Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely assoc...Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely associated with cognitive impairment.Therefore,this research aimed to explore whether the HMGB1/TLR4 pathway involves in chronic stress-induced cognitive dysfunction.Methods The chronic unpredictable mild stress(CUMS)mouse model was established by randomly giving different types of stress every day for four consecutive weeks.Cognitive function was detected by novel object recognition test,Y-maze test,and Morris water maze test.The protein expressions of HMGB1,TLR4,B-cell lymphoma 2(BCL2),and BCL2 associated X(BAX)were determined by Western blot.The damage of neurons in the hippocampal CA1 region was observed by hematoxylin-eosin(HE)staining.Results The protein expressions of HMGB1 and TLR4 were significantly increased in the hippocampus of chronic stress mice.Furthermore,inhibition of the HMGB1/TLR4 pathway induced by ethyl pyruvate(EP,a specific inhibitor of HMGB1)and TAK242(a selective inhibitor of TLR4)treatment attenuated cognitive impairment in chronic stress mice,according to the novel object recognition test,Y-maze test,and Morris water maze test.In addition,administration of EP and TAK242 also mitigated the increase of apoptosis in the hippocampus of chronic stress mice.Conclusion These results indicate that the hippocampal HMGB1/TLR4 pathway contributes to chronic stress-induced apoptosis and cognitive dysfunction.展开更多
OBJECTIVE A causal relationshiphas been postulated between cholinergic dysfunction and the progression of cognitive decline in neurodegenerative disorders. However,the cause of the cognitive dysfunction remains unclea...OBJECTIVE A causal relationshiphas been postulated between cholinergic dysfunction and the progression of cognitive decline in neurodegenerative disorders. However,the cause of the cognitive dysfunction remains unclear. METHODS Gab1^(loxP/loxP) were bred with ChAT-Cre mice to generate ChAT-Cre; Gab1^(f/f) mice. Excitability of cholinergic neurons wererecorded using whole-cel patch clump. A series of behavioral analyses were used to address the changes of cognitive function in ChAT-Cre; Gab1^(f/f) mice. Neurochemical changes on brain of conditional knockout mice were evaluated by using immunohistochemistry and Western blotting analysis. RESULTS Grb2-associated-binding protein 1(Gab1) is adocking/scaffolding molecule known to play an important role in cell growth and survival. Here,wereport that Gab1 is decreased in cholinergic neurons in a mousemodel of AD. We found that selective downregulation of Gab1 in the septum impaired learning and memory and hippocampal long-term potentiation,whereas overexpression of Gab1 in the same area rescued the cognitive deficitsseen in ChAT-Cre; Gab1^(f/f) and APP^(swe)/PS1 mice.^(18)F-FDGmicroP ET imaging data indicated that Gab1 treatment had no effect on metabolic activity of glucose in APPswe/PS1 mice. Moreover,we identify abnormal function of SKchannelscontributes to increased firing in cholinergic neuronsof ChAT-Cre; Gab1^(f/f) mice. CONCLUSION Gab1 signaling may serve as a potential treatment target for neurological disorders involving dysfunction of central cholinergic neurons.展开更多
Chondrocyte dysfunction has been demonstrated to be a major inducer of osteoarthritis(OA).The pathological mechanism of chondrocyte dysfunction is definitely multifactoral,but oxidative stressis regarded as one of the...Chondrocyte dysfunction has been demonstrated to be a major inducer of osteoarthritis(OA).The pathological mechanism of chondrocyte dysfunction is definitely multifactoral,but oxidative stressis regarded as one of the leading causes of apoptosis,autophagy,senescence,and mitochondrial dysfunctionin chondrocytes.Strategies for arresting oxidative stress-induced chondrocyte dysfunction have been considered as potential therapeutic targets for OA.Recently,fork head box O(Fox O)transcription factors have been determined to play a protective role in chondrocytes through the regulation of autophagy and defense against oxidative stress;they also regulate growth,maturation,and matrix synthesis.To explore Fox O′s potential role in the treatment of OA,we first discussed the recent advances in the field of oxidative stress-induced chondrocyte dysfunction and then emphasized the protective role of fox otranscription factors as a potential molecular target for the treatment of OA.Understanding the function of fox otranscription factors will be important in designing next-generation therapies to prevent or reverse the development of OA.展开更多
Current pharmacological therapies used in clinical practice for individuals with cardiac, hepatic, renal or pulmonary fibrosis do not show desirable effects; therefore, new targets of therapy are urgently required. Mi...Current pharmacological therapies used in clinical practice for individuals with cardiac, hepatic, renal or pulmonary fibrosis do not show desirable effects; therefore, new targets of therapy are urgently required. Mitochon- dria play pivotal role in energy production, metabolism, serving as storage tanks of calcium ions and cell fate deter- mination. Recent results of our experiments and other authors＇ studies suggest that the electron transport chain dys- function, electron leakage increasing, the accumulation of fragmented mitochondria, and the impairment in the mi- tophagy system contribute to pathogenesis of tissue fibrosis. Mitochondria targeting compounds exert promise in trea- ring and attenuating the progress of these diseases, indicating potential strategies to target mitochondria in the treat- ment of tissue fibrosis.展开更多
Type 2 diabetes increase the risk of development of cognitive dysfunction in the elderly, in the form of short-term memory and executive function deficits. Genetic and diet-induced models of type 2 diabetes further su...Type 2 diabetes increase the risk of development of cognitive dysfunction in the elderly, in the form of short-term memory and executive function deficits. Genetic and diet-induced models of type 2 diabetes further sup- port this link displaying deficits in working memory, learning, and memory performance. The risk factors for dia- betic cognitive dysfunction include vascular disease, hypoglycemia, hyperlipidemia, adiposity, lifestyle factors, and genetic factors. Using neuronimage technologies, diabetic patients with cognitive dysfunction shows whole brain atrophy, gray matter atrophy, hippocampal atrophy, and amygdala atrophy, increased ventricular volume and white matter volume, brain infarcts, impaired network integrity, microstructural abnormality, reduced cerebral blood flow and amplitude of low-frequency fluctuations. The pathogenesis mechanisms of type 2 diabetes with cognitive dys- function involve hyperglycemia, macrovascular and microvascular diseases, insulin resistance, inflammation, apop- tosis, impaired neurogenesis, impaired blood-brain barrier, and disorder neurotransmitters. Some antidiabetic drugs and Traditional Chinese Medicine partly improve diabetic cognitive dysfunction, but more clinical investigations are demanded to verify their efficiencies and novel drugs are urgent need to develop. Large clinical studies will provide further evidences of risks factors and biomarkers for diabetic cognitive dysfunction. Both novel disease animal mod- els and advanced neuronimage technologies will help to investigate the exact pathogenesis mechanisms and to devel- op better therapeutic interventions and treatment.展开更多
OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TME...OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TMEM16A in the vascular endothelial dysfunction in hypertension is unclear.METHODS In the study,RT-PCR,Western blotting,co-immunopricipitation,confocal imaging,patch-clamp,and endothelial-specific TMEM16A transgenic and knockout mice were employed.RESULTS We found that TMEM16A was expressed abundantly and functioned as Ca CC in endothelial cells.AngiotensinⅡ(AngⅡ)induced endothelial dysfunction with an increase in TMEM16A expression,which was alleviated by TMEM16A inhibitor.Further studies revealed that TMEM16A endothelial-specific knockout significantly lowered the blood pressure and ameliorated endothelial dysfunction in AngⅡ-induced hypertension,whereas,TMEM16A endothelial-specific overexpression showed the opposite effects.These results were related to the increased reactive oxygen species(ROS)generation,NADPH oxidase activation,and Nox2,p22phox expression facilitated by TMEM16A upon AngⅡ-induced hypertensive challenges.Moreover,TMEM16A directly interacted with Nox2 monomer and reduced the degradation of Nox2 through the proteasome-dependent endoplasmic recticulum-associated degradation pathway.TMEM16A also potentiated the translocation of p47phox and p67phox from cytosol to cell membrane and the subsequent interaction with Nox2.CONCLUSION Our results demonstrated that TMEM16A,as Ca CC,is a positive regulator of ROS generation via upregulating the activation of Nox2 NADPH oxidase in the vascular endothelium,and therefore facilitates endothelial dysfunction and hypertension.Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated cardiovascular diseases.展开更多
OBJECTIVE To investigate the effects of Huanglian Jiedu decoction on cognitive dysfunction of zebrafish with Alzheimer disease.METHODS 126 g of coptis chinensis,84 g of phellorescent phellorescent chinensis,84 g of sc...OBJECTIVE To investigate the effects of Huanglian Jiedu decoction on cognitive dysfunction of zebrafish with Alzheimer disease.METHODS 126 g of coptis chinensis,84 g of phellorescent phellorescent chinensis,84 g of scutellaria chinensis and 126 g of gardenia chinensis were immersed in 10,8 and 8 times of water for 30 min,and then extracted at 100℃for 2,1.5 and 1.5 h,respectively.The three extracts were coarse filtered and concentrated into 308 g·L-1 and stored in refrigerator for later use.200 zebrafish were selected for behavioral train⁃ing in T-shaped tank for seven days.After that,the behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis.Qualified zebrafish were selected as the blank group.Except for the blank group,zebrafish in the other 5 groups were exposed to AlCl3100μg·L-1 aquaculture water for modeling,and exposed for 6 d.The behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis,and Select the successfully modeled zebraf⁃ish.After that,huperzine A(4μg·L-1)and Huan⁃glian Jiedu decoction of low,medium and high doses(154,308 and 616 mg·L-1)were adminis⁃tered respectively,and exposed for six days.Then,the behavior analysis was conducted again through the behavioral record analysis soft⁃ware Smart 3.0 to select qualified zebrafish.After the training,the brain and gut of zebrafish in each group were collected,and the expression changes of N-cadherin,p-P38/p38MAPK and p-Tau in the brain were detected by Western blot⁃ting and qPCR to show the effect of Huanglian Jiedu decoction on cognitive dysfunction of Zebrafish with Alzheimer disease.RESULTS Western blotting and qPCR results showed that the contents of N-cadherin increased(P<0.05),and the contents of p-P38/p38MAPK and p-Tau decreased(P<0.05)compared with the model group,indicating that Huanglian Jiadu decoction had an effect on the cognitive dysfunction of zebrafish with Alzheimer disease.CONCLU⁃SION Huanglian Jiedu decoction can alleviate cognitive dysfunction of zebrafish model with Alzheimer disease to a certain extent.展开更多
Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, ...Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on agonist-induced vasorelaxation and vasoconstriction using the isolated rat aortic rings in in vitro organ bath system. Treatment with inorganic arsenite (AsⅢ) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium.展开更多
Objective:Pelvic floor dysfunction is common among pregnant and postpartum women and significantly impacts quality of life.This study aims to translate the German Pelvic Floor Questionnaire for Pregnant and Postpartum...Objective:Pelvic floor dysfunction is common among pregnant and postpartum women and significantly impacts quality of life.This study aims to translate the German Pelvic Floor Questionnaire for Pregnant and Postpartum Women into Chinese and to evaluate its reliability and validity in the Chinese population.Methods:The questionnaire was translated using the Brislin model.A cross-sectional study was conducted among pregnant and postpartum women to assess the content validity,construct validity,Cronbach’sαcoefficient,test-retest reliability,and split-half reliability of the Chinese version.Results:A total of 72 women were included,with 6.9% being pregnant and 93.1% postpartum;the age was(32.3±3.6)years.The Chinese version of the questionnaire contains 4 dimensions and 45 items.The content validity index of individual items ranged from 0.833 to 1.000,with a scale-level content validity index of 0.977 and intraclass correlation coefficients(ICCs)exceeding 0.90.The overall Cronbach’s α coefficient was 0.891,with subscale coefficients ranging from 0.732 to 0.884(all ICCs>0.70).The testretest reliability of the total scale was 0.833,and for the 4 dimensions,bladder,bowel,prolapse,and sexual function,the values were 0.776,0.579,0.732,and 0.645,respectively.The split-half reliability was 0.74.Conclusion:The Chinese version of the questionnaire demonstrated good reliability and validity,indicating its applicability in assessing pelvic floor dysfunction and associated risk factors during pregnancy and postpartum.展开更多
Aim Salidroside （SAL） is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density li...Aim Salidroside （SAL） is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor - deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Method Six-week old apoE-/- male mice were fed a high-fat diet for 8 weeks and then were ad- ministered with SAL for another 8 weeks. Atherosclerotic lesion and vascular function were analyzed. Primary cul- tured human umbilical vein endothelial cells （HUVECs） were prepared. Superoxide anion （O2^-）, NO produc- tion, mitochondrial membrane potential （△ψm） and intracellular ATP and AMP levels were measured. Expression of eNOS and AMPK were analyzed by Western blot. Result SAL significantly improved endothelial function asso- ciated with increasing eNOS activation thus reduced the atherosclerotic lesion area. SAL increased eNOS-Serl177 phosphorylation and decreased eNOS-Thr495 phosphorylation. SAL significantly activated AMP-activated protein ki- nase （AMPK）. Both AMPK inhibitor and AMPK small interfering RNA （siRNA） abolished SAL-induced Akt- Ser473 and eNOS-Serl177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. SAL decreased cellular ATP content and increased the cel- lular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease A^m, which is likely consequence of reduced ATP production. Conclusion The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide （NO） production, which was associated with mitochondria depolarization and subsequent activation of the AMPK/PI3 IC/ Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.展开更多
Objective To explore the molecular mechanism of enhancing the effect of risperidone on the cognitive function of schizophrenic mice by fluoxetine. Methods Schizophrenic mice were injected with M K-801 and drugs( fluox...Objective To explore the molecular mechanism of enhancing the effect of risperidone on the cognitive function of schizophrenic mice by fluoxetine. Methods Schizophrenic mice were injected with M K-801 and drugs( fluoxetine and / or risperidone) were adm inistrated orally 30 min before the injection of M K-801.Mice of the control group adm inistrated the same dose of norm al saline. The cognitive function, distance of activity, and stereotyped behavior of mice were observed. The expressions of key param eters of MEK / ERK pathway in hippocam pus were detected by Western blotting or real-time qPCR. The participation of MEK / ERK pathway in isolated hippocam palneuron injuries induced by M K-801 mediation was also analyzed. Results The mice of M K-801 group showed prolonged activity distance, increased stereotyped behavior scores, and cognitive im pairm ent. Expressions of pMEK/MEK, pERK/ERK1 /2, MMP2 /9, and TIMP1 /2 of the MK-801 group increased. The aforem entioned proteins of drug adm inistration groups decreased dram atically. For schizophrenic m ice, fluoxetine enhanced effects of risperidone in norm alizing abnorm al behaviors, affecting cognitive function, and unusual protein expressions( P < 0. 05). Results of in vitro experim ents were sim ilar to those of in vivo experim ents. Conclusion Fluoxetine enhances the anti-schizophrenic effect of risperidone by norm alizing the activated MEK / ERK signaling pathway.展开更多
OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-...OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups:wild-type group(WT Con group,n=10),APP/PS1 group(Tg Con group,n=10) and PHPB treated APP/PS1 group(PHPB group,n=10).PHPB group received 30 mg · kg-1 PHPB by oral gavage once daily for 3 months.WT Con group and Tg Con group received the same volume of water.Three months later,mice were sacrificed for biochemical and pathological testing such as transmission electron microscopy,Golgi staining and Western boltting analysis.RESULTS Under the transmission electron microscope,most hippocampal neurons and subcel ular organel es in WT Con group exhibited normal morphology.However,the degenerative changes were observed in Tg Con group such as nuclear fragmentation,mitochondrial swelling,ribosomes detachment and autophagic vacuoles accumulation.The hippocampal synapses number and the thickness of postsynaptic density(PSD) were significantly decreased in Tg Con group compared with the WT Con group(P<0.05).After PHPB treatment,the degenerative changes in APP/PS1 mice were alleviated to some extent.The synapse number has been elevated significantly(P<0.05) and the PSD has been thickened as well.Golgi staining showed that the spine density of secondary and tertiary apical dendritic branches was significantly decreased in CA1 and DG areas of Tg Con group(P<0.05).Sholl analysis revealed a decrease of dendritic complexity in Tg Con group compared with WT Con group(P<0.05).These abnormalities were alleviated to some extent after PHPB treatment.Western blotting study showed that the protein levels of synaptic marker PSD-95 and synaptophysin were significantly decreased in the hippocampus of Tg Con group(P<0.05).A significant increase of PSD-95(P<0.05) and a slight increase of SYP were observed after the PHPB treatment.Besides,we found a significant increase in the ratio of LC3-Ⅱ/LC3-Ⅰ in Tg Con group compared with the WT Con group(P<0.01) and the relevant improvement after PHPB treatment(P<0.05),which showed the regulatory effect of PHPB on autophagy impairment.CONCLUSION PHPB showed protective effects on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice,which might help explain its role on cognitive improvement in Alzheimer disease treatment.展开更多
Objective To elucidate the transformation of energy metabolism patterns in the process of myocardial remodeling induced by volumeoverload and to explore a novel intervention target for the prevention,delay or even rev...Objective To elucidate the transformation of energy metabolism patterns in the process of myocardial remodeling induced by volumeoverload and to explore a novel intervention target for the prevention,delay or even reversal of structural heart dysfunction.Methods Thirty C57/BL6 mice,20-30 g,half male and half female,were randomly divided into model group(n=15)and sham operation group(n=15).Each group was divided into subacute phase(2 weeks after surgery,n=5),cardiac functional compensation phase(5 weeks after surgery,n=5)and decompensation phase(15 weeks after surgery,n=5).展开更多
OBJECTIVE Peroxisome proliferator activated receptor alpha(PPARα)is an important protective factor in neurovascular diseases such as ischemic stroke.Although PPARαexpression is higher in neurons than astrocytes and ...OBJECTIVE Peroxisome proliferator activated receptor alpha(PPARα)is an important protective factor in neurovascular diseases such as ischemic stroke.Although PPARαexpression is higher in neurons than astrocytes and microglia,the pathophysiological functions of neuronal specific-PPARαin isch⁃emic stroke remains unknown.Here,we report that neuronal PPARαdeficiency is a key factor of neuronal injury.PPARαexpression markedly decreased in neurons after ischemic stroke.METHODS AND RESULTS Neuronal-specific PPARαknockout(NCKO)exacerbates neuronal damage and brain ischemic injury.PPARαdefi⁃ciency disrupts axonal microtubule organization and mitochondrial transport by decreasing the expression of dynein light chain Tctex-type 1(Dynlt1),which is implicated in cytoprotective role with damaged neurons.Furthermore,resto⁃ration of Dynlt1 expression in neurons of NCKO mice rescue mitochondrial transport disorder,cognitive deficits and brain ischemic injury asso⁃ciated with PPARαdeletion.CONCLUSION These results reveal a critical role for neuronal PPARαin ischemic brain injury by modulating axonal mitochondrial transportation.展开更多
OBJECTIVE To clarify the role of translocator protein 18 ku(TSPO)on cecum liga⁃tion and puncture(CLP)induced sepsis associat⁃ed encephalopathy(SAE)mice,which consis⁃tently demonstrated astrocyte activation and neu⁃roi...OBJECTIVE To clarify the role of translocator protein 18 ku(TSPO)on cecum liga⁃tion and puncture(CLP)induced sepsis associat⁃ed encephalopathy(SAE)mice,which consis⁃tently demonstrated astrocyte activation and neu⁃roinflammation.Background SAE,a brain dys⁃function,caused by systemic infection without clinical or laboratory evidence of direct infection.Most patients have symptoms such as long-term cognitive dysfunction.As the pathogenesis of SAE is very complex,neuroinflammation for SAE is one of the causes of the disease.TSPO as a marker of neuroinflammation that has the poten⁃tial to regulate neuroinflammation and SAE.METHODS The animal model of SAE was in⁃duced by CLP.TSPO ligands and TSPO knock⁃out mice were used for behavioral and molecular biology research.Survival rate of mice within 120 h on CLP mice was observed.The changes of cog⁃nitive function in mice were observed by Morris water maze and open field test.The changes of proinflammatory factors(IL-1β,TNF-α,IL-6)in hippocampus were observed by ELISA;Astro⁃cyte activation,marked by GFAP,in hippocam⁃pal was analyzed by tissue immunofluorescence and Western blotting.RESULTS Pretreatment with the TSPO ligands,XBD173 or PK11195,sig⁃nificantly improved the survival rate of CLP mice.The results of Morris water maze showed that TSPO ligands significantly increased the number of crossing the platform and the target quadrant time on CLP mice,suggesting that TSPO ligands may improve the learning and memory ability of CLP mice.Subsequent experiments revealed that TSPO ligands can reduce the inflammatory factors(IL-1β,TNF-α,IL-6)and astrocyte activa⁃tion in hippocampus of CLP mice.Similar results were also confirmed in TSPO knockout CLP mice,suggesting intervention of TSPO can reduce neuroinflammatory response and play a protec⁃tive role on SAE mice.CONCLUSION TSPO may play a critical role on SAE mice.Targeting TSPO by pharmacological means may improve the survival rate and cognitive function on CLP mice,which may through inhibiting astrocyte acti⁃vation and neuroinflammation in hippocampal.展开更多
Increasing evidence points towards a strong association between cerebrovascular dysfunction and neurodegenerative diseases in aging population.The global disease projection indicates that the healthcare burden derived...Increasing evidence points towards a strong association between cerebrovascular dysfunction and neurodegenerative diseases in aging population.The global disease projection indicates that the healthcare burden derived from these disease problems will continue to rise.Many traditional Chinese medicines(CMs)have been used to prevent and treat the multi-faceted diseases in China and other Asian countries.These herbs are potential rich sources of new leads that may also reveal previously unidentified mechanisms.Previously,our team has initiated a research program to analyze and characterize the bioactive extracts and pure natural components from the CMs using multipleexperimental models of vascular and neurodegenerative diseases.Some of the natural bioactive compounds have been further chemically modified to series of derivatives using different organic chemistry approaches(e.g.heterodimer and one-pot synthesis)and proven improved potency.The advantages of zebrafish modelfor in vivo high content screening of CMs will be presented.Our resultsprovide scientific rationales for clinical usage of the CMs and also probablylead to develop reproducible,higher potency and lower toxic agents for healthcare in the future.展开更多
文摘Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely associated with cognitive impairment.Therefore,this research aimed to explore whether the HMGB1/TLR4 pathway involves in chronic stress-induced cognitive dysfunction.Methods The chronic unpredictable mild stress(CUMS)mouse model was established by randomly giving different types of stress every day for four consecutive weeks.Cognitive function was detected by novel object recognition test,Y-maze test,and Morris water maze test.The protein expressions of HMGB1,TLR4,B-cell lymphoma 2(BCL2),and BCL2 associated X(BAX)were determined by Western blot.The damage of neurons in the hippocampal CA1 region was observed by hematoxylin-eosin(HE)staining.Results The protein expressions of HMGB1 and TLR4 were significantly increased in the hippocampus of chronic stress mice.Furthermore,inhibition of the HMGB1/TLR4 pathway induced by ethyl pyruvate(EP,a specific inhibitor of HMGB1)and TAK242(a selective inhibitor of TLR4)treatment attenuated cognitive impairment in chronic stress mice,according to the novel object recognition test,Y-maze test,and Morris water maze test.In addition,administration of EP and TAK242 also mitigated the increase of apoptosis in the hippocampus of chronic stress mice.Conclusion These results indicate that the hippocampal HMGB1/TLR4 pathway contributes to chronic stress-induced apoptosis and cognitive dysfunction.
文摘OBJECTIVE A causal relationshiphas been postulated between cholinergic dysfunction and the progression of cognitive decline in neurodegenerative disorders. However,the cause of the cognitive dysfunction remains unclear. METHODS Gab1^(loxP/loxP) were bred with ChAT-Cre mice to generate ChAT-Cre; Gab1^(f/f) mice. Excitability of cholinergic neurons wererecorded using whole-cel patch clump. A series of behavioral analyses were used to address the changes of cognitive function in ChAT-Cre; Gab1^(f/f) mice. Neurochemical changes on brain of conditional knockout mice were evaluated by using immunohistochemistry and Western blotting analysis. RESULTS Grb2-associated-binding protein 1(Gab1) is adocking/scaffolding molecule known to play an important role in cell growth and survival. Here,wereport that Gab1 is decreased in cholinergic neurons in a mousemodel of AD. We found that selective downregulation of Gab1 in the septum impaired learning and memory and hippocampal long-term potentiation,whereas overexpression of Gab1 in the same area rescued the cognitive deficitsseen in ChAT-Cre; Gab1^(f/f) and APP^(swe)/PS1 mice.^(18)F-FDGmicroP ET imaging data indicated that Gab1 treatment had no effect on metabolic activity of glucose in APPswe/PS1 mice. Moreover,we identify abnormal function of SKchannelscontributes to increased firing in cholinergic neuronsof ChAT-Cre; Gab1^(f/f) mice. CONCLUSION Gab1 signaling may serve as a potential treatment target for neurological disorders involving dysfunction of central cholinergic neurons.
基金supported by National Natural Science Foundation of China(81560662)China Postdoctoral Science Foundation(2017M610543)
文摘Chondrocyte dysfunction has been demonstrated to be a major inducer of osteoarthritis(OA).The pathological mechanism of chondrocyte dysfunction is definitely multifactoral,but oxidative stressis regarded as one of the leading causes of apoptosis,autophagy,senescence,and mitochondrial dysfunctionin chondrocytes.Strategies for arresting oxidative stress-induced chondrocyte dysfunction have been considered as potential therapeutic targets for OA.Recently,fork head box O(Fox O)transcription factors have been determined to play a protective role in chondrocytes through the regulation of autophagy and defense against oxidative stress;they also regulate growth,maturation,and matrix synthesis.To explore Fox O′s potential role in the treatment of OA,we first discussed the recent advances in the field of oxidative stress-induced chondrocyte dysfunction and then emphasized the protective role of fox otranscription factors as a potential molecular target for the treatment of OA.Understanding the function of fox otranscription factors will be important in designing next-generation therapies to prevent or reverse the development of OA.
文摘Current pharmacological therapies used in clinical practice for individuals with cardiac, hepatic, renal or pulmonary fibrosis do not show desirable effects; therefore, new targets of therapy are urgently required. Mitochon- dria play pivotal role in energy production, metabolism, serving as storage tanks of calcium ions and cell fate deter- mination. Recent results of our experiments and other authors＇ studies suggest that the electron transport chain dys- function, electron leakage increasing, the accumulation of fragmented mitochondria, and the impairment in the mi- tophagy system contribute to pathogenesis of tissue fibrosis. Mitochondria targeting compounds exert promise in trea- ring and attenuating the progress of these diseases, indicating potential strategies to target mitochondria in the treat- ment of tissue fibrosis.
文摘Type 2 diabetes increase the risk of development of cognitive dysfunction in the elderly, in the form of short-term memory and executive function deficits. Genetic and diet-induced models of type 2 diabetes further sup- port this link displaying deficits in working memory, learning, and memory performance. The risk factors for dia- betic cognitive dysfunction include vascular disease, hypoglycemia, hyperlipidemia, adiposity, lifestyle factors, and genetic factors. Using neuronimage technologies, diabetic patients with cognitive dysfunction shows whole brain atrophy, gray matter atrophy, hippocampal atrophy, and amygdala atrophy, increased ventricular volume and white matter volume, brain infarcts, impaired network integrity, microstructural abnormality, reduced cerebral blood flow and amplitude of low-frequency fluctuations. The pathogenesis mechanisms of type 2 diabetes with cognitive dys- function involve hyperglycemia, macrovascular and microvascular diseases, insulin resistance, inflammation, apop- tosis, impaired neurogenesis, impaired blood-brain barrier, and disorder neurotransmitters. Some antidiabetic drugs and Traditional Chinese Medicine partly improve diabetic cognitive dysfunction, but more clinical investigations are demanded to verify their efficiencies and novel drugs are urgent need to develop. Large clinical studies will provide further evidences of risks factors and biomarkers for diabetic cognitive dysfunction. Both novel disease animal mod- els and advanced neuronimage technologies will help to investigate the exact pathogenesis mechanisms and to devel- op better therapeutic interventions and treatment.
基金The project supported by National Natural Science Foundation of China(81230082,81302771,81525025,81573422,81500226)Natural Science Foundation of Guangdong Province(2014A030313087)by Science and Technology program of Guangzhou City(201607010255)
文摘OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TMEM16A in the vascular endothelial dysfunction in hypertension is unclear.METHODS In the study,RT-PCR,Western blotting,co-immunopricipitation,confocal imaging,patch-clamp,and endothelial-specific TMEM16A transgenic and knockout mice were employed.RESULTS We found that TMEM16A was expressed abundantly and functioned as Ca CC in endothelial cells.AngiotensinⅡ(AngⅡ)induced endothelial dysfunction with an increase in TMEM16A expression,which was alleviated by TMEM16A inhibitor.Further studies revealed that TMEM16A endothelial-specific knockout significantly lowered the blood pressure and ameliorated endothelial dysfunction in AngⅡ-induced hypertension,whereas,TMEM16A endothelial-specific overexpression showed the opposite effects.These results were related to the increased reactive oxygen species(ROS)generation,NADPH oxidase activation,and Nox2,p22phox expression facilitated by TMEM16A upon AngⅡ-induced hypertensive challenges.Moreover,TMEM16A directly interacted with Nox2 monomer and reduced the degradation of Nox2 through the proteasome-dependent endoplasmic recticulum-associated degradation pathway.TMEM16A also potentiated the translocation of p47phox and p67phox from cytosol to cell membrane and the subsequent interaction with Nox2.CONCLUSION Our results demonstrated that TMEM16A,as Ca CC,is a positive regulator of ROS generation via upregulating the activation of Nox2 NADPH oxidase in the vascular endothelium,and therefore facilitates endothelial dysfunction and hypertension.Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated cardiovascular diseases.
基金National Natural Science Foundation of china(8216140711)Natural Science Foundation of Guangxi Province(2017GXNSFAA198255)+2 种基金Natural Science Foun⁃dation of Guangxi Province(2018GXNSFBA138028)Open Project Program of Guangxi Key Laboratory of Brain and Cognitive Neuroscience,GuilinMedicalUniversity(GKLBCN-20180105-03)and 2019 College Student Innovation and Entre⁃preneurship Project Training Program(201910601038)。
文摘OBJECTIVE To investigate the effects of Huanglian Jiedu decoction on cognitive dysfunction of zebrafish with Alzheimer disease.METHODS 126 g of coptis chinensis,84 g of phellorescent phellorescent chinensis,84 g of scutellaria chinensis and 126 g of gardenia chinensis were immersed in 10,8 and 8 times of water for 30 min,and then extracted at 100℃for 2,1.5 and 1.5 h,respectively.The three extracts were coarse filtered and concentrated into 308 g·L-1 and stored in refrigerator for later use.200 zebrafish were selected for behavioral train⁃ing in T-shaped tank for seven days.After that,the behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis.Qualified zebrafish were selected as the blank group.Except for the blank group,zebrafish in the other 5 groups were exposed to AlCl3100μg·L-1 aquaculture water for modeling,and exposed for 6 d.The behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis,and Select the successfully modeled zebraf⁃ish.After that,huperzine A(4μg·L-1)and Huan⁃glian Jiedu decoction of low,medium and high doses(154,308 and 616 mg·L-1)were adminis⁃tered respectively,and exposed for six days.Then,the behavior analysis was conducted again through the behavioral record analysis soft⁃ware Smart 3.0 to select qualified zebrafish.After the training,the brain and gut of zebrafish in each group were collected,and the expression changes of N-cadherin,p-P38/p38MAPK and p-Tau in the brain were detected by Western blot⁃ting and qPCR to show the effect of Huanglian Jiedu decoction on cognitive dysfunction of Zebrafish with Alzheimer disease.RESULTS Western blotting and qPCR results showed that the contents of N-cadherin increased(P<0.05),and the contents of p-P38/p38MAPK and p-Tau decreased(P<0.05)compared with the model group,indicating that Huanglian Jiadu decoction had an effect on the cognitive dysfunction of zebrafish with Alzheimer disease.CONCLU⁃SION Huanglian Jiedu decoction can alleviate cognitive dysfunction of zebrafish model with Alzheimer disease to a certain extent.
文摘Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on agonist-induced vasorelaxation and vasoconstriction using the isolated rat aortic rings in in vitro organ bath system. Treatment with inorganic arsenite (AsⅢ) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium.
基金supported by the Natural Science Foundation of Hunan Province(2024JJ6626)the Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control(HPKL202320),China.
文摘Objective:Pelvic floor dysfunction is common among pregnant and postpartum women and significantly impacts quality of life.This study aims to translate the German Pelvic Floor Questionnaire for Pregnant and Postpartum Women into Chinese and to evaluate its reliability and validity in the Chinese population.Methods:The questionnaire was translated using the Brislin model.A cross-sectional study was conducted among pregnant and postpartum women to assess the content validity,construct validity,Cronbach’sαcoefficient,test-retest reliability,and split-half reliability of the Chinese version.Results:A total of 72 women were included,with 6.9% being pregnant and 93.1% postpartum;the age was(32.3±3.6)years.The Chinese version of the questionnaire contains 4 dimensions and 45 items.The content validity index of individual items ranged from 0.833 to 1.000,with a scale-level content validity index of 0.977 and intraclass correlation coefficients(ICCs)exceeding 0.90.The overall Cronbach’s α coefficient was 0.891,with subscale coefficients ranging from 0.732 to 0.884(all ICCs>0.70).The testretest reliability of the total scale was 0.833,and for the 4 dimensions,bladder,bowel,prolapse,and sexual function,the values were 0.776,0.579,0.732,and 0.645,respectively.The split-half reliability was 0.74.Conclusion:The Chinese version of the questionnaire demonstrated good reliability and validity,indicating its applicability in assessing pelvic floor dysfunction and associated risk factors during pregnancy and postpartum.
文摘Aim Salidroside （SAL） is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor - deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Method Six-week old apoE-/- male mice were fed a high-fat diet for 8 weeks and then were ad- ministered with SAL for another 8 weeks. Atherosclerotic lesion and vascular function were analyzed. Primary cul- tured human umbilical vein endothelial cells （HUVECs） were prepared. Superoxide anion （O2^-）, NO produc- tion, mitochondrial membrane potential （△ψm） and intracellular ATP and AMP levels were measured. Expression of eNOS and AMPK were analyzed by Western blot. Result SAL significantly improved endothelial function asso- ciated with increasing eNOS activation thus reduced the atherosclerotic lesion area. SAL increased eNOS-Serl177 phosphorylation and decreased eNOS-Thr495 phosphorylation. SAL significantly activated AMP-activated protein ki- nase （AMPK）. Both AMPK inhibitor and AMPK small interfering RNA （siRNA） abolished SAL-induced Akt- Ser473 and eNOS-Serl177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. SAL decreased cellular ATP content and increased the cel- lular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease A^m, which is likely consequence of reduced ATP production. Conclusion The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide （NO） production, which was associated with mitochondria depolarization and subsequent activation of the AMPK/PI3 IC/ Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.
基金Special Project from Ministry of Science and Technology of China(2012ZX09303-003)Shanghai Natural Science Foundation(13ZR1435800)Training Project of Excellent Talents in Shanghai(XBR2011049)
文摘Objective To explore the molecular mechanism of enhancing the effect of risperidone on the cognitive function of schizophrenic mice by fluoxetine. Methods Schizophrenic mice were injected with M K-801 and drugs( fluoxetine and / or risperidone) were adm inistrated orally 30 min before the injection of M K-801.Mice of the control group adm inistrated the same dose of norm al saline. The cognitive function, distance of activity, and stereotyped behavior of mice were observed. The expressions of key param eters of MEK / ERK pathway in hippocam pus were detected by Western blotting or real-time qPCR. The participation of MEK / ERK pathway in isolated hippocam palneuron injuries induced by M K-801 mediation was also analyzed. Results The mice of M K-801 group showed prolonged activity distance, increased stereotyped behavior scores, and cognitive im pairm ent. Expressions of pMEK/MEK, pERK/ERK1 /2, MMP2 /9, and TIMP1 /2 of the MK-801 group increased. The aforem entioned proteins of drug adm inistration groups decreased dram atically. For schizophrenic m ice, fluoxetine enhanced effects of risperidone in norm alizing abnorm al behaviors, affecting cognitive function, and unusual protein expressions( P < 0. 05). Results of in vitro experim ents were sim ilar to those of in vivo experim ents. Conclusion Fluoxetine enhances the anti-schizophrenic effect of risperidone by norm alizing the activated MEK / ERK signaling pathway.
基金National Natural Sciences Foundation of China(8147320081673420)CAMS InnovationFund for Medical Sciences (2017-I2M-2-004).
文摘OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups:wild-type group(WT Con group,n=10),APP/PS1 group(Tg Con group,n=10) and PHPB treated APP/PS1 group(PHPB group,n=10).PHPB group received 30 mg · kg-1 PHPB by oral gavage once daily for 3 months.WT Con group and Tg Con group received the same volume of water.Three months later,mice were sacrificed for biochemical and pathological testing such as transmission electron microscopy,Golgi staining and Western boltting analysis.RESULTS Under the transmission electron microscope,most hippocampal neurons and subcel ular organel es in WT Con group exhibited normal morphology.However,the degenerative changes were observed in Tg Con group such as nuclear fragmentation,mitochondrial swelling,ribosomes detachment and autophagic vacuoles accumulation.The hippocampal synapses number and the thickness of postsynaptic density(PSD) were significantly decreased in Tg Con group compared with the WT Con group(P<0.05).After PHPB treatment,the degenerative changes in APP/PS1 mice were alleviated to some extent.The synapse number has been elevated significantly(P<0.05) and the PSD has been thickened as well.Golgi staining showed that the spine density of secondary and tertiary apical dendritic branches was significantly decreased in CA1 and DG areas of Tg Con group(P<0.05).Sholl analysis revealed a decrease of dendritic complexity in Tg Con group compared with WT Con group(P<0.05).These abnormalities were alleviated to some extent after PHPB treatment.Western blotting study showed that the protein levels of synaptic marker PSD-95 and synaptophysin were significantly decreased in the hippocampus of Tg Con group(P<0.05).A significant increase of PSD-95(P<0.05) and a slight increase of SYP were observed after the PHPB treatment.Besides,we found a significant increase in the ratio of LC3-Ⅱ/LC3-Ⅰ in Tg Con group compared with the WT Con group(P<0.01) and the relevant improvement after PHPB treatment(P<0.05),which showed the regulatory effect of PHPB on autophagy impairment.CONCLUSION PHPB showed protective effects on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice,which might help explain its role on cognitive improvement in Alzheimer disease treatment.
文摘Objective To elucidate the transformation of energy metabolism patterns in the process of myocardial remodeling induced by volumeoverload and to explore a novel intervention target for the prevention,delay or even reversal of structural heart dysfunction.Methods Thirty C57/BL6 mice,20-30 g,half male and half female,were randomly divided into model group(n=15)and sham operation group(n=15).Each group was divided into subacute phase(2 weeks after surgery,n=5),cardiac functional compensation phase(5 weeks after surgery,n=5)and decompensation phase(15 weeks after surgery,n=5).
文摘OBJECTIVE Peroxisome proliferator activated receptor alpha(PPARα)is an important protective factor in neurovascular diseases such as ischemic stroke.Although PPARαexpression is higher in neurons than astrocytes and microglia,the pathophysiological functions of neuronal specific-PPARαin isch⁃emic stroke remains unknown.Here,we report that neuronal PPARαdeficiency is a key factor of neuronal injury.PPARαexpression markedly decreased in neurons after ischemic stroke.METHODS AND RESULTS Neuronal-specific PPARαknockout(NCKO)exacerbates neuronal damage and brain ischemic injury.PPARαdefi⁃ciency disrupts axonal microtubule organization and mitochondrial transport by decreasing the expression of dynein light chain Tctex-type 1(Dynlt1),which is implicated in cytoprotective role with damaged neurons.Furthermore,resto⁃ration of Dynlt1 expression in neurons of NCKO mice rescue mitochondrial transport disorder,cognitive deficits and brain ischemic injury asso⁃ciated with PPARαdeletion.CONCLUSION These results reveal a critical role for neuronal PPARαin ischemic brain injury by modulating axonal mitochondrial transportation.
基金Joint Funds for the Innovation of Science and Technology of Fujian Province(2019Y9009)and Natural Science Foundation of Fujian Province(2020J01618)。
文摘OBJECTIVE To clarify the role of translocator protein 18 ku(TSPO)on cecum liga⁃tion and puncture(CLP)induced sepsis associat⁃ed encephalopathy(SAE)mice,which consis⁃tently demonstrated astrocyte activation and neu⁃roinflammation.Background SAE,a brain dys⁃function,caused by systemic infection without clinical or laboratory evidence of direct infection.Most patients have symptoms such as long-term cognitive dysfunction.As the pathogenesis of SAE is very complex,neuroinflammation for SAE is one of the causes of the disease.TSPO as a marker of neuroinflammation that has the poten⁃tial to regulate neuroinflammation and SAE.METHODS The animal model of SAE was in⁃duced by CLP.TSPO ligands and TSPO knock⁃out mice were used for behavioral and molecular biology research.Survival rate of mice within 120 h on CLP mice was observed.The changes of cog⁃nitive function in mice were observed by Morris water maze and open field test.The changes of proinflammatory factors(IL-1β,TNF-α,IL-6)in hippocampus were observed by ELISA;Astro⁃cyte activation,marked by GFAP,in hippocam⁃pal was analyzed by tissue immunofluorescence and Western blotting.RESULTS Pretreatment with the TSPO ligands,XBD173 or PK11195,sig⁃nificantly improved the survival rate of CLP mice.The results of Morris water maze showed that TSPO ligands significantly increased the number of crossing the platform and the target quadrant time on CLP mice,suggesting that TSPO ligands may improve the learning and memory ability of CLP mice.Subsequent experiments revealed that TSPO ligands can reduce the inflammatory factors(IL-1β,TNF-α,IL-6)and astrocyte activa⁃tion in hippocampus of CLP mice.Similar results were also confirmed in TSPO knockout CLP mice,suggesting intervention of TSPO can reduce neuroinflammatory response and play a protec⁃tive role on SAE mice.CONCLUSION TSPO may play a critical role on SAE mice.Targeting TSPO by pharmacological means may improve the survival rate and cognitive function on CLP mice,which may through inhibiting astrocyte acti⁃vation and neuroinflammation in hippocampal.
文摘Increasing evidence points towards a strong association between cerebrovascular dysfunction and neurodegenerative diseases in aging population.The global disease projection indicates that the healthcare burden derived from these disease problems will continue to rise.Many traditional Chinese medicines(CMs)have been used to prevent and treat the multi-faceted diseases in China and other Asian countries.These herbs are potential rich sources of new leads that may also reveal previously unidentified mechanisms.Previously,our team has initiated a research program to analyze and characterize the bioactive extracts and pure natural components from the CMs using multipleexperimental models of vascular and neurodegenerative diseases.Some of the natural bioactive compounds have been further chemically modified to series of derivatives using different organic chemistry approaches(e.g.heterodimer and one-pot synthesis)and proven improved potency.The advantages of zebrafish modelfor in vivo high content screening of CMs will be presented.Our resultsprovide scientific rationales for clinical usage of the CMs and also probablylead to develop reproducible,higher potency and lower toxic agents for healthcare in the future.
