was aimed to investigate the hypothesis that EA could regulate hypothalamic CRF in surgical trauma rats. In experiment one, Sprague-Dawley (SD) male rats were divided into intact, model (10% partial hepatectomy), sham EA and EA group. Rats from the Sham EA and EA group were stimulated at ST36-Zusanli and SP6-Sanyiniiao acupoints twice, 24 hours before the surgery and immediately after the surgery. Expressions of hypothalamic CRF and CRFR, GABA receptors, glutamate decarboxylase (GAD), serum adrenocorticotropic hormone (ACTH) and Corticosterone (CORT) were observed at 2, 4, 8 and 24 h after the surgery by radioimmunoassay (RIA), western blot, real-time PCR and immunohistochemistry. In the experiment two, SD male rats were divided into the intact, model, model + vehicle, model + L-838,417 EA and EA + L838,417 group. It was found that hypothalamus CRF, serum ACTH and CORT levels were increased in model group compared with the intact group, and those in the EA group decreased in comparison with the model group. Compared with the model group, hypothalamus-aminobutyric acid (GABA) receptor Aα3 mRNA and protein expressions of the EA group raised strikingly. In conclusion, EA alleviated surgical stress response by improving the GABA synthesis in hypothalamus, thus enhancing GABA receptors’ inhibitory regulation of the HPA axis dysfunction in rats with acute surgical trauma.
文摘Neuroinflammation is implicated in the pathophysiology of depression.The reduction of hippocampal volume in depression remains controversial because of interindividual variability in clinical studies.Herein,we studied the effects of clomipramine,a tricyclic antidepressant(TCA)that modulates serotonin and norepinephrine uptake,on chronic mild unpredictable stress(CMS)-induced depressive-like behaviors,hippocampal neuroinflammation,and hippocampal volume.
文摘Neuroinflammation is implicated in the pathophysiology of depression. The reduction of hippocampal volume indepression remains controversial because of interindividual variability in clinical studies. Herein, we studied theeffects of clomipramine, a tricyclic antidepressant (TCA) that modulates serotonin and norepinephrine uptake, onchronic mild unpredictable stress (CMS) induced depressive-like behaviors, hippocampal neuroinflammation, and hippocampal volume. Using a rat model of CMS induced depression, we administered clomipramine every day for4 weeks, starting 8 weeks after the beginning of the CMS procedure. Behavioral changes were measured by forcedswim test, open field test, and elevated plus maze. Neuroinflammation in the hippocampus was assessed byimmunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction. Hippocampal volumeswere dynamically measured using T2- weighted imaging with 7T structural magnetic resonance imaging.
基金supported by the Zhongshan-Fudan Joint Innovation Center,Zhongshan,Guangdong Province,China(528437)the National Natural Science Foundation of China(82271258,82271248,82204830,81971056)+1 种基金Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic pain.At present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be achieved.Hence,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs.Herein,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root ganglion.The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to CIBP.The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.
基金This work was supported by the Natural Science Foundation(NSF)of China(31970942 and 81573408 to N.A.)Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab,and Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘Studies have demonstrated that a functional network of meningeal lymphatic vessels exists in the brain.However,it is unknown whether lymphatic vessels could also extend deep into the brain parenchyma and whether the vessels could be regulated by stressful life events.We used tissue clearing techniques,immunostaining,light-sheet whole-brain imaging,confocal imaging in thick brain sections and flow cytometry to demonstrate the existence of lymphatic vessels deep in the brain parenchyma.Chronic unpredictable mild stress or chronic corticosterone treatment was used to examine the regulation of brain lymphatic vessels by stressful events.Western blotting and coimmunoprecipitation were used to provide mechanistic insights.We demonstrated the existence of lymphatic vessels deep in the brain parenchyma and characterized their features in the cortex,cerebellum,hippocampus,midbrain,and brainstem.Furthermore,we showed that deep brain lymphatic vessels can be regulated by stressful life events.Chronic stress reduced the length and areas of lymphatic vessels in the hippocampus and thalamus but increased the diameter of lymphatic vessels in the amygdala.No changes were observed in prefrontal cortex,lateral habenula,or dorsal raphe nucleus.Chronic corticosterone treatment reduced lymphatic endothelial cell markers in the hippocampus.Mechanistically,chronic stress might reduce hippocampal lymphatic vessels by down-regulating vascular endothelial growth factor C receptors and up-regulating vascular endothelial growth factor C neutralization mechanisms.Our results provide new insights into the characteristic features of deep brain lymphatic vessels,as well as their regulation by stressful life events.
文摘The purpose of the present study was to investigate whether catalpol exhibited neuro-protective effects in chronic unpredictable mild stress(CUMS)mice through oxidative stress-mediated nucleotide-binding oligomerization domain,leucine-rich repeat,and pyrin-domain-containing 3(NLRP3)inflammasome and neuroinflammation.
基金supported by the National Natural Science Foundation of China (No. 81973639 and 81573712)the Innovative Research Team of High-level Local Universities in ShanghaiShanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function (No. 21DZ2271800)。
文摘The hypothalamic–pituitary–adrenal(HPA) axis is a critical component of the neuroendocrine system,playing a central role in regulating the body's stress response and modulating various physiological processes. Dysregulation of HPA axis function disrupts the neuroendocrine equilibrium, resulting in impaired physiological functions. Acupuncture is recognized as a non-pharmacological type of therapy which has been confirmed to play an important role in modulating the HPA axis and thus favorably targets diseases with abnormal activation of the HPA axis. With numerous studies reporting the promising efficacy of acupuncture for neuroendocrine disorders, a comprehensive review in terms of the underlying molecular mechanism for acupuncture, especially in regulating the HPA axis, is currently in need. This review fills the need and summarizes recent breakthroughs, from the basic principles and the pathological changes of HPA axis dysfunction, to the molecular mechanisms by which acupuncture regulates the HPA axis. These mechanisms include the modulation of multiple neurotransmitters and their receptors, neuropeptides and their receptors, and microRNAs in the paraventricular nucleus,hippocampus, amygdala and pituitary gland, which alleviate the hyperfunctioning of the HPA axis.This review comprehensively summarizes the mechanism of acupuncture in regulating HPA axis dysfunction for the first time, providing new targets and prospects for further exploration of acupuncture.
基金supported by grants from the National Natural Science Foundation of China (31271215, 81770423, 81973945, and 81673766)the Health Vocational and Technical Education Research Program of Jiangsu Province, China (J201506)。
文摘The present study was designed to investigate the mechanisms by which P2X7 receptors(P2X7Rs)mediate the activation of vasopressinergic neurons thereby increasing sympathetic hyperactivity in the paraventricular nucleus(PVN) of the hypothalamus of rats with acute myocardial ischemia(AMI). The left anterior descending branch of the coronary artery was ligated to induce AMI in rats. The rats were pretreated with BBG(brilliant blue G, a P2X7R antagonist), nelivaptan(a vasopressin V1b receptor antagonist), or diphenyleneiodonium(DPI) [an nicotinamide adenine dinucleotide phosphate(NADPH)oxidase inhibitor]. Hemodynamic parameters of the heart were monitored. Myocardial injury and cardiomyocyte apoptosis were assessed. In the PVN of AMI rats, P2X7R mediated microglial activation, while reactive oxygen species(ROS) and NADPH oxidase 2(NOX2) were higher than in the sham group. Intraperitoneal injection of BBG effectively reduced ROS production and vasopressin expression in the PVN of AMI rats. Moreover, both BBG and DPI pretreatment effectively reduced sympathetic hyperactivity and ameliorated AMI injury, as represented by reduced inflammation and apoptosis of cardiomyocytes.Furthermore, microinjection of nelivaptan into the PVN improved cardiac function and reduced the norepinephrine(AE) levels in AMI rats. Collectively, the results suggest that, within the PVN of AMI rats, P2X7R upregulation mediates microglial activation and the overproduction of ROS, which in turn activates vasopressinergic neuron V1b receptors and sympathetic hyperactivity, hence aggravating myocardial injury in the AMI setting.
基金supported by the National Natural Science Fundation of China(81473749,81371247,31600852,and 31421091)WuXi AppTec
文摘Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a highfat diet, we found that:(1) the acute thermal pain sensory threshold did not change in obese mice;(2) the model obese mice had fewer nociceptive responses in formalininduced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation;(3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice,indicating the dysmodulation of topical leptin–leptin receptor signaling in these mice; and(4) leptin–leptin receptor signaling-deficient mice(ob/ob and db/db) or leptin–leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wildtype mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin–leptin receptor pathway could be a peripheral target against acute inflammatory pain.