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To study the cognitive effects of diterpene ginkgolides (DG), transient middle cerebral artery occlusion (tMCAO)-induced rats were established. tMCAO-rats induced by suture method were divided into sham operation group, solvent control group, NBP group, DG group. The animal experiments in the present study were performed in accordance with the Ethical Guidelines of the Laboratory Animal Welfare Ethical Committee of Peking Union Medical College (00000646, 00000635). The effects of DG on tMCAO rats were evaluated by neurological severity score, cerebral infarction volume measurement, step-down and Morris water maze test. In the acute tMCAO rat model, 100 mg·kg-1 DG improved the neural score and infarction volume. In the chronic tMCAO rat model, DG 100 mg·kg-1 significantly improved the survival rate of tMCAO-induced rats. The Morris water maze results showed 100 mg·kg-1 DG decreased the latency of tMCAO-induced rats to find the platform, while the effect was weaker than the NBP. However, DG 30 mg·kg-1 did not show a significant effect. In conclusion, DG exerted a therapeutic effect on transient middle cerebral artery occlusion.
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To compare the neuroprotective and anti-dementia pharmacological effects of chiral oxiracetam, glutamate and calcium ions were used to establish neuronal injury models in vitro, and the protective effects of chiral oxiracetam on primary neurons were assayed by MTT. Permanent bilateral common carotid artery occlusion (2-VO)-induced rats were randomly divided into sham group, model group, galantamine 3 mg‧kg-1 group, oxiracetam groups (30, 100 and 200 mg‧kg-1), S-oxiracetam groups (30, 100 and 200 mg‧kg-1) and R-oxiracetam 200 mg‧kg-1 group. The animal experiments in the present study were performed in accordance with the Ethical Guidelines of the Laboratory Animal Welfare Ethical Committee of Peking Union Medical College. Morris water maze and step-down test were applied to evaluate the cognitive dysfunction induced by cerebral hypoperfusion in rats. Oxiracetam, S-oxiracetam and R-oxiracetam exerted protective effects on primary neuronal damage caused by various stimuli, and oxiracetam and S-oxiracetam showed better neuro-protective effects. Morris water maze and step-down results showed that oxiracetam, S-oxiracetam and R-oxiracetam improved the cognition of 2-VO rats. In summary, S-oxiracetam exerted a better neuro-protective effect than oxiracetam and R-oxiracetam.
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Neurodegenerative diseases (ND) mainly include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, and other diseases. The number of patients with ND is increasing, but the proportion of patients who can be diagnosed and treated early is less than 30% and the cause of ND is still unclear. In order to intervene in the disease as early as possible, researchers are committed to finding biomarkers that facilitate the early diagnosis of ND. Among them, cerebrospinal fluid (CSF) closely reflects the composition of the extracellular space of the brain, and may be the most sensitive biomarker for evaluating ND. However, the method of taking cerebrospinal fluid is more complicated, and it is not a common method in primary care or elderly medical institutions for the treatment of ND patients. Imaging examinations are expensive and difficult to spread among the community. The peripheral blood collection is convenient and less traumatic, which is a potential early screening and follow-up method. There are many components in the blood for analysis and research. This article reviews the research progress of the changes of apolipoprotein in the blood of ND patients as markers.
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Objective: To analyze the clinical characteristics of Chenopodiaceae pollen induced seasonal allergic rhinitis (SAR) as well as the distribution and sensitization characteristics of Chenopodiaceae pollen in Inner Mongolia grassland of northern China. Methods: From May 2015 to August 2015, using stratified, cluster and random sampling, a field interviewer-administered survey study and skin prick test (SPT) were conducted in six areas of Inner Mongolia grassland (Xilinhot, Erenhot, Duolun, Tongliao, Jarud, Kailu), and pollen monitoring was carried out in the above six areas from January 1 to December 31 of 2015. The clinical characteristics of Chenopodiaceae pollen induced SAR, distribution and sensitization characteristics of Chenopodiaceae pollen in these regions were observed. SAS software 9.4 was used for data processing. Results: A total of 6 043 subjects completed the study. The prevalence of Chenopodiaceae pollen induced SAR was 13.2% (795/6 043). The highest prevalence was found in the 18-39 age group. Subjects from urban areas showed higher prevalence of SAR than rural areas (61.2% vs 37.9%, P<0.001). There was significant regional difference in the prevalence rate of Chenopodiaceae pollen induced SAR among the above six areas (Xilinhot 21.5%, Erenhot 17.8%, Duolun 8.9%, Tongliao 6.9%, Jarud 15.3%, Kailu 9.7%, P<0.001). The main clinical symptoms of Chenopodiaceae pollen induced SAR were sneezing (96.5%) and nasal itching (92.2%). Eye itching was more obvious among the ocular symptoms (69.1%), while fatigue (32.1%) and drowsiness (31.5%) were more prominent among other related symptoms. Among comorbidities of Chenopodiaceae pollen induced SAR, allergic conjunctivitis accounted for 71.4% (568/795), food allergy accounted for 86.7% (689/795) and asthma accounted for 16.7% (133/795). The peak of Chenopodiaceae pollen spread was in August. The prevalence of Chenopodiaceae pollen induced SAR was positively correlated with the concentration of Chenopodiaceae pollen (R2=0.78, P=0.043). The SPT positive rate of Chenopodiaceae pollen was 21.2% (1 282/6 043), and Xilinhot had the highest rate in six regions (28.0%, 236/842). Conclusions: The prevalence of Chenopodiaceae pollen induced SAR in Inner Mongolia grassland stays at a high level. Sneezing is the most obvious symptom of SAR. The peak of Chenopodiaceae pollen spread is in August and the prevalence of Chenopodiaceae pollen induced SAR is positively correlated with the pollen concentration.
Subject(s)
Humans , Allergens , Chenopodiaceae , China/epidemiology , Grassland , Pollen , Rhinitis, Allergic, Seasonal/epidemiologyABSTRACT
@# There is no specific drug that has been approved for 2019-nCoV. There are a number of factors that pose major challenges in their development. Approaches to the development of anti-2019-nCoV include screening existing broad-spectrum antiviral drugs, repositioning of readily available clinical compounds, and <italic>de novo</italic> development of novel and specific agents for 2019-nCoV. Candidate compounds can be developed either to inhibit virus-based targets, such as RNA proteases, polymerase, spike glycoproteins, and viral envelop and membrane proteins, or to inhibit host-based targets, such as receptors and proteases that are utilized by virus for viral entry and endocytosis. Recently, the RNA polymerase remdesivir had demonstrated clinical efficacy in one patient with severe novel coronavirus pneumonia (NCP). The broad-spectrum viral protease inhibitor Kaletra<sup>®</sup> is also recommended in the current NCP clinical practice. Both drugs had lately been proceeded into multiple controlled phase III clinical trials to test their safety and efficacy in NCP. Combinational therapies consisting of multiple drugs provide other viable options against 2019-nCoV, based on scientific and clinical rationales. Using bioinformatics and database analysis, we have identified 75 clinically compounds, including 20 marketed compounds, that are efficacious in inhibiting key targets in virus- and host-based approaches, which may facilitate the development of new therapeutic options for 2019-nCoV.
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Two-pore domain potassium channels (K2P) make up a subfamily of potassium channels discovered in the 1990s, and TREK-1 is the most widely studied subtype of K2P. TREK-1 is widely expressed in the body and especially in the central nervous system, where its main role is to control cell excitability and maintain the membrane potential below the depolarization threshold. It thereby participates in regulating various physiological and pathological processes. TREK-1 is also a potential drug target in many diseases. It is known that many marketed drugs can affect the function of TREK-1, but currently there are no specific TREK-1 modulators or drugs. We review the structure, distribution and regulation of TREK-1 and focus on recent progress in understanding the pharmacology of TREK-1 and its role in neuroprotection, depression, anesthesia and epilepsy. The research status of TREK-1 modulators is discussed.
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To identify potential serum proteins that might serve as biomarkers for Alzheimer's disease (AD), we performed comparative proteomic profiling of sera from AD and healthy control subjects using label-free LC-MS/MS. Our study identified 387 proteins, 61 of which showed significant changes in the serum of AD patients compared to healthy controls. Gene ontology (GO) enrichment analysis showed that some GO terms related to the pathogenesis of AD were significantly enriched in differentially expressed proteins, including cholesterol and lipid metabolism, inflammation, coagulation and hemostasis processes, and immune responses. Therefore, based on the above results and the consistency of protein content changes in the 8 comparison groups, 18 proteins were selected as candidate biomarkers. Protein-protein interaction results suggest that these 18 proteins can directly or indirectly interact with APP. Therefore, changes in the levels or functions of these proteins may affect Aβ metabolism and participate in the occurrence of AD, and have the potential to become AD blood biomarkers.
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Amyotrophic lateral sclerosis (ALS) is among the most common type of motor neuron diseases, and its pathogenesis remains unclear. In recent years, our understanding of the genetic basis of ALS has led to the development of various ALS disease models, which allow for screening of ALS-related drugs and treatment methods. This review focuses on the research progress of ALS, summarizes the systems of commonly used experimental animal models, including transgenic animals, gene knockout approaches and autonomous animal models, points to the problems needing attention in standardized ALS non-clinical research, and proposes the criteria for selection of standardized R&D model.
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The rat models of focal cerebral ischemic reperfusion and subarachnoid hemorrhage were used to evaluate the therapeutic effects of artificial musk to provide support for its clinical application. All animal experiments were performed following the regulations of the Animal Ethics Committee of Peking Union Medical College. The results showed that oral administration of artificial musk had significant protective effects on acute ischemic and hemorrhagic stroke. In the dose range of 10-200 mg·kg-1, the mortality, neurobehavioral and cerebral infarction volume of rats in model group indicated a clear dose dependent relationship. The effective dose of artificial musk is 10 mg·kg-1 in ischemic stroke and 200 mg·kg-1 in hemorrhagic stroke. These findings suggest that the treatments of artificial musk in ischemic stroke and in hemorrhagic stroke are different, and such differences should be noted for its clinical use.
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Voltage-dependent anion channels (VDACs), which are located at the mitochondrial outer membrane, playing an important role in the regulation of mitochondrial energy metabolism and mitochondria- mediated apoptotic events, are considered as potential targets for tumor therapy. Studies have indicated that neurodegenerative diseases such as Alzheimer's disease (AD) generally lead to mitochondrial dysfunction. During this process, VDAC1, changing in expression, interacting with disease-related molecules, was involved in the occurrence and development of diseases. This review summarizes the characteristics and physiological functions of VDAC1, common important structural units and its role in apoptosis. The focus is on the research progress of VDAC1 in AD, as well as the effects in learning and memory related functions by modulating VDAC1 expression or function.
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This study was designed to investigate the role of CD36 in palmitic acid (PA)-induced apoptosis of astrocytes and the potential mechanisms of the action. MTT assay was used to detect cell viability and TUNEL assay to detect cell apoptosis. It was found that PA significantly decreased astrocyte cell viability and increased cell apoptosis. The uptake of BODIPY FL C16 by astrocytes was measured by flow cytometry. The results showed that CD36 played a key role in the process of PA uptake by astrocytes. The changes of intracellular calcium concentration were detected by FLIPR real-time fluorescence recording system. It was found that IP3R mediated PA signal to induce intracellular calcium release and finally caused endoplasmic reticulum calcium depletion. The intracellular ROS level was detected with CM-H2DCFDA fluorescence staining. The ROS level was induced by PA in astrocytes. The effect was blocked by CD36 inhibitor SSO through inhibition of the uptake of PA. PA-induced calcium overload and ROS increase were prevented by IP3R inhibitor APB. SSO, APB and antioxidant NAC all had significant inhibitory effects on PA-induced astrocyte cell viability decrease. In conclusion, CD36 mediates the translocation of PA into astrocytes, which leads to calcium overload, oxidative stress and eventually cell apoptosis.
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Neural stem cell is a cell type with the ability of self-renewing and the potential to differentiate into neurons, astrocytes or oligodendrocytes. Neurogenesis is beneficial for the recovery of many neurological diseases, such as stroke, Alzheimer's disease and so on. Neurogenesis capacity can maintain through the whole life, which includes the proliferation, migration and differentiation of neural stem cell, as well as the incorporation into the neuronal network of newborn neurons. The self-renewal and differentiation activities of neural stem cell are regulated by the microenvironment, which is defined as neural stem cell niche. Components of neural stem cell niche include cell-cell interactions, cytokines, extracellular matrix and vascular niche. Illustration of neural stem cell niche impact is far more significant for the treatment of certain nervous system diseases. This review summarizes the current understanding of the relationship between neural stem cell niche and the fate of neural stem cell.
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Studies have shown that acetylcholinesterase inhibitors donepezil and galantamine have effects of reducing neuronal damage caused by glucose deprivation and reducing the cerebral infarction volume of cerebral ischemic animals, but their effects may not be entirely dependent on its inhibition of cholinesterase activity. In order to study the effects of donepezil and galantamine on neuronal injury of cerebral ischemia, the rat neuron-astrocyte co-culture model was successfully established in this study. In this model, we studied the effects of donepezil and galantamine on neuron apoptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R) and investigated the mechanism. The results showed that donepezil and galantamine significantly reduced the neuron apoptosis, and promoted the synthesis and secretion of BDNF and NGF in astrocytes in the co-culture system. Donepezil and galantamine activated the PI3K/Akt pathway and ERK pathway, and promoted the phosphorylation of the nuclear transcription factor CREB. These results suggest that donepezil and galantamine exhibit protective effects on neuronal damage induced by OGD/R. The mechanism may be related to activation of PI3K/Akt pathway and ERK pathway in astrocytes and promote phosphorylation of CREB, which lead to the synthesis and secretion of BDNF and NGF from astrocytes.
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Diabetic neuropathic pain (DNP) is the most common chronic complication of diabetes mellitus, significantly affecting people's quality of life. Studies have indicated that ion channels play a very important role in the occurrence of DNP. This review provides a summary in the role of ion channels in diabetic neuropathic pain and treatment strategies for diabetic neuropathy targeting ion channels.
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Translating of scientific advances into clinical practice is a major challenge in the stroke research field in the past decades. There were many reasons involved:animal models might not accurately capture all aspects of clinical stroke in humans, the blind and randomized design principle was not closely followed, the inclusion and exclusion criteria was not previously established, sample size was inadequate, endpoint was not scientific nor blindly assessed, inadequate reporting of data and statistical flaws. To bridge the gap between experimental and clinical research, international consortia have attempted to establish standardized guidelines for study design and data report, which include optimizing animal models as well as experimental design, using innovative approaches to assess endpoint, making raw data and negative results available, establishing prior registration mechanism, conducting multicenter preclinical randomized controlled trials (pRCTs), systematic reviews and meta-analysis of preclinical studies, evolving the original focus on neuroprotection into a broader consideration of the role of neurovascular unit and ischemic cascade.
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Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease. The pathogenesis of AD is unclear, and it is presently incurable. Medicines currently available for AD treatment are only for improving the cognitive symptoms, but not able to stop or delay disease progression. Here, we summarized the interventions in early phases of AD in clinical trial. As a complex disease, AD is difficult to be restored through a treatment on a single target. Multi-target and cocktail drugs might be a strategy for development of AD therapies. In addition, AD is characterized by progressive neuronal loss in the cortex and hippocampus. The induction of neurogenesis by small molecule compounds has drawn attention in the AD field. The study of natural products in China is leading the way in the AD world. Numerous natural products have been identified for pharmacological effects on multi-targets in the regulation of neurogenic activity, which may open up a new avenue for AD treatments.
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Fourteen new compounds with 2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline or 2,3,5,9b-tetrahydro- 1H-pyrrolo[3,2-c]quinoline scaffold were designed and synthesized, and their inhibitory activities against Kv2.1 were evaluated. As a result, 2,3-dihydro-1H-pyrrolo[3,2-c]quinoline derivatives 3a and 5a were identified as potent inhibitors of Kv2.1 with IC50 values of 10.2 and 9.0 μmol·L-1, respectively.
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Gastrodin, parishin and parishin C were purified from a water extract of GE (rhizome of Gastrodia elata, an herb medicine for treatment of neuronal disorders). In order to compare the pharmacological effects of gastrodin, parishin and parishin C on improving cognition deficits, we tested them in an animal model of cognition disorders induced by scopolamine and in a study of in vivo long-term potentiation (LTP) recordings. In the Morris water maze task, parishin C (15 and 50 mg·kg-1, P -1, P -1. In vivo LTP recordings showed that parishin C at 5, 10 and 20 mg·kg-1, parishin at 10, 30 and 100 mg·kg-1 reversed the suppression of LTP by scopolamine in rats in a dose-dependent manner. However, gastrodin at 100 mg·kg-1 showed only a modest effect. In summary, the action of parishin C in the improvement of dementia induced by scopolamine was more potent than parishin and gastrodin.
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<p><b>OBJECTIVE</b>To investigate the effect of premature rupture of the membrane (PROM) on neonatal complications in premature infants.</p><p><b>METHODS</b>The registration information of 7684 preterm infants with gestational age <37 weeks were collected from the cooperative units in the task group between January 1, 2014 to December 31, 2014. Specially trained personnel from each cooperative units filled in the unified form in a standardized format to record the gender, gestational age, birth weight, PROM, placental abruption, antenatal corticosteroid, Apgar score, amniotic fluid pollution, and complications of the infants. The data were analyzed comparatively between the cases with PROM and those without (control).</p><p><b>RESULTS</b>The preterm mortality rate was significantly lower but the incidences of ICH, NEC, ROP and BPD were significantly higher in PROM group than in the control group (P<0.05). The 95% confidence interval of the OR value was <1 for mortality, and was >1 for ICH, NEC, ROP and BPD. After adjustment for gestational age, birth weight, gender, mode of delivery, placental abruption, placenta previa, prenatal hormones, gestational diabetes mellitus (GDM), gestational period hypertension and 5-min Apgar score <7, the incidences of NEC, ROP and BPD were significantly different between the two groups (P<0.05) with 95% confidence interval of OR value >1, but the mortality rate and incidence of ICH were not significantly different between the two groups (P>0.05).</p><p><b>CONCLUSION</b>PROM is a risk factor for NEC, ROP and BPD in preterm infants, and adequate intervention of PROM can reduce the incidences of such complications as NEC, ROP and BPD in the infants.</p>
Subject(s)
Female , Humans , Infant, Newborn , Pregnancy , Apgar Score , Birth Weight , Fetal Membranes, Premature Rupture , Pathology , Gestational Age , Incidence , Infant, Newborn, Diseases , Infant, Premature , Risk FactorsABSTRACT
To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.