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Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.
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Stroke at the acute stage is a major cause of disability in adults, and is associated with dysfunction of brain networks. However, the mechanisms underlying changes in brain connectivity in stroke are far from fully elucidated. In the present study, we investigated brain metabolism and metabolic connectivity in a rat ischemic stroke model of middle cerebral artery occlusion (MCAO) at the acute stage using F-fluorodeoxyglucose positron emission tomography. Voxel-wise analysis showed decreased metabolism mainly in the ipsilesional hemisphere, and increased metabolism mainly in the contralesional cerebellum. We used further metabolic connectivity analysis to explore the brain metabolic network in MCAO. Compared to sham controls, rats with MCAO showed most significantly reduced nodal and local efficiency in the ipsilesional striatum. In addition, the MCAO group showed decreased metabolic central connection of the ipsilesional striatum with the ipsilesional cerebellum, ipsilesional hippocampus, and bilateral hypothalamus. Taken together, the present study demonstrated abnormal metabolic connectivity in rats at the acute stage of ischemic stroke, which might provide insight into clinical research.
Subject(s)
Animals , Male , Acute Disease , Brain , Diagnostic Imaging , Metabolism , Brain Mapping , Disease Models, Animal , Fluorodeoxyglucose F18 , Glucose , Metabolism , Infarction, Middle Cerebral Artery , Diagnostic Imaging , Metabolism , Neural Pathways , Diagnostic Imaging , Metabolism , Positron-Emission Tomography , Radiopharmaceuticals , Random Allocation , Rats, Sprague-DawleyABSTRACT
Objective To observe the effect of electroacupuncture at Baihui (GV20) and Shenting (GV24) on learning-memory function and ultrastructure in hippocampal CA1 region of rats after cerebral ischmeia-reperfusion. Methods A total of 25 male Sprague-Dawley rats were randomly divided into sham group (n=6) and operation group (n=19). The operation group was occluded the left middle cerebral arter-ies with modified Longa's methods for 90 minutes and reperfused, and twelve qualified rats of them were randomly divided into model group (n=6) and electroacupuncture group (n=6), the later accepted electroacupuncture at Baihui and Shenting for seven days. They were as-sessed with Longa's scores, and tested with Barnes maze. Their cerebral infarct volume was tested with magnetic resonance imaging T2-weighted image. The ultrastructure of synapse in hippocampal CA1 region was observed with transmission electron microscope. Results Compared with the model group, the Longa's score improved (P<0.05), the infarct volume decreased (P<0.01), the average escape latency decreased (P<0.01) and the times entering the wrong hole decreased (P<0.001) in the electroacupuncture group. Under the transmission elec-tron microscope, the number of synapse decreased in the model group, with the structure damage and vesicles sparse;compared with the model group, the number of synapse increased in the electroacupuncture group, with clear and complete structure and rich vesicles. Conclu-sion Electroacupuncture at Baihui and Shenting can improve the learning-memory function in rats after cerebral ischmeia-reperfusion, which may relate to improvement of synaptic plasticity and ameliorating ultrastructure in hippocampal CA1 region.
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@#Objective To explore the effect of electroacupuncture at Quchi (LI11) and Zusanli (ST36) acupoints on motor behaviors, the axonal integrity and nerve bundle of motor cortex and striatum in rat model of ischemic stroke induced by middle cerebral artery occlusion (MCAO) using diffusion tensor imaging (DTI). Methods Thirty-six adult male Sprague-Dawley rats were randomly assigned to sham opera-tion group (sham group), ischemia control group (model group) and electroacupuncture treatment group (EA group) with twelve rats in each group. The later two groups were occluded their middle cerebral arteries for two hours. Twenty-four hours after modeling, EA group re-ceived electroacupuncture at Quchi (LI11) and Zusanli (ST36) acupoints on the paralyzed limb, once a day, for 14 days. They were assessed with modified Neurological Severity Scores (mNSS) and Rota-rod test, and scanned with small animal magnetic resonance imaging system for T2-weighted image (T2WI) and DTI, the infarct size, related fractional anisotropy (rFA) and related number of tracks of motor cortex and striatum were recorded. Results Compared with the sham group, the score of mNSS increased in the model group and EA group after model-ing, and was lower in EA group than in the model group seven days and 14 days after intervention (P<0.05). Rota-rod test showed that the retention time was significantly longer in EA group than in the model group (P<0.05). T2WI showed that the infarct size was smaller in EA group than in the model group (P<0.05). DTI showed that rFA in motor cortex and striatum was higher in EA group than in the model group (P<0.05), as well as the related number of tracks (P<0.05) in motor cortex. Conclusion Electroacupuncture at Quchi and Zusanli acupoints could improve the motor function in rats with ischemic stroke, which may be related to the recovery of nerve bundle of motor cortex and stri-atum in ischemic side.
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Diffusion tensor imaging (DTI) can detect the integrity of white matter in vivo, through which various white matter damages of the brains have been found in patients with Alzheimer's disease (AD), even mild cognitive impairment. These damages of white matter may relate to the impairment of cognitive function, otherwise, damages in various area may result in various clinical features. DTI may fur-ther be used in the study of AD development and therapeutic evaluation.
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There are two phenotypes of microglia, M1 and M2. Microglia in M2 polarization may associate with the phagorytosis of be-ta-amyloid and inhibition of Tau hyperphosphorylation, as well as in other pathology. Electroacupuncture can impact the phenotypes of mi-croglia, which may play a role in the treatment for Alzheimer's disease.
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Vigorously development of the health service industry has received great attention,but the health service industry faces many difficulties.By analyzing the current predicament,this paper put forward the KY3H health care service model and systematically analyzed its six innovations:from "disease as the center" to "health as the center",from "homogenized group health service" to "Personalized and Humanized Health Service",from "Extensive Health Service"to "Precise Intervention of Individual Health Status",from "Single Health Service" to "Trinity Service of Health,Culture,Health Management and Health Insurance",from the "seeking medical" service model to "seeking one's own"service model,as well as from the "fixed (fixed-time,fixed-point,fixed-mode) service" to "anytime,anywhere full-time service".This model has achieved initial success in practice.It is an important way to solve the dilemma.
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KY3H is a traditional Chinese medicine health care service mode based on the existing problem,focusing on an interconnected and continuous integration of four key technological innovation,which promotes the service model transformation from passive "doctor-searching" to "asking yourself ".There are four features on KY3H mode.First,based on traditional Chinese medicine meridian and viscera theory,it can accurately identify the health status and take risk assessment of individuals through digital quantitative model.Then,the mode realizes the personalized health status recognition and precisious intervention through integrated technology products of dynamic monitoring and identification,assessment and intervention with independent intellectual property rights.The third is to improve the intelligence,realtime and accessibility of KY3H health care services through developing the Chinese-western medicine informationalized software system about health status identification,assessment and intervention.The last one is formulating traditional Chinese medicine health care standards,industry standards and service package design,which drive KY3H health service model spreading effectively and practical applying,achieving remarkable social and economic benefits.
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This paper systematically summarized the core problems in the field of medical and health services and did the root analysis.It is concluded that the current domestic and international related medical service modes deviated from the essence of health services and led to difficulties in the idea and method,bringing people to new problems and new crises.KY3H health care service model,set innovative ideas,innovative technical methods,innovative products,innovative processes,standards and standards into one,by providing a full range and the whole cycle of people-oriented,self-help,"diagnosis and treatment of security" integration of health careservice,improve people's health status,fundamentally change the traditional passive "seeking medical treatment" service mode,to active "seeking one's own" health service mode,so as to achieve "health status continues to rise,the medical costs continue to decline,"which is the social development aims.The paper systematically analyzes the idea,operational logic,goal,mode structure,characteristics of the model,and its significance to individuals,industries,society,countries and even the international community in order to make a positive contribution to the healthy development strategy in China and provide a Chinese case for global Health.
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@#With the development of aging population, the morbidity of Alzheimer's disease (AD) is increasing. Electroacupuncture on several acupoints, especially Baihui (GV20), may improve the cognitive function, brain morphology, and reduceβ-amyloid deposition and tau protein phosphorylation, in AD models.
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Objective To investigate the relationship between learning and memory deficit and demyelination of the corpus callosum in twelve-month old APP/PS1 transgenic mice. Methods Twelve twelve-month old APP/PS1 transgenic mice were as AD group, and age-matched wild type (WT) littermates were as WT group. Learning and memory ability was tested with Morris water maze, and the mor-phology of nerve fiber of corpus callosum was detected with Luxol Fast Blue staining. Immunohistochemistry was used to detect myelin ba-sic protein (MBP) in the corpus callosum. Thioflavine S staining was used to detect amyloid plaque in the corpus callosum. Results Com-pared with WT group, the latency increased (Z>2.873, P<0.01) and the times crossing the location of the platform decreased (t=-7.339, P<0.001) in AD group. The nerve fibers were sparse and disorganized, with a lot of vacuoles in the corpus callosum of AD group. The positive expression of MBP in the corpus callosum was significantly decreased (t=-4.481, P<0.001) in AD group compared with WT group. There were amyloid plaques in the corpus callosum of AD group. Conclusion Twelve-month old APP/PS1 transgenic mice exhibit learning and memory deficit, which may be attributed to the deposition of the amyloid plaque mediated demyelinated injury of the corpus callosum.
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@#Objective To explore the effects of electroacupuncture at Shenting (DU24) and Baihui (DU20) on cognitive dysfunction after stroke. Methods Forty-five Sprague-Dawley rats were randomly divided into control group (n=15), model group (n=15) and electroacupuncture group (n=15). The latter two groups were occluded their middle cerebral artery for two hours and reperfused. The electroacupuncture group accepted electroacupuncture at Shenting and Baihui 24 hours after modeling for seven days. They were assessed with Morris water maze once a day since the second day of intervention. Their brains were stained with TTC staining to measure cerebral infarction volume after treatment, while the expression of cyclic AMP response element binding protein (CREB) and phosphorylation (p-CREB) in hippocampal CA1 area were detected with immunohistochemistry. Results The escape latency and swimming distance of place navigation shortened in the electroacupuncture group compared with those in the model group (P<0.05) from the fourth day of intervention. The number of cross platform of spatial probe increased (P<0.05). The infarction volume was less in the electroacupuncture group than in the model group (P< 0.05), with increased expression of CREB and p-CREB in hippocampal CA1 area (P<0.05). Conclusion Electroacupuncture at Shenting and Baihui can increase the expression of CREB and phosphorylation in hippocampal CA1 area in rats after cerebral ischemia-reperfusion, to protect the neurons from ischemia and improve the learning and memory function.
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Objective To observe the expression of P2X receptors in the hippocampus of telomerase gene knockout mice after acupuncturing the bilateral ST36 acupoints.Methods Eighteen telomerase gene knockout homozygous mice were randomly divided into a blank control group (group A),a manual acupuncture group (group B) and an electric acupuncture group (group C),each of 6.Group A was not given any intervention,while groups B and C were provided with manual or electric acupuncture at point ST36 for 7 days.The expression of P2X receptors and cAMP response element bound protein (CREB) in the hippocampus were observed and compared among the 3 groups.Results The expression of P2X4 in the hippocampus was not significantly different among the 3 groups in groups B and C decreased significantly compared with group A,but there were no significant differences between group Bs and C.The expression of CREB in group C decreased significantly compared with groups A and B.Conclusion EA inhibits the expression of P2X4 receptor and CREB the hippocampus.The signaling pathway may play an important role in the mechanism of action of acupuncture in neurodegenerative diseases.
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Objective To explore the effect of electroacupuncture at Quchi (LI11), Zusanli (ST36) on differentiation of neural stem cells after cerebral ischemia-reperfusion in rats. Methods Thirty-six male Sprague-Dawley rats were randomly divided into sham group (n=12), model group (n=12) and electroacupuncture group (n=12). The latter two groups were occluded the left middle cerebral arteries for 90 min-utes and reperfused. The electroacupuncture group received electroacupuncture at Quchi and Zusanli acupoints for 21 days. They were evalu-ated with modified Neurological Severity Scores 7, 14 and 21 days after electroacupuncture. Their infarct volumes were tested with MRI T2WI 21 days after electroacupuncture, while the differentiation of neural stem cells was observed with double-immunopositive BrdU/Dcx and BrdU/NeuN. Results Compared with the model group, the neurological deficits score improved in the electroacupuncture group in all the time points (P<0.05). The infarct volumes decreased in the electroacupuncture group (P<0.05), with less number of BrdU+/Dcx+cells in subventricular zone (P<0.001) and more number of BrdU+/NeuN+ cells in peri-infarct cortex (P<0.001) 21 days after electroacupuncture. Conclusion Electroacupuncture at Quchi and Zusanli acupoints can improve neurological function and decrease the infarct volumes in rats after cerebral ischemia-reperfusion, which may be associated with promoting differentiation of neural stem cells to neurons.
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Objective To explore the mechanism of brain function connection (FC) by observing the changes of unilateral spatial neglect (USN) and non-USN patients, using functional magnetic resonance imaging technique (fMRI). Methods 8 USN and 8 control patients participated in the study and fMRI data were collected. The data was analyzed by independent component analysis method. Results USN group showed increased FC in the left frontal/temporal lobeas well and decreased FC in the right cingulate gyrus, precuneus, temporalgyrus compared with control group. These were highly related to behavioral scores. Conclusions Abnormal brain function connection may be related to USN. The findings were helpful for understanding the potential mechanism underlying of USN.
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Objective To study the relationship between injury site (right or left) or pathological type (hemorrhage or infarct) and atten-tion impairment in post stroke cognitive impairment (PSCI). Methods June, 2014 to June 2015, 49 patients with PSCI were assessed with Test of Attentional Performance (TAP) within 1 week of admission. The reaction time and the numbers of correct response were recorded. Results The reaction time of alertness (with or without alarm) was shorter in the patients with left infarction (Z=-2.32, t=-3.76, P2.32, t=-3.10, P<0.05). Conclusion A trend of lateralization was found in patients with PSCI, rather than in the pathology.
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@#Objective To observe the effects of electroacupuncture on learning and memory, and discuss the therapeutic mechanism. Methods 45 Sprague-Dawley rats were randomly divided into sham group (n=15), model group (n=15) and electroacupuncture group (n= 15). The latter 2 groups were modeled with middle cerebral artery occlusion for 1.5 h and reperfusion. The rats of electroacupuncture group received electroacupuncture at Shenting (DU24) and Baihui (DU20) for 7 days. Learning and memory ability was tested with Morris water maze. Neurologic impairment was assessed with Longa's score. Their hippocampus were observed under HE staining and the level of brain-derived neurotrophic factor (BDNF) and p75 neurotrophin receptor (p75NTR) protein were determined with Western blotting. Results Compared with the model group, the latency of water maze decreased and the times crossing the platform increased in electroacupuncture group (P<0.05), while the Longa's score significantly reduced (P<0.05), and the lesion of nerve cells were alleviated, with the decrease of p75NTR and increase of BDNF in the ischemic hippocampus (P<0.01). Conclusion Electroacupuncture can improve the learning and memory of cerebral ischemia-reperfusion rats, which may relate with up-regulating BDNF and down-regulating p75NTR in hippocampus.
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@#Objective To investigate the effects of electroacupuncture (EA) at Quchi (LI11) and Zusanli (ST36) acupoints on the ultrastructural structure of cortical neurons in peripheral area and the protein expression of caspase- 3, Bcl- 2, Bax in rats with cerebral ischemia- reperfusion injury. Methods 36 male adult Sprague-Dawley rats were randomly divided into sham operation group, model group, and electroacupuncture group, with 12 rats in each group. The model group and electroacupuncture group were performed with left middle cerebral artery occlusion (MCAO) according to the modified Longa' methods. The electroacupuncture group received electroacupuncture at Quchi (LI11) and Zusanli (ST36) on the paralyzed limb, for 30 minute. The neurobehavioral scores were recorded before and after treatment. The ultrastructural structure of cortical neurons was observed with transmission electron microscope (TEM). The protein expression of caspase- 3, Bcl-2 and Bax were detected by Western blotting technique. Results The neurobehavioral score was lower in the electroacupuncture group than in the control group (P<0.05). Compared with the model group, the chromatin of neurons was even relatively, and the number of mitochondria increased. The expression of Bcl-2 was higher and the expression of caspase-3 and Bax was lower in the electroacupuncture group than in the model group (P<0.05). Conclusion Electroacupuncture at Quchi (LI11) and Zusanli (ST36) acupoints can inhibit the neurons apoptosis in peripheral area through mitochondria-caspase-3 pathway.
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@#Objective To explore the central mechanism of acupuncture at Baihui (GV20) for memory impairment after stroke. Methods 32 stroke patients were randomized to receive acupuncture at Baihui (GV20) (as observation group) and acupuncture at Yanglingquan (GB34) (as control group) for 8 weeks. At the meantime, all participants received routine treatment including physical and occupational therapies. They were scanned with resting-state functional magnetic resonance imaging (fMRI) to find functional connectivity and assessed with Wechsler Memory Scale (WMS) before and after treatment. The results of WMS and functional connectivity were analyzed with Pearson's correlation. Results The memory scores and memory quotient improved significantly after treatment in the observation group (P<0.05). The functional connectivity significantly increased occurred in the left hippocampus to right inferior frontal gyrus, right middle frontal gyrus and left inferior frontal gyrus; and right hippocampus to left middle frontal gyrus, left superior frontal gyrus and left parietal lobe. Significant correlations were found between memory quotient and functional connectivity of hippocampus to frontal lobe and left parietal lobe in the observation group. There was no statistical significance in memory scores and memory quotient in the control group. The functional connectivity significantly decreased in left hippocampus to right middle occipital gyrus, and right hippocampus to right superior temporal gyrus and right posterior lobe of cerebellum. There was no statistical correlation between functional connectivity and results of WMS. Conclusion The acupuncture at Baihui can improves memory ability of stroke patients, which may associate with the increase of functional connectivity of hippocampus with frontal lobes and parietal lobes.
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@#Objective To explore the effects of electroacupuncture at Shenting (DU24) and Baihui (DU20) on learning and memory ability in the cerebral ischemia-reperfusion rats and its possible mechanism. Methods 45 male Sprague-Dawley rats were randomly divided into sham group (n=15), ischemia group (n=15) and electroacupuncture group (n=15). The latter 2 groups were modeled as focal cerebral ischemia-reperfusion injury, and the electroacupuncture group received electroacupuncture at Shenting (DU24) and Baihui (DU20) for 7 days. They were tested with Morris Water Maze, observed with Nissl's staining. The protein expression of RhoA was detected with Western blotting. Results The learning and memory ability improved in the electroacupuncture group (P<0.05), the injury of the neurons reduced (P<0.05) and the expression of RhoA in hippocampus decreased compared with the ischemia group (P<0.05). Conclusion Electroacupuncture could ameliorate the learning and memory ability in ischemia- reperfusion rats, which may relate with the inhibition of the expression of RhoA in hippocampus.
