Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.

[Spatial Network of Urban Heat Environment in Beijing-Tianjin-Hebei Urban Agglomeration Based on MSPA and Circuit Theory].

Rapid urbanization has increased the complexity of the urban heat environment system, which has negative impacts on the health of the urban ecological system and the human habitat. By combining theories and technologies such as geographic information systems, remote sensing, morphological spatial pattern analysis, and circuit theory with data from MODIS land surface temperature production, urban heat island patches in the Beijing-Tianjin-Hebei urban agglomeration were quantitatively identified in terms of their spatial and temporal distribution characteristics and their spatial and temporal transfer paths. This foundation revealed the geographical network structure of the urban heat environment as well as the spatial and temporal evolution process of critical corridors. According to the findings, urban heat island patches covered 16610 km2 in 2020, accounting for 7.68% of the study area. In the Beijing-Tianjin-Hebei urban agglomeration, both the area and the number of urban heat island patches considerably increased between 2005 and 2020, going from being dominated by isolated island types of urban heat island patches in 2005 to being dominated by core types in 2020. In particular, the non-urban heat island patches, core type, and edge type of urban heat island patches in 2005 were the major ancestors of the core type and edge type urban heat island patches in 2020. In the Beijing-Tianjin-Hebei urban agglomeration, there were more urban heat environment source sites, corridor length, densities, and present densities in 2020 than there were in 2005. The sensitive corridor was found to be the predominant type of urban heat island corridor in the Beijing-Tianjin-Hebei urban agglomeration in 2020. The number of sensitive corridors increased the highest in the period from 2005-2020. As the coefficient of urban heat environment corridors increased concurrently, it was apparent that the urban heat environment corridor had a propensity to grow continuously in the Beijing-Tianjin-Hebei urban agglomeration. The active adaptation and mitigation measures of the urban heat environment were proposed, and a spatial network model of the urban heat environment was finally provided. To adapt to, mitigate, and promote urban sustainable development risks, these research findings will serve as a paradigm for the identification of the urban heat environment spatial network actively and methodically.

Disease-Modifying Activity of Huperzine A on Alzheimer's Disease: Evidence from Preclinical Studies on Rodent Models.

(1) Background: Huperzine A, a natural cholinesterase (AChE) inhibitor isolated from the Chinese herb Huperzia Serrata, has been used as a dietary supplement in the United States and a drug in China for therapeutic intervention on Alzheimer's disease (AD). This review aims to determine whether Huperzine A exerts disease-modifying activity through systematic analysis of preclinical studies on rodent AD models. (2) Methods: Sixteen preclinical studies were included based on specific criteria, and the methodological qualities were analyzed by SYRCLE's risk of bias tool. Some outcomes were meta-analyzed: latencies and time spent in quadrant of Morris water maze, soluble amyloid-ß (Aß) level measured by ELISA in the cortex and hippocampus, Aß plaque numbers measured by immunohistochemistry in hippocampus, choline acetyltransferase (ChAT) activity, and AChE activity. Finally, the mechanisms of Huperzine A on AD models were summarized. (3) Conclusions: The outcomes showed that Huperzine A displayed AChE inhibition, ChAT activity enhancement, memory improvement, and Aß decreasing activity, indicating the disease-modifying effect of Huperzine A. However, due to the uneven methodological quality, the results need to be rationally viewed, and extensively repeated.

α-mangostin derivative 4e as a PDE4 inhibitor promote proteasomal degradation of alpha-synuclein in Parkinson's disease models through PKA activation.

BACKGROUND: Parkinson's disease (PD) is a multi-factorial neurodegenerative disease affecting motor function of patients. The hall markers of PD are dopaminergic neuron loss in the midbrain and the presence of intra-neuronal inclusion bodies mainly composed of aggregation-prone protein alpha-synuclein (α-syn). Ubiquitin-proteasome system (UPS) is a multi-step reaction process responsible for more than 80% intracellular protein degradation. Impairment of UPS function has been observed in the brain tissue of PD patients. PDE4 inhibitors have been shown to activate cAMP-PKA pathway and promote UPS activity in Alzheimer's disease model. α-mangostin is a natural xanthonoid with broad biological activities, such as antioxidant, antimicrobial and antitumour activities. Structure-based optimizations based on α-mangostin produced a potent PDE4 inhibitor, 4e. Herein, we studied whether 4e could promote proteasomal degradation of α-syn in Parkinson's disease models through PKA activation. METHODS: cAMP Assay was conducted to quantify cAMP levels in samples. Model UPS substrates (Ub-G76V-GFP and Ub-R-GFP) were used to monitor UPS-dependent activity. Proteasome activity was investigated by short peptide substrate, Suc-LLVY-AMC, cleavage of which by the proteasome increases fluorescence sensitivity. Tet-on WT, A30P, and A53T α-syn-inducible PC12 cells and primary mouse cortical neurons from A53T transgenic mice were used to evaluate the effect of 4e against α-syn in vitro. Heterozygous A53T transgenic mice were employed to assess the effect of 4e on the clearance of α-syn in vivo, and further validations were applied by western blotting and immunohistochemistry. RESULTS: Taken together, α-mangostin derivative 4e, a PDE4 inhibitor, efficiently activated the cAMP/PKA pathway in neuronal cells, and promoted UPS activity as evidenced by enhanced degradation of UPS substrate Ub-G76V-GFP and Ub-R-GFP, as well as elevated proteasomal enzyme activity. Interestingly, 4e dramatically accelerated degradation of inducibly-expressed WT and mutant α-syn in PC12 cells, in a UPS dependent manner. Besides, 4e consistently activated PKA in primary neuron and A53T mice brain, restored UPS inhibition and alleviated α-syn accumulation in the A53T mice brain. CONCLUSIONS: 4e is a natural compound derived highly potent PDE4 inhibitor. We revealed its potential effect in promoting UPS activity to degrade pathogenic proteins associated with PD.

The effect and underlying mechanisms of garlic extract against cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis of experimental animal studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is the main cause of dementia, and according to traditional Chinese medicine (TCM), it is leaded by the deficiency of essence, qi, and blood. Allii sativi bulbus, acrid and warm, is traditionally used as the important adjuvant and conductant drug to distribute essence-qi throughout the body, fortify the spleen and harmonize the stomach. Garlic (Allium sativum L., Alliaceae) has also been reported to display potential anti-AD effect both in vitro and in vivo studies, while no systematic review of these studies has been conducted. AIM OF THE STUDY: This review aims to provide a comprehensive evaluation of the effect and underlying mechanism of garlic extract against cognitive impairment and AD neuropathology through meta-analysis and sensitivity analysis. MATERIALS AND METHODS: Eligible studies were searched from PubMed, Web of Science and EMBASE from February to March in 2020, and 13 studies describing the effect of garlic extract in AD animal models (551 mice and 88 rats) were identified. RESULTS: Analysis of these studies showed that garlic extract could reduce cerebral Aß levels [Aß40: SMD -8.62(-11.75, -5.49), p < 0.00001 and Aß42: SMD -11.70(-18.01, -5.39), p=0.0003], and increase the number of right crossings in MWM [SMD 2.87(1.48, 4.26), p < 0.0001] in AD animals. However, moderate risk of bias (quality score ranged from 40% to 60%) is revealed by SYRCLE's checklist, mainly because of the lacks of sample size calculation, random allocation and blind assessment. CONCLUSIONS: This review shows that garlic extract may be effective in alleviating cognitive impairment and neuropathology in AD animal models. High quality AD animal studies with enough sample size and more comprehensive evaluation of outcomes are needed to further confirm the results.

Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models.

BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative motor disorders, and is characterized by the presence of Lewy bodies containing misfolded α-synuclein (α-syn) and by selective degeneration of midbrain dopamine neurons. Studies have shown that upregulation of ubiquitin-proteasome system (UPS) activity promotes the clearance of aggregation-prone proteins such as α-syn and Tau, so as to alleviate the neuropathology of neurodegenerative diseases. PURPOSE: To identify and investigate lycorine as a UPS enhancer able to decrease α-syn in transgenic PD models. METHODS: Dot blot was used to screen α-syn-lowering compounds in an inducible α-syn overexpression cell model. Inducible wild-type (WT) and mutant α-syn-overexpressing PC12 cells, WT α-syn-overexpressing N2a cells and primary cultured neurons from A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vitro. Heterozygous A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vivo. mCherry-GFP-LC3 reporter was used to detect autophagy-dependent degradation. Ub-R-GFP and Ub-G76V-GFP reporters were used to detect UPS-dependent degradation. Proteasome activity was detected by fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC (Suc-LLVY-AMC). RESULTS: Lycorine significantly promoted clearance of over-expressed WT and mutant α-syn in neuronal cell lines and primary cultured neurons. More importantly, 15 days' intraperitoneal administration of lycorine effectively promoted the degradation of α-syn in the brains of A53T transgenic mice. Mechanistically, lycorine accelerated α-syn degradation by activating cAMP-dependent protein kinase (PKA) to promote proteasome activity. CONCLUSION: Lycorine is a novel α-syn-lowering compound that works through PKA-mediated UPS activation. This ability to lower α-syn implies that lycorine has the potential to be developed as a pharmaceutical for the treatment of neurodegenerative diseases, such as PD, associated with UPS impairment and protein aggregations.

The pharmacological activity of epigallocatechin-3-gallate (EGCG) on Alzheimer's disease animal model: A systematic review.

BACKGROUND: Alzheimer's disease (AD) is currently incurable and there is an urgent need to develop new AD drugs. Many studies have revealed the potential neuroprotective effect of Epigallocatechin-3-O-gallate (EGCG), the main antioxidant in green tea, on animal models of AD. However, a systematic review of these reports is lacking. PURPOSE: To assess the effectiveness of EGCG for AD treatment using systematic review and meta-analysis of pre-clinical trials. METHODS: We conducted a systematic search of all available randomized controlled trials (RCTs) performed up to November 2019 in the following electronic databases: ScienceDirect, Web of Science, and PubMed. 17 preclinical studies assessing the effect of EGCG on animal AD models have been identified. Meta-analysis and subgroup analysis was performed to evaluate cognition improvement of various types of AD models. The study quality was assessed using the CAMARADES checklist and the criteria of published studies. RESULTS: Our analysis shows that the methodological quality ranges from 3 to 5, with a median score of 4. According to meta-analysis of random-effects method, EGCG showed a positive effect in AD with shorter escape latency (SMD= -9.24, 95%CI= -12.05 to -6.42) and decreased Aß42 level (SD= -25.74,95%CI= -42.36 to -9.11). Regulation of α-, ß-, γ-secretase activity, inhibition of tau phosphorylation, anti-oxidation, anti-inflammation, anti-apoptosis, and inhibition of AchE activity are reported as the main neuroprotective mechanisms. Though more than 100 clinical trials have been registered on the ClinicalTrials.gov, only one clinical trial has been conducted to test the therapeutic effects of EGCG on the AD progression and cognitive performance. CONCLUSION: Here, we conducted this review to systematically describe the therapeutic potential of EGCG in animal models of AD and hope to provide a more comprehensive assessment of the effects in order to design future clinical trials. Besides, the safety, blood-brain barrier (BBB) penetration and bioavailability issues in conducting clinical trials were also discussed.

Quercetin in Animal Models of Alzheimer's Disease: A Systematic Review of Preclinical Studies.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. It involves progressive impairment of cognitive function. A growing number of neuroprotective compounds have been identified with potential anti-AD properties through in vitro and in vivo models of AD. Quercetin, a natural flavonoid contained in a wide range of plant species, is repeatedly reported to exert neuroprotective effects in experimental animal AD models. However, a systematic analysis of methodological rigor and the comparison between different studies is still lacking. A systematic review uses a methodical approach to minimize the bias in each independent study, providing a less biased, comprehensive understanding of research findings and an objective judgement of the strength of evidence and the reliability of conclusions. In this review, we identified 14 studies describing the therapeutic efficacy of quercetin on animal AD models by electronic and manual retrieval. Some of the results of the studies included were meta-analyzed by forest plot, and the methodological quality of each preclinical trial was assessed with SYRCLE's risk of bias tool. Our results demonstrated the consistent neuroprotective effects of quercetin on different AD models, and the pharmacological mechanisms of quercetin on AD models are summarized. This information eliminated the bias of each individual study, providing guidance for future tests and supporting evidence for further implementation of quercetin into clinical trials. However, the limitations of some studies, such as the absence of sample size calculations and low method quality, should also be noted.

Resveratrol in experimental Alzheimer's disease models: A systematic review of preclinical studies.

Alzheimer's disease (AD) is a progressive dementia caused by degeneration of the central nervous system with a high incidence in the elderly. Resveratrol is a natural compound contained in a wide range of plant species, including grapes. Recent studies have shown positive effects of resveratrol in animal models of AD; however, whether these results justify clinical trials is uncertain. Furthermore, there are multiple theories about the mechanism(s) by which resveratrol works and knowing how it works can suggest targets for future drug development. So far, systematic evaluation of both of these aspects is lacking. In this study, we selected 19 studies describing the efficacy of resveratrol in rodent AD models by electronic and manual retrieval. The method quality of the study were analyzed by the SYRCLE's risk of bias tool and the experimental data were retrieved and meta-analyzed using forest plot. Analysis of these studies demonstrates the consistent neuroprotective effects of resveratrol in AD models and offers insights into the possible pharmacological mechanisms. This information eliminates the bias of each study, providing supporting evidence for the implementation of clinical trials. However, the limits of studies were also noticed: low method quality, lack of sample size calculation and high risks of bias.

[Effects of sewage and Cd combined stress on metabolites of maize seedling]. / 污水与镉复合胁迫对玉米幼苗代谢物的影响.

To investigate the influences of sewage and cadmium combined stress on maize seedling metabolites, we took GC-MS metabonomics technology to analyze the metabolite species, content and metabolic pathways. A total of 50 kinds of metabolites were identified. Under single stress of Cd, the malic acid content in maize seedling decreased, the citric acid content increased significantly, and the tricarboxylic acid cycle was relatively stable. Under the combined stress, both malic acid and citric acid contents increased significantly, and the tricarboxylic acid cycle was inhibited. Both single Cd stress and combined stress of sewage and Cd, especially the latter, led to the decrease of glucose and the increase of those substances related to resistance, such as proline, putrescine, muscle and γ-aminobutyric acid, which indicated the photosynthesis was inhibited. It was concluded that sewage and cadmium combined stress influence on maize seedling metabolites mainly by inhibiting the tricarboxylic acid cycle and photosynthesis.

Validation of the Chinese version of EORTC QLQ-BM22 in patients with bone metastases.

PURPOSE: Our aim is to test the validity, reliability, and acceptability of the Chinese version of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Bone Metastases 22 (EORTC QLQ-BM22) module to assess health-related quality of life (HRQOL) in patients with bone metastases in China. METHODS: Patients with histological confirmation of malignancy and bone metastases from Tianjin Cancer Institution and Hospital from June 2013 to April 2014 were enrolled in this study. All patients self-administered the EORTC QLQ-BM22 and the EORTC QLQ-C30. The Karnofsky Performance Scale (KPS) was performed to evaluate scores. The reliability and validity tests of the questionnaires were based on Cronbach's α coefficients, Pearson correlation test, and Wilcoxon rank sum nonparametric test. RESULTS: Internal consistency reliabilities of all the four scales were acceptable. Scales measuring similar HRQOL aspects were found to correlate with one another between EORTC QLQ-BM22 and EORTC QLQ-C30, but differences still existed. Significant differences were demonstrated in the scores of all four subscales of the QLQ-BM22 between the two KPS subgroups (KPS ≤ 80; KPS > 80). Meanwhile, the compliance for item completion of the QLQ-BM22 was satisfactory. CONCLUSIONS: The Chinese version of EORTC QLQ-BM22 is a reliable and valid instrument, which is appropriate for measuring the HRQOL of patients with bone metastases in China.