Peripheral inflammation in behavioural variant frontotemporal dementia: associations with central degeneration and clinical measures.

BACKGROUND: Neuroinflammation plays a significant role in the progression of frontotemporal dementia (FTD). However, the association between peripheral inflammatory factors and brain neurodegeneration is poorly understood. We aimed to examine changes in peripheral inflammatory markers in patients with behavioural variant FTD (bvFTD) and explore the potential association between peripheral inflammation and brain structure, metabolism, and clinical parameters. METHODS: Thirty-nine bvFTD patients and 40 healthy controls were enrolled and underwent assessment of plasma inflammatory factors, positron emission tomography/magnetic resonance imaging, and neuropsychological assessments. Group differences were tested using Student's t test, Mann‒Whitney U test, or ANOVA. Partial correlation analysis and multivariable regression analysis were implemented using age and sex as covariates to explore the association between peripheral inflammatory markers, neuroimaging, and clinical measures. The false discovery rate was used to correct for the multiple correlation test. RESULTS: Plasma levels of six factors, including interleukin (IL)-2, IL-12p70, IL-17A, tumour necrosis superfamily member 13B (TNFSF/BAFF), TNFSF12 (TWEAK), and TNFRSF8 (sCD30), were increased in the bvFTD group. Five factors were significantly associated with central degeneration, including IL-2, IL-12p70, IL-17A, sCD30/TNFRSF8, and tumour necrosis factor (TNF)-α; the association between inflammation and brain atrophy was mainly distributed in frontal-limbic-striatal brain regions, whereas the association with brain metabolism was mainly in the frontal-temporal-limbic-striatal regions. BAFF/TNFSF13B, IL-4, IL-6, IL-17A and TNF-α were found to correlate with clinical measures. CONCLUSION: Peripheral inflammation disturbance in patients with bvFTD participates in disease-specific pathophysiological mechanisms, which could be a promising target for diagnosis, treatment, and monitoring therapeutic efficacy.

Clinical efficacy and safety of compound Congrong Yizhi Capsules on Alzheimer's disease in mainland China: A systematic review with trial sequential analysis and GRADE assessment.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a degenerative disease of the central nervous system (CNS) with insidious onset. AD is also the most common cause of dementia. Compound Congrong Yizhi Capsules (CCYC), a traditional Chinese medicine compound developed by the team of Beijing University of Chinese Medicine, has been widely used to treat AD. AIM OF THIS STUDY: To systematically evaluate the clinical efficacy and safety of CCYC for AD by meta-analysis, Trial Sequential Analysis (TSA) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. METHODS: This study was registered at PROSPERO (CRD42022295496). Randomized controlled trials (RCTs) of CCYC as the treatment for AD published before December 1, 2021 were retrieved from 4 Chinses databases, 4 English databases and 2 clinical trials registration systems. RevMan 5.4 and STATA 17.0 was used to conduct the meta-analysis of the included studies, the quality of outcomes was rated by the GRADE system, the TSA was conducted by TSA 0.9.5.10 software. RESULTS: Seven studies were included, and the total sample size was 746. Meta-analysis showed that 6 months of treatment with CCYC plus conventional western medicine treatments (CTs) improved MMSE scores compared with CTs alone (WMD: 4.32, 95% CI: 3.23, 5.42), and TSA confirmed that more trials in the future will not reverse the result. Among which, CCYC combined with donepezil can significantly improve MMSE scores (WMD: 3.54, 95% CI: 2.86, 4.22). CCYC combined with olanzapine also showed good effect on both MMSE (WMD: 6.49, 95% CI: 5.54, 7.44) and ADL scores (WMD: 5.23, 95% CI: 4.63, 5.83). No serious adverse events were reported. The strengths of the evidences above are MODERATE. CONCLUSION: CCYC combined with cognition-modifying western medicine can improve cognitive function, mental behavioural symptoms, and activities of daily living in AD patients with good safety.

Emerging trends in epigenetic and childhood trauma: Bibliometrics and visual analysis.

Background: The epigenetic study of childhood trauma has become a valuable field. However, the evolution and emerging trends in epigenetics and childhood trauma have not been studied by bibliometric methods. Objective: This study aims to evaluate status of epigenetic studies in childhood trauma and reveal the research trends based on bibliometrics. Methods: A total of 1,151 publications related to childhood trauma and epigenetics published between 2000 and 2021 were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace (5.8. R 3) was used to implement bibliometric analysis and visualization. Results: Since 2010, the number of related publications has expanded quickly. The United States and McGill University are the most influential countries and research institutes, respectively. Elisabeth Binder is a leading researcher in childhood trauma and epigenetic-related research. Biological Psychiatry is probably the most popular journal. In addition, comprehensive keyword analysis revealed that "glucocorticoid receptor," "brain development," "epigenetic regulation," "depression," "posttraumatic stress disorder," "maternal care," "histone acetylation," "telomere length," "microRNA," and "anxiety" reflect the latest research trends in the field. A comprehensive reference analysis demonstrated NR3C1 gene methylation, FKBP5 DNA methylation, BDNF DNA methylation, and KITLG methylation have been hot spots in epigenetic studies in the field of childhood trauma in recent years. Notably, the relationship between childhood adversity and NR3C1 gene methylation levels remains unresolved and requires well-designed studies with control for more confounding factors. Conclusion: As the best of our knowledge, this is the first bibliometric analysis of the association between childhood trauma and epigenetics. Our analysis of the literature suggests that childhood trauma may induce depression, anxiety, and post-traumatic stress disorder through epigenetic regulation of glucocorticoid receptor expression and brain development. The hypothalamic-pituitary-adrenal axis is the key points of epigenetic research. The current researches focus on NR3C1 gene methylation, FKBP5 DNA methylation, BDNF DNA methylation, and KITLG methylation. These results provide a guiding perspective for the study of epigenetic effects of childhood trauma, and help researchers choose future research directions based on current keywords.

Berberine protects against chronic cerebral hypoperfusion-induced cognitive impairment and hippocampal damage via regulation of the ERK/Nrf2 pathway.

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood-brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.

Tanhuo Formula Inhibits Astrocyte Activation and Apoptosis in Acute Ischemic Stroke.

Tanhuo formula (THF), a traditional Chinese medicinal formula, has been demonstrated to be effective in the clinical treatment of acute ischemic stroke (AIS). However, its active ingredients, potential targets, and molecular mechanisms remain unknown. Based on the validation of active ingredient concentrations, our study attempted to elucidate the possible mechanisms of THF based on network pharmacological analysis and experimental validation. Components of THF were screened using network pharmacological analysis, and a compound-target network and protein-protein interaction (PPI) network were constructed. In total, 42 bioactive compounds and 159 THF targets related to AIS were identified. The PPI network identified AKT1, TNF, IL6, IL1B, and CASP3 as key targets. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that the inflammation and apoptotic pathways were enriched by multiple targets. The main components of THF were identified via high-performance liquid chromatography. Subsequently, a validation experiment was conducted, and the expressions of GFAP, C3, TNF-α, and IL-6 were detected via immunofluorescence staining, confirming the inflammatory response at 30 min and 3 days post injury. Immunohistochemical staining for caspase-3 and TUNEL was also performed to assess apoptosis at the same time points. These results indicate that THF can effectively decrease neural cell apoptosis through the caspase-3 pathway and restrain excessive abnormal activation of astrocytes and the release of TNF-α and IL-6, which might be accompanied by the recovery of motor function. Thus, THF may serve as a promising therapeutic strategy for AIS through multiple targets, components, and pathways.

Depressive Symptoms Among Children and Adolescents in China During the Coronavirus Disease-19 Epidemic: A Systematic Review and Meta-Analysis.

Background: The Coronavirus Disease-19 (COVID-19) pandemic negatively impacts mental health. Some published studies have investigated the prevalence of depression among children and adolescents in China during the pandemic. However, the results vary widely. We aimed to systematically analyze and estimate the prevalence of depressive symptoms and attempted to reveal the reasons for prevalence variety in previous studies. Methods: Published studies were searched in PubMed, Embase, Cochrane Central, the Chinese Scientific Journal Database (VIP Database), China National Knowledge database (CNKI), and the WanFang database from December 2019 to May 2021. The quality of all included studies was assessed by the Joanna Briggs Institute (JBI) checklist and the American Agency for Health Care Quality and Research's (AHRQ) cross-sectional study quality evaluation items. Meta-analysis was performed using random-effects modeling. Results: Of the 1,708 references screened, 13 related reports that involve 41,729 participants were included. The results suggested that the pooled prevalence of depressive symptoms among Chinese children and adolescents during the COVID-19 epidemic was 28.6%. Subgroup analyses showed that the pooled prevalence was highest among the studies using the Patient Health Questionnaire (PHQ)-9 (46.8%) and lowest among these using Depression Self-Rating Scale for Children (DSRSC) (11.4%). All studies using PHQ-9 set the cutoff at 5 points instead of 10. The pooled prevalence of studies that include primary school students was lower (16.5%) than that of studies excluding primary school students (39.1%). Conclusion: The meta-analysis suggests that depressive symptoms were relatively prevalent among Chinese children and adolescents during COVID-19, especially among the secondary school students. The suitable screening tools and cutoff should be carefully chosen in the survey.

Berberine Ameliorates Cognitive Impairment by Regulating Microglial Polarization and Increasing Expression of Anti-inflammatory Factors following Permanent Bilateral Common Carotid Artery Occlusion in Rats.

BACKGROUND: Chronic cerebral hypoperfusion is associated with vascular cognitive impairment, and there are no specific therapeutic agents for use in clinical practice. Berberine has demonstrated good neuroprotective effects in models of acute cerebral ischemia; however, whether it can alleviate cognitive impairment caused by chronic cerebral hypoperfusion has rarely been investigated. OBJECTIVE: The present study aimed to explore the mechanism by which berberine alleviates cognitive impairment resulting from chronic cerebral hypoperfusion. METHODS: Forty-two male Sprague-Dawley rats were randomly divided into three groups: sham, model, and berberine. The models of chronic cerebral hypoperfusion were established via permanent bilateral common carotid artery occlusion (BCCAO). Cognitive function was evaluated using the Morris water maze, while neuronal damage and microglial activation and polarization were evaluated using western blotting and immunofluorescence, respectively. Enzyme-linked immunosorbent assays were used to detect the expression of anti-inflammatory factors including interleukin- 4 (IL-4) and interleukin-10 (IL-10). RESULTS: Rats exhibited cognitive dysfunction after BCCAO, which was significantly attenuated following the berberine intervention. Levels of synaptophysin and NeuN were decreased in states of chronic cerebral hypoperfusion, during which microglial activation and a transition from the M2 to M1 phenotype were observed. Berberine treatment also significantly reversed these features. Moreover, levels of IL-4 and IL-10 expression increased significantly after berberine treatment. CONCLUSION: Berberine may mitigate vascular cognitive dysfunction by promoting neuronal plasticity, inhibiting microglial activation, promoting transformation from an M1 to an M2 phenotype, and increasing levels of IL-4 and IL-10 expression.

Xi-Xian-Tong-Shuan capsule alleviates vascular cognitive impairment in chronic cerebral hypoperfusion rats by promoting white matter repair, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors.

BACKGROUND: While the number of cases of vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has been increasing every year, there are currently no clinically effective treatment methods. At present, Xi-Xian-Tong-Shuan capsule is predominantly used in patients with acute cerebral ischemia; however, its protective effect on CCH has rarely been reported. OBJECTIVE: To explore the underlying mechanisms by which Xi-Xian-Tong-Shuan capsule alleviates cognitive impairment caused by CCH. METHODS: A model of CCH was established in specific-pathogen-free (SPF)-grade male Sprague-Dawley (SD) rats using bilateral common carotid artery occlusion (BCCAO). Xi-Xian-Tong-Shuan capsules were intragastrically administered for 42 days after the BCCAO surgery. We then assessed for changes in cognitive function, expression levels of pro-inflammatory factors, and coagulation function as well as for the presence of white matter lesions and neuronal loss. One-way ANOVA and Tukey's test were used to analyze the experimental data. RESULTS: The rats showed significant cognitive dysfunction after the BCCAO surgery along with white matter lesions, a loss of neurons, and elevated levels of inflammatory factors, all of which were significantly reversed after intervention with Xi-Xian-Tong-Shuan capsules. CONCLUSION: Xi-Xian-Tong-Shuan capsules can ameliorate vascular cognitive impairment in CCH rats by preventing damage of white matter, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors. Our study provides a new reference for the clinical treatment of chronic cerebral ischemia with Xi-Xian-Tong-Shuan capsules.

cGAS- Stimulator of Interferon Genes Signaling in Central Nervous System Disorders.

Cytosolic nucleic acid sensors contribute to the initiation of innate immune responses by playing a critical role in the detection of pathogens and endogenous nucleic acids. The cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), mediate innate immune signaling by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. These biomolecules are suggested to play critical roles in host defense, senescence, and tumor immunity. Recent studies have demonstrated that cGAS-STING signaling is strongly implicated in the pathogenesis of central nervous system (CNS) diseases which are underscored by neuroinflammatory-driven disease progression. Understanding and regulating the interactions between cGAS-STING signaling and the nervous system may thus provide an effective approach to prevent or delay late-onset CNS disorders. Here, we present a review of recent advances in the literature on cGAS-STING signaling and provide a comprehensive overview of the modulatory patterns of the cGAS-STING pathway in CNS disorders.

Traditional Chinese Medicine and Western Medicine Share Similar Philosophical Approaches to Fight COVID-19.

Though disciplines in the same field, modern medicine (Western medicine) and traditional medicine (Traditional Chinese medicine, TCM) have been viewed as two distinct and divergent fields of medicine and thus differ greatly in their ways of diagnosing, treating, and preventing disease. In brief, Western medicine is primarily an evidence (laboratory)-based science, whereas TCM is more of a healing art based on the theory of Yin and Yang and the five elements in the human body. Therefore, whether TCM and Western medicine could use similar philosophical approaches to treat disease remains unclear. It is well-known that vitamin D enhances immune function and reduces the spread of some viruses. Indeed, recent evidence shows that the blood calcium level is strongly associated with COVID-19 severity, and vitamin D supplementation has shown favorable effects in viral infections. According to TCM theory, the pathogenesis of COVID-19 is closely associated with cold-dampness, an etiological factor in TCM. Cold-dampness could be attenuated by sun exposure and Wenyang herbs, both of which can restore the vitamin D level in the blood in Western medicine. Therefore, TCM and Western medicine could share similar philosophical methods to fight COVID-19 and understanding their philosophical theories could achieve the maximum benefits for treatment of COVID-19 and other diseases.

Prevalence and risk factors of overweight and obesity in Chinese patients with first-episode drug-naïve major depressive disorder.

BACKGROUNDS: Obesity and overweight are common in patients with major depressive disorder (MDD); the results are inconsistent due to confounding variables involved in studies. Furthermore, no well-designed study has been published to investigate the prevalence, risk factors and underlying mechanisms of obesity/overweight in Chinese MDD patients. This study aimed to investigate the prevalence of obesity/overweight and related risk factors in first-episode, drug-naïve (FEDN) patients with MDD in China. METHODS: A total of 1718 patients were recruited. Their clinical and anthropometric data, thyroid function and biochemical parameters were collected. All patients were evaluated on the 17-item Hamilton Rating Scale for Depression, 14-item Hamilton Anxiety Rating Scale and the Positive and Negative Syndrome Scale. RESULTS: The prevalence of obesity and overweight was 3.73% and 56.00%, respectively. Multivariable logistic regression analysis showed that TSH was the only independent risk factor for weight gain in MDD patents. The fitting curve of the relationship between TSH and BMI formed an inverted U-shaped parabola. The ordinal logit mode showed that when TSH<=2.68 was set as a reference, the odd rates of weight increased with the increase of TSH, and the highest rate was 3.929 (95%CI: 2.879-5.361, P<0.0001). LIMITATION: Causality cannot be drawn due to cross-sectional design. CONCLUSION: Our results suggest that overweight is very common among patients with FEDN MDD rather than obesity. TSH is a promising predictor and potential biomarker of high weight in MDD patients, and there is an inverted U-shaped parabolic relationship between TSH and BMI.

The Effects of Yuan-Zhi Decoction and Its Active Ingredients in Both In Vivo and In Vitro Models of Chronic Cerebral Hypoperfusion by Regulating the Levels of Aß and Autophagy.

Chronic cerebral hypoperfusion (CCH) is closely related to the occurrence of Alzheimer's disease (AD) in the elderly. CCH can induce overactivation of autophagy, which increases the deposition of amyloid-ß (Aß) plaques in the brain, eventually impairing the cognitive function. Yuan-Zhi decoction (YZD) is a traditional Chinese medicine (TCM) formulation that is used to treat cognitive dysfunction in the elderly, but the specific mechanism is still unclear. In this study, we simulated CCH in a rat model through bilateral common carotid artery occlusion (BCCAO) and treated the animals with YZD. Standard neurological tests indicated that YZD significantly restored the impaired cognitive function after BCCAO in a dose-dependent manner. Furthermore, YZD also decreased the levels of Aß aggregates and the autophagy-related proteins ATG5 and ATG12 in their hippocampus. An in vitro model of CCH was also established by exposing primary rat hippocampal neurons to hypoxia and hypoglycemia (H-H). YZD and its active ingredients increased the survival of these neurons and decreased the levels of Aß1-40 and Aß1-42, autophagy-related proteins Beclin-1 and LC3-II, and the APP secretases BACE1 and PS-1. Finally, both Aß aggregates showed a positive statistical correlation with the expression levels of the above proteins. Taken together, YZD targets Aß, autophagy, and APP-related secretases to protect the neurons from hypoxic-ischemic injury and restore cognitive function.

Neuroprotective effects of tenuigenin on neurobehavior, oxidative stress, and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats.

BACKGROUND: Tenuigenin (TEN), a major active component of the Chinese herb Polygala tenuifolia root, has been used to improve memory and cognitive function in Traditional Chinese Medicine for centuries. PURPOSE: The present study was designed to explore the possible neuroprotective effect of TEN on the streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD). METHODS: STZ was injected twice intracerebroventrically (3 mg/kg, ICV) on alternate days (day 1 and day 3) in Rats. Daily treatment with TEN (2, 4, and 8 mg/kg) starting from the first dose of STZ for 28 days. Memory-related behaviors were evaluated using the Morris water maze test. Hyperphosphorylation of tau proteins in hippocampus were measured by western blot assay. Superoxide dismutase activities, malondialdehyde, glutathione peroxidase and 4-hydroxy-2-nonenal adducts contents were also measured in the hippocampus. RESULTS: Treatment with TEN significantly improved STZ-induced cognitive damage, markedly reduced changes in malondialdehyde and 4-hydroxy-2-nonenal adducts, and significantly inhibited STZ-induced reduction in superoxide dismutase and glutathione peroxidase activities in the hippocampus. In addition, TEN decreased hyperphosphorylation of tau resulting from intracerebroventricular STZ (ICV-STZ) injection, and Nissl staining results showed that TEN has protective effects on hippocampal neurons. CONCLUSION: These results provide experimental evidence demonstrating preventive effect of TEN on cognitive dysfunction, oxidative stress, and hyperphosphorylation of tau in ICV-STZ rats. This study indicates that TEN may have beneficial effects in the treatment of neurodegenerative disorders such as AD.

Psychometric properties of a Chinese asthma quality of life questionnaire.

PURPOSE: To assess the acceptability, reliability, validity, and responsiveness of the Chinese Asthma Quality of Life Questionnaire (C-AQLQ) in a sample of Chinese asthma patients. METHODS: The C-AQLQ and Short Form 36 Health Survey (SF-36) scales were administered to patients at baseline and 3 months later. Asthma severity condition and lung function were evaluated. Necessary data were gathered to assess the psychometric properties such as the feasibility, internal consistency, test-retest reliability, structural validity, discriminant validity, convergent validity, and responsiveness of the C-AQLQ. RESULTS: One hundred and thirty-seven patients completed the investigation. The Cronbach's alpha coefficient for the total scale was 0.96. Factor analysis yielded five factors that generally corresponded to the five proposed subscales. Patients with mild asthma reported higher scores than patients with moderate/severe asthma on all subscales other than environmental stimuli. Lung function measurement and the asthma severity score correlated significantly with domains of the C-AQOL but with fewer domains of the SF-36. The questionnaire detected within-subject changes in patients' asthma status during follow-up. CONCLUSIONS: Results indicated preliminary support that the C-AQLQ is a reliable, valid, discriminating, and responsive measure of quality of life in Chinese asthma patients. It is more sensitive than the generic SF-36 in detecting differences in asthma severity.

Herba Cistanches: Anti-aging.

The Cistanche species ("Rou Cong Rong" in Chinese) is an endangered wild species growing in arid or semi-arid areas. The dried fleshy stem of Cistanches has been used as a tonic in China for many years. Modern pharmacological studies have since demonstrated that Herba Cistanches possesses broad medicinal functions, especially for use in anti-senescence, anti-oxidation, neuroprotection, anti-inflammation, hepatoprotection, immunomodulation, anti-neoplastic, anti-osteoporosis and the promotion of bone formation. This review summarizes the up-to-date and comprehensive information on Herba Cistanches covering the aspects of the botany, traditional uses, phytochemistry and pharmacology, to lay ground for fully elucidating the potential mechanisms of Herba Cistanches' anti-aging effect and promote its clinical application as an anti-aging herbal medicine.

Herbal Medicine Cordyceps sinensis Improves Health-Related Quality of Life in Moderate-to-Severe Asthma.

Moderate-to-severe asthma has a substantial impact on the health-related quality of life (HR-QOL) of the patients. Cordyceps sinensis is a traditional Chinese medicine that is evaluated clinically for the treatment of many diseases, such as chronic allograft nephropathy, diabetic kidney disease, and lung fibrosis. In order to investigate the effects of Cordyceps sinensis on patients with moderate-to-severe persistent asthma, 120 subjects were randomized to receive Corbin capsule containing Cordyceps sinensis for 3 months (treatment group, n = 60), whereas the control group (n = 60) did not receive treatment with Corbin capsule. Inhaled corticosteroid and as-needed ß-agonists were used in the treatment of both groups. HR-QOL was measured with the Juniper's Asthma Quality of Life Questionnaire (AQLQ). The incidence of asthma exacerbation, pulmonary function testing, and serum measurements of inflammatory mediators were also evaluated. The results showed that the treatment group indicated a significant increase in AQLQ scores and lung function compared with the control group. The expression levels of the inflammation markers IgE, ICAM-1, IL-4, and MMP-9 in the serum were decreased and IgG increased in the treatment group compared with the control group. Therefore, the conclusion was reached that a formulation of Cordyceps sinensis improved the HR-QOL, asthma symptoms, lung function, and inflammatory profile of the patients with moderate-to-severe asthma. This trial is registered with ChiCTR-IPC-16008730.

Luoyutong Treatment Promotes Functional Recovery and Neuronal Plasticity after Cerebral Ischemia-Reperfusion Injury in Rats.

Luoyutong (LYT) capsule has been used to treat cerebrovascular diseases clinically in China and is now patented and approved by the State Food and Drug Administration. In this retrospective validation study we investigated the ability of LYT to protect against cerebral ischemia-reperfusion injury in rats. Cerebral ischemia-reperfusion injury was induced by middle cerebral artery occlusion followed by reperfusion. Capsule containing LYT (high dose and medium dose) as treatment group and Citicoline Sodium as positive control treatment group were administered daily to rats 30 min after reperfusion. Treatment was continued for either 3 days or 14 days. A saline solution was administered to control animals. Behavior tests were performed after 3 and 14 days of treatment. Our findings revealed that LYT treatment improved the neurological outcome, decreased cerebral infarction volume, and reduced apoptosis. Additionally, LYT improved neural plasticity, as the expression of synaptophysin, microtubule associated protein, and myelin basic protein was upregulated by LYT treatment, while neurofilament 200 expression was reduced. Moreover, levels of brain derived neurotrophic factor and basic fibroblast growth factor were increased. Our results suggest that LYT treatment may protect against ischemic injury and improve neural plasticity.

Activation of T-LAK-cell-originated protein kinase-mediated antioxidation protects against focal cerebral ischemia-reperfusion injury.

T-LAK-cell-originated protein kinase (TOPK), a MAPKK-like kinase, is crucial for neural progenitor cell proliferation; however, the function of TOPK and the molecular mechanism underlying cerebral ischemia-reperfusion injury remains unknown. Therefore, we investigated the role of TOPK in experimental stroke. Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCAO) and reperfusion, and TOPK small interfering RNA (siRNA) was delivered by intracerebroventricular injection at the beginning of MCAO. After TOPK overexpression and H2O2 stimulation in PC12 neuronal cells, antioxidative proteins, apoptosis-related proteins and signal pathways were detected by western blot analysis, the levels of the peroxidation products (malondialdehyde and 3-nitrotyrosine) were measured with ELISA. Phosphorylation of TOPK was increased in rat cortical neurons following tMCAO. TOPK overexpression in PC12 cells augmented levels of antioxidative proteins (peroxiredoxin 1 and 2, heme oxygenase 1 and manganese superoxide dismutase), as well as total superoxide dismutase activity, along with inhibition of malondialdehyde and 3-nitrotyrosine upon H2O2 stimulation. TOPK overexpression increased cell viability and reduced expression of caspase 3 and caspase 12 in PC12 cells in response to H2O2 . The p-ERK level was increased by TOPK overexpression, and antioxidative protection afforded by TOPK was abolished by blocking the extracellular signal-regulated kinase pathway in PC12 cells. TOPK siRNA increased the infarct volume and reduced total superoxide dismutase activity in the cortex in vivo after MCAO. These data reveal that activating TOPK confers neuroprotection against focal cerebral ischemia-reperfusion injury by antioxidative function, in part through activation of the extracellular signal-regulated kinase pathway.

DaoTan decoction (DTD) inhibits tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1), p53 and p21, in human umbilical vein endothelia cells (HUVECs).

CONTEXT: DTD is a Chinese herb prescription used for centuries to treat atherosclerosis or dizziness. Previous studies show that DTD could inhibit ICAM-1 expression induced by TNF-α. However, its mechanism has never been clearly described. OBJECTIVE: To examine the hypothesis that DTD might inhibit TNF-α-induced ICAM-1 expression through regulating the expression of p53 and p21. MATERIALS AND METHODS: The rats were orally treated with DTD for 3 d (2.3 g/kg per day), and then the serum was collected. HUVECs were cultured and stimulated by TNF-α with or without DTD serum (5, 10, and 20%). The expression of ICAM-1 mRNA was examined by RT-PCR and the expression of p53 and p21 was examined by western blot analysis. RESULTS: The ICAM-1 mRNA levels induced by TNF-α were significantly reduced from 23 to 47%, and the expression of p53 and p21 mRNA levels were significantly reduced from 13 to 43% and 14 to 42%, as the concentration of DTD serum increased. In western blot, TNF-α-induced the expression of p53 and was inhibited from 15 to 53%, by DTD serum in a concentration-dependent manner. TNF-α-induced expression of p21 was inhibited from 2 to 37%, by DTD serum in a concentration-dependent manner. DISCUSSION AND CONCLUSION: DTD has a function of "dissolving phlegm", thus it is chosen for the treatment of atherosclerosis. This study demonstrated that DTD could significantly inhibit the expression of ICAM-1, p53 and p21, which are important factors of atherosclerosis. Therefore, the present study indicates the pharmacological basis for treatment of atherosclerosis with DTD.

Characterization of the properties of seven promoters in the motor cortex of rats and monkeys after lentiviral vector-mediated gene transfer.

Lentiviral vectors deliver transgenes efficiently to a wide range of neuronal cell types in the mammalian central nervous system. To drive gene expression, internal promoters are essential; however, the in vivo properties of promoters, such as their cell type specificity and gene expression activity, are not well known, especially in the nonhuman primate brain. Here, the properties of five ubiquitous promoters (murine stem cell virus [MSCV], cytomegalovirus [CMV], CMV early enhancer/chicken ß-actin [CAG], human elongation factor-1α [EF-1α], and Rous sarcoma virus [RSV]) and two cell type-specific promoters (rat synapsin I and mouse α-calcium/calmodulin-dependent protein kinase II [CaMKIIα]) in rat and monkey motor cortices in vivo were characterized. Vesicular stomatitis virus G (VSV-G)-pseudotyped lentiviral vectors expressing enhanced green fluorescent protein (EGFP) under the control of the various promoters were prepared and injected into rat and monkey motor cortices. Immunohistochemical analysis revealed that all of the VSV-G-pseudotyped lentiviral vectors had strong endogenous neuronal tropisms in rat and monkey brains. Among the seven promoters, the CMV promoter showed modest expression in glial cells (9.4%) of the rat brain, whereas the five ubiquitous promoters (MSCV, CMV, CAG, EF-1α, and RSV) showed expression in glial cells (7.0-14.7%) in the monkey brain. Cell type-specific synapsin I and CaMKIIα promoters showed excitatory neuron-specific expression in the monkey brain (synapsin I, 99.7%; CaMKIIα, 100.0%), but their specificities for excitatory neurons were significantly lower in the rat brain (synapsin I, 94.6%; CaMKIIα, 93.7%). These findings could be useful in basic and clinical neuroscience research for the design of vectors that efficiently deliver and express transgenes into rat and monkey brains.