Upregulation of TRPC1 in microglia promotes neutrophil infiltration after ischemic stroke.

Neutrophil infiltration has been linked to worse clinical outcomes after ischemic stroke. Microglia, a key type of immune-competent cell, engage in cross-talk with the infiltrating immune cells in the inflamed brain area, yet the molecular mechanisms involved remain largely unexplored. In this study, we investigated the mechanisms of how canonical transient receptor potential 1 (TRPC1) modulated neutrophil infiltration in male mouse cerebral ischemia and reperfusion injury (CIRI) models. Our findings revealed a notable upregulation of TRPC1 in microglia within both middle cerebral artery occlusion reperfusion (MCAO/R) and in vitro oxygen-glucose deprivation/regeneration (OGD/R) model. Conditional Trpc1 knockdown in microglia markedly reduced infarct volumes and alleviated neurological deficits. Microglia conditional Trpc1 knockdown mice displayed less neutrophil infiltration in peri-infarct area. Trpc1 knockdown microglia exhibited a reduced primed proinflammatory phenotype with less secretion of CC-Chemokines ligand (CCL) 5 and CCL2 after MCAO/R. Blocking CCL5/2 significantly mitigated neutrophil infiltration in microglia/neutrophil transwell co-culture system upon OGD/R condition. Trpc1 knockdown markedly reduced store-operated calcium entry and nuclear factor of activated T-cells c1 (NFATc1) level in OGD/R treated microglia. Overexpression of Nfatc1 reversed the CCL5/2 reducing effect of Trpc1 knockdown, which is mediated by small interfering RNA in BV2 cells upon OGD/R. Our data indicate that upregulation of TRPC1 in microglia stimulates the production of CCL5/2 through the Ca2+/NFATc1 pathway. Upregulated CCL5/2 leads to an increase in neutrophil infiltration into the brain, thereby aggravating reperfusion injury. Our results demonstrate the importance of TRPC1 in microglia-mediated neuroinflammation and suggest a potential means for reducing CIRI induced neurological injury.

Astrocyte KDM4A mediates chemokines and drives neutrophil infiltration to aggravate cerebral ischemia and reperfusion injury.

Neutrophils plays a crucial role in acute ischemic brain injury and have emerged as potential treatment targets to mitigate such injuries. Lysine-specific demethylase 4 A (KDM4A), a member of the histone lysine demethylase family of enzymes involved in transcriptional regulation of gene expression, is upregulated during hypoxic events. However, the exact role of KDM4A in the pathological process of ischemic stroke remains largely unexplored. Our findings reveal that there was an upregulation of KDM4A levels in reactive astrocytes within both stroke mouse models and in vitro oxygen-glucose deprivation/regeneration (OGD/R) models. Using a conditional knockout mouse, we observed that astrocytic Kdm4a knockout regulates neutrophil infiltration and alleviates brain injury following middle cerebral artery occlusion reperfusion. Furthermore, Kdm4a deficiency astrocytes displayed lower chemokine C-X-C motif ligand 1 (CXCL1) level upon OGD/R and decreased neutrophil infiltration in a transwell system. Mechanistically, KDM4A, in cooperation with nuclear factor-kappa B (NF-κB), activates Cxcl1 gene expression by demethylating histone H3 lysine 9 trimethylation at Cxcl1 gene promoters in astrocytes upon OGD/R injury. Our findings suggest that astrocyte KDM4A-mediated Cxcl1 activation contributes to neutrophil infiltration via cooperation with NF-κB, and KDM4A in astrocytes may serve as a potential therapeutic target to modulate neutrophil infiltration after stroke.

TOM40 mediates the effect of TSPO on postpartum depression partially through regulating calcium homeostasis in microglia.

AIMS: To assess the effect of the translocator protein 18 kDa (TSPO) on postpartum depression and explore its mechanism. METHODS: Postpartum depression (PPD) mouse model was established, and flow cytometry, immunofluorescence, Western blot analysis, real-time quantitative PCR, adeno-associated virus (AAV), co-immunoprecipitation-mass spectrometry and immunofluorescence co-staining were used to detect the effect of TSPO ligand ZBD-2 on PPD mice. RESULTS: ZBD-2 inhibits the overactivation of microglia in the hippocampus and amygdala of PPD model mice. ZBD-2 not only inhibited the inflammation but also repressed the burst of reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Meanwhile, ZBD-2 protects mitochondria from LPS-induced damages through inhibiting the influx of calcium. ZBD-2 modulated the calcium influx by increasing the level of translocase of the outer mitochondrial membrane 40 (TOM40) and reducing the interaction of TSPO and TOM40. In addition, the effect of ZBD-2 was partially dependent on anti-oxidative process. Knockdown of TOM40 by adeno-associated virus (AAV) in the hippocampus or amygdala dramatically reduced the effect of ZBD-2 on PPD, indicating that TOM40 mediates the effect of ZBD-2 on PPD. CONCLUSIONS: TOM40 is required for the effect of ZBD-2 on treating anxiety and depression in PPD mice. This study reveals the role of microglia TSPO in PPD development and provides the new therapeutic strategy for PPD.

Case report of severe coronary artery tortuosity with coexisting connective tissue disease.

Coronary artery tortuosity (CAT) is frequently detected during coronary angiography or coronary electron-beam computed tomography angiography by cardiovascular interventionalists. In this article, we described the case of a 69-year-old female patient with recurrent chest discomfort for 1 month and recurrence 1 week ago, accompanied by emaciation, gastrointestinal discomfort, and low skin temperature at the extremities. After a series of tests, the patient was finally diagnosed with severe CAT and coexisting connective tissue disease. Accordingly, she was treated with conventional medications, and diet and lifestyle modifications. The symptoms of the patient resolved gradually after 1 year of follow-up. Although there is no unanimous conclusion on the pathogenesis and clinical characteristics of CAT, this disease may provide a clue to the diagnosis of connective tissue disease, and warrants exploration through further research.

Design and optimization of complex mechanism flip shaping subsystem based on genetic algorithm and rigid-flexible coupled dynamic model.

In this paper, the cam connecting rod system of the high-speed group vertical machine flipping shaping mechanism is the research object. In order to solve the key problem that the flipping shaping mechanism cannot accurately complete the action when the vibration of the mechanism is large. In this paper, the finite element method is used to construct the dynamic model of the connecting rod subsystem of the flipped shaping mechanism. And The dynamic model of cam roller subsystem is established by centralized parameter method. Based on the MATLAB Genetic Algorithm toolbox and using Newmark's method, the dynamic equations of the flipped plastic mechanism system are solved. The optimal parameters of the connecting rod of the mechanism, the cam profile curve and the swing power and swing torque of the mechanism at different speeds are analyzed. The results show that the speed and convex contour line are important factors affecting the performance of the mechanism. And the pendulum force (swing torque) is the main cause of the vibration of the mechanism on the frame. Therefore, the mechanism pendulum dynamic and the swing moment are selected as the objective functions of the optimization model. By selecting the node parameters of the sixth order spline motion law and the cross-section parameters of the connecting rod as the design variables. The cam linkage system is optimally designed to obtain the optimal value. Finally, the optimal design of the flipped shaping mechanism was analyzed and compared with the original mechanism.

Chemical composition analysis and value evaluation of stems and leaves of Astragalus membranaceus var. mongholicus / 中国中药杂志

This study aimed to provide data support for resource utilization of the stems and leaves of Astragalus membranaceus var. mongholicus(SLAM) by analyzing and evaluating the chemical constituents. The crude protein, crude fiber, and soluble saccharide of SLAM were analyzed by Kjeldahl method, filtration method, and UV-Vis spectrophotometry, respectively. The nucleosides, amino acids, flavonoids, and saponins of SLAM were analyzed by ultraperformance liquid chromatography-triple quadrupole mass spectrometry(UPLC-TQ-MS). Combined with principal component analysis(PCA), the quality difference of resource components of SLAM was comprehensively evaluated. The results showed that the average content of crude protein, crude fiber, total polysaccharide, and redu-cing sugar in SLAM was 5.11%, 30.33%, 11.03 mg·g~(-1), and 31.90 mg·g~(-1), respectively. Six nucleosides, 15 amino acids, 22 flavonoids, and one saponin were detected, with an average content of 1.49 mg·g~(-1), 6.00 mg·g~(-1), 1.86 mg·g~(-1), and 35.67 μg·g~(-1), respectively. The content of various types of chemical components in SLAM differed greatly in different harvesting periods and growing years. The results of PCA showed that the quality of SLAM produced in Ningxia was superior. The results can provide references for the utilization of SLAM.

Preparation of Huoluo Xiaoling gel plaster and its transdermal penetration in vitro / 中国中药杂志

Huoluo Xiaoling Dan is a classical prescription commonly used for blood circulation and pain relief in clinic with obvious effects. To make it directly treat lesion and improve the effect, this research optimized the preparation process of Huoluo Xiaoling gel paste and further evaluated its in vitro transdermal absorption performance, so as to provide a scientific basis for its development and utilization. Using primary viscosity, holding viscosity, and sensory score as evaluation indexes, the matrix amount of gel paste was determined by the single factor test and Box-Behnken response surface method. The ultra-performance liquid chromatography(UPLC) method was established to determine the content of eight active ingredients, including Danshensu, ferulic acid, salvianolic acid B, salvianolic acid A, ligustilide, tanshinone Ⅱ_A, 11-keto-β-boswellic(KBA), and 3-acetyl-11-keto-β-boswellic acid(AKBA). A mo-dified Franz diffusion cell method was used to evaluate and compare the absorption properties of the gel paste without volatile oil and with volatile oil microemulsion. The results showed that the optimal prescription for Huoluo Xiaoling gel paste matrix was NP700(1.35 g), glycerol(7.00 g), micropowder silica gel(1.25 g), sodium carboxymethyl cellulose(0.20 g), tartaric acid(0.06 g), and glyceryl aluminum(0.04 g). The mass fractions of eight active ingredients in the paste were successively 0.48, 0.014, 0.95, 0.39, 0.57, 0.055, 0.35, and 0.97 mg·g~(-1). The results of the in vitro transdermal absorption test showed that the addition of the volatile oil or the volatile oil microemulsion promoted the transdermal absorption of the active ingredients, and the law of drug penetration conformed to the zero equation or the Higuchi equation. The gel paste prepared by the optimal prescription has good appearance and adhesion, with no residue, and has the characteristics of skeletal slow-release preparation, which is easy to reduce the number of administration, la-ying a foundation for the development of new external dosage forms of Huoluo Xiaoling Dan.

Incidence of coexistence of multiple diseases in patients over 65 years of age and its impact on the risk of death in hospital / 公共卫生与预防医学

Objective To investigate the incidence of multiple disease coexistence in emergency department patients over 65 years old and its impact on the risk of death in hospital, so as to provide theoretical basis for reducing the risk of death in emergency department patients over 65 years old. Methods From January 2019 to January 2020, elderly patients over 65 years old who received emergency treatment in our hospital were selected as subjects to analyze the coexistence of multiple diseases. The information of current disease, blood pressure, blood glucose level and other potential influencing factors, as well as the incidence of hospitalization after emergency treatment were collected, and the factors influencing the risk of death in hospital were analyzed and discussed. Results During the study period, there were 1 195 patients over 65 years old, including 469 patients with multi-disease coexistence (excluding malignant tumors), with an incidence rate of 39.25%. Among the elderly patients in the emergency department, the top four diseases with multiple coexisting diseases are as follows: ischemic stroke (43.92%), acute myocardial infarction (24.95%), hemorrhagic stroke (16.84%), and falls (11.30%). In addition, “ischemic stroke + hypertension + diabetes + coronary heart disease” accounted for the highest proportion (42.22%) in the combination of multi-disease coexisting diseases, followed by "myocardial infarction + ischemic stroke + hypertension + Diabetes + coronary heart disease” (21.11%), and the third in the composition ratio was “fall + ischemic stroke + hypertension + diabetes + coronary heart disease” (0.66%). Among the 469 patients with multi-disease coexistence, a total of 68 died during hospitalization after emergency department; 469 patients were divided into two groups: the dead and the survivors, and the potential factors affecting the risk of death were analyzed. The multivariate regression analysis showed that male (OR=1.485 , P<0.001), age over 80 years (OR=3.090, P<0.05), more than four types of comorbidities (OR=4.407, P<0.001), BMI level showed weight loss (OR=4.366, P<0.001) and Comorbidities included hypertension (OR=3.564, P<0.001) as a potential risk factor, which would increase the risk of death; while normal blood pressure (OR=0.581, P<0.001) might potentially reduce the risk of death. Conclusion Special attention should be paid to the elderly patients over 65 years old who are male, over 80 years old, thin and with many types of comorbidities (more than four types), especially those with hypertension at the same time, in order to reduce hospitalization after emergency department risk of death during the period.

Irisin: A promising treatment for neurodegenerative diseases.

The beneficial effects of exercise on human brain function have been demonstrated in previous studies. Myokines secreted by muscle have attracted increasing attention because of their bridging role between exercise and brain health. Regulated by PPARγ coactivator 1α, fibronectin type III domain-containing protein 5 releases irisin after proteolytic cleavage. Irisin, a type of myokine, is secreted during exercise, which induces white adipose tissue browning and relates to energy metabolism. Recently, irisin has been shown to exert a protective effect on the central nervous system. Irisin secretion triggers an increase in brain-derived neurotrophic factor levels in the hippocampus, contributing to the amelioration of cognition impairments. Irisin also plays an important role in the survival, differentiation, growth, and development of neurons. This review summarizes the role of irisin in neurodegenerative diseases and other neurological disorders. As a novel positive mediator of exercise in the brain, irisin may effectively prevent or decelerate the progress of neurodegenerative diseases in models and also improve cognitive functions. We place emphasis herein on the potential of irisin for prevention rather than treatment in neurodegenerative diseases. In ischemic diseases, irisin can alleviate the pathophysiological processes associated with stroke. Meanwhile, irisin has anxiolytic and antidepressant effects. The potential therapeutic effects of irisin in epilepsy and pain have been initially revealed. Due to the pleiotropic and beneficial properties of irisin, the possibility of irisin treating other neurological diseases could be gradually explored in the future.

Tanshinone IIA improves contextual fear- and anxiety-like behaviors in mice via the CREB/BDNF/TrkB signaling pathway.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re-experience, avoidance, and hyperarousal. However, there are few drugs for PTSD treatment. In this study, conditioned fear and single-prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD-like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety-like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity-related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p-CREB, BDNF, TrkB, and synaptic plasticity-related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB-binding protein. These findings indicate that TanIIA ameliorates PTSD-like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment.

Mechanism of CNS regulation by irisin, a multifunctional protein.

Exercise not only builds up our body but also improves cognitive function. Skeletal muscle secretes myokine during exercise as a large reservoir of signaling molecules, which can be considered as a medium between exercise and brain health. Irisin is a circulating myokine derived from the Fibronectin type III domain-containing protein 5 (FNDC5). Irisin regulates energy metabolism because it can stimulate the "Browning" of white adipose tissue. It has been reported that irisin can cross the blood-brain barrier and increase the expression of a brain-derived neurotrophic factor (BDNF) in the hippocampus, which improves learning and memory. In addition, the neuroprotective effect of irisin has been verified in various disease models. Therefore, this review summarizes how irisin plays a neuroprotective role, including its signal pathway and mechanism. In addition, we will briefly discuss the therapeutic potential of irisin for neurological diseases.

Prevention of Ulcerative Colitis in Mice by Sweet Tea (Lithocarpus litseifolius) via the Regulation of Gut Microbiota and Butyric-Acid-Mediated Anti-Inflammatory Signaling.

Sweet tea (Lithocarpus litseifolius [Hance] Chun) is a new resource for food raw materials, with plenty of health functions. This study aimed to investigate the preventive effect and potential mechanism of sweet tea extract (STE) against ulcerative colitis (UC). Briefly, BABL/c mice were treated with STE (100 and 400 mg/kg) for 2 weeks to prevent 3% dextran sulfate sodium (DSS)-induced UC. It was found that STE supplementation significantly prevented DSS-induced UC symptoms; suppressed the levels of pro-inflammatory mediators, such as myeloperoxidase and tumor necrosis factor-α; increased the levels of anti-inflammatory cytokines; and up-regulated the expression of tight junction proteins (Zonula occludens-1 and Occludin). STE also altered the gut microbiota profile of UC mice by increasing Bacteroidetes, Lactobacillus, Akkermansia, Lachnospiraceae_NK4A136_group, and Alistipes and inhibiting Firmicutes, Proteobacteria, and Helicobacter, accompanied by a significant increase in the content of butyric acid. Moreover, STE increased the expression of G-protein-coupled receptor (GPR) 43 and GPR109A and inhibited the expression of histone deacetylase 3 (HDAC3) and nuclear factor-κB p65 (NF-κB p65) in the colon. In conclusion, this study indicated that STE has a good preventive effect on UC by regulating gut microbiota to activate butyrate-GPR-mediated anti-inflammatory signaling and simultaneously inhibit HDAC3/NF-κB inflammatory signaling.

Activation of GIPR Exerts Analgesic and Anxiolytic-Like Effects in the Anterior Cingulate Cortex of Mice.

Background: Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. Methods: The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala2-GIP) and antagonist (Pro3-GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR. Results: In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala2-GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro3-GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice. Conclusions: GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.

Disrupting cannabinoid receptor interacting protein 1 rescues cognitive flexibility in long-term estrogen-deprived female mice.

Hormone therapy (HT) has failed to improve learning and memory in postmenopausal women according to recent clinical studies; however, the reason for failure of HT in improving cognitive performance is unknown. In our research, we found cognitive flexibility was improved by 17ß-Estradiol (E2) in mice 1 week after ovariectomy (OVXST), but not in mice 3 months after ovariectomy (OVXLT). Isobaric tags for relative and absolute quantitation (iTRAQ) revealed increased cannabinoid receptor interacting protein 1 (CNRIP1) in E2-treated OVXLT mice compared with E2-treated OVXST mice. Adeno-associated virus 2/9 (AAV2/9) delivery of Cnrip1 short-hairpin small interfering RNA (Cnrip1-shRNA) rescued the impaired cognitive flexibility in E2 treated OVXLT mice. This effect is dependent on CB1 function, which could be blocked by AM251-a CB1 antagonist. Our results indicated a new method to increasing cognitive flexibility in women receiving HT by disrupting CNRIP1.

DNA methylation diversity analysis of Lycium barbarum samples from different cultivation areas based on MSAP / 中国中药杂志

Obvious epigenetic differentiation occurred on Lycium barbarum in different cultivation areas in China. To investigate the difference and change rule of DNA methylation level and pattern of L. barbarum from different cultivation areas in China, the present study employed fluorescence-assisted methylation-sensitive amplified polymorphism(MSAP) to analyze the methylation level and polymorphism of 53 genomic DNA samples from Yinchuan Plain in Ningxia, Bayannur city in Inner Mongolia, Jingyuan county and Yumen city in Gansu, Delingha city in Qinghai, and Jinghe county in Xinjiang. The MSAP technical system suitable for the methylation analysis of L. barbarum genomic DNA was established and ten pairs of selective primers were selected. Among amplified 5'-CCGG-3' methylated sites, there were 35.85% full-methylated sites and 39.88% hemi-methylated sites, showing a high degree of epigenetic differentiation. Stoichiometric analysis showed that the ecological environment was the main factor affecting the epigenetic characteristics of L. barbarum, followed by cultivated varieties. Precipitation, air temperature, and soil pH were the main ecological factors affecting DNA methylation in different areas. This study provided a theoretical basis for the analysis of the epigenetic mechanism of L. barbarum to adapt to the diffe-rent ecological environments and research ideas for the introduction, cultivation, and germplasm traceability of L. barbarum.

Determination of eight active components of Bufei Huoxue Capsules in rat plasma and their pharmacokinetics by UHPLC-MS/MS / 中国中药杂志

An ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method was established to investigate the pharmacokinetic behaviors of psoralenoside, isopsoralenoside, calycosin-7-glucoside, ononin, psoralen, isopsoralen, methylnissolin, and neobavaisoflavone in rat plasma after oral administration of Bufei Huoxue Capsules. After SD rats were administered with Bufei Huoxue Capsules suspension by gavage, blood samples were collected from the inner canthus at different time points. After protein precipitation, plasma samples were separated on ACQUITY UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 μm). The mobile phase consisted of acetonitrile(A) and water(B) containing 0.1% formic acid in gradient elution. The positive and negative ions were measured simultaneously in the multi-reaction monitoring(MRM) mode. The pharmacokinetic parameters were calculated and fitted by DAS 3.2.8. Psoralenoside, isopsoralenoside, calycosin-7-glucoside, ononin, psoralen, isopsoralen, methylnissolin, and neobavaisoflavone were detected in the rat plasma after drug administration, with AUC_(0-t) of(3 357±1 348),(3 555±1 696),(3.03±0.88),(2.21±0.33),(1 787±522),(2 295±539),(5.69±1.41) and(3.40±0.75) μg·L~(-1)·h, and T_(max) of(1.56±0.62),(1.40±0.70),(0.21±0.05),(0.25±0.12),(0.26±0.11),(0.34±0.29),(0.74±0.59), and 0.25 h. The method is proved specific and repeatable and is suitable for the determination of psoralenoside, isopsoralenoside, calycosin-7-glucoside, ononin, pso-ralen, isopsoralen, methylnissolin, and neobavaisoflavone in the rat plasma, which can be applied to pharmacokinetic study.

Tenuifolin in Treatment of Dementia： A Review / 中国实验方剂学杂志

Tenuifolin， a main component in Polygalae Radix， is frequently used as an important indicator for quality control of Polygalae Radix and its processed products. Dementia is a serious and persistent cognitive disorder， and the number of dementia patients is increasing worldwide， which brings great economic burden and mental pressure to families and society. At present， cholinesterase inhibitor and other drugs can only alleviate the symptoms of dementia， and there are some toxic and side effects. It has been found that tenuifolin can significantly improve cognitive disorder， learning and memory and is expected to be a potential drug for treating dementia. Tenuifolin exerts protective effects on amyloid-β （Aβ） deposition， acetylcholine reduction， neuroinflammation， cellular oxidative damage and nerve cell apoptosis caused by neurodegenerative diseases via multiple mechanisms， and can be applied to various types of dementia. In addition， it can be quickly absorbed into the blood， mainly distributed in liver and kidney， and can enter into the brain through the blood-brain barrier. However， because of its large molecular mass and poor fat solubility， tenuifolin can be rapidly eliminated， generating some problems such as low oral absoBrbability and permeability of blood-brain barrier. Therefore， the information of chemistry， pharmacology， pharmacokinetics and toxicology of tenuifolin was summarized in this paper to provide reference and ideas for further research and application.

Scutellarin alleviates depression-like behaviors induced by LPS in mice partially through inhibition of astrocyte-mediated neuroinflammation.

Depression is a kind of common mental disorder associated with neuroinflammation, and astrocytes play a vital role in regulating and mediating neuroinflammation in central nervous system. Scutellarin has significant anti-inflammatory and neuroprotective effects. However, whether scutellarin exerts antidepressant effect remains unknown. In present study, it was found that scutellarin suppressed LPS-induced neuroinflammation in the hippocampus and alleviated depression-like behaviors in mice. In addition, scutellarin inhibited LPS-induced elevation of TNFα, IL-1ß, IL-6 and iNOS, and reversed the downregulation of IL-4 and BDNF in astrocytes in vitro. Furthermore, the activated TLR4/NF-κB pathway in LPS-treated astrocytes was suppressed by scutellarin. Collectively, these results suggest that scutellarin ameliorates depression-like behaviors induced by neuroinflammation partially through inhibiting the TLR4/NF-κB pathway in astrocytes.

Activation of microglial G­protein-coupled receptor 30 protects neurons against excitotoxicity through NF-κB/MAPK pathways.

Neuroexcitotoxicity is a common feature in neuronal damage and neurodegenerative diseases. Our previous studies have confirmed that neuronal and astrocytic G­protein-coupled receptor 30 (GPR30) play a key role in neuroprotection in vivo and in vitro. Microglia are considered as immune cells in the central nervous system. However, the role of microglial GPR30 in neuroprotection against neuroexcitotoxicity remained unclear. In this study, MTT, Western blot, immunocytochemical staining, phagocytosis assay and wound healing assay were employed to detect the effect of GPR30 in N9 microglial cells after exposure to glutamate. We found that the treatment of GPR30 specific agonist G1 inhibited glutamate-induced proliferation and activation in N9 microglial cells. G1 inhibited M1 polarization, facilitated M2 polarization, and decreased over-phagocytosis but had no effect on migration ability in microglia. The result of neurons and microglia co-culture showed that the activation of microglial GPR30 protected neurons from excitotoxicity through the NF-κB/MAPK signaling pathways. Our findings suggested a key role of microglial GPR30 in excitatory neuronal damage and neurodegenerative diseases.

Effect and Mechanism of Didangtang on NLRP3 Inflammasomes in Diabetic Cardiomyopathy Mice / 中国实验方剂学杂志

Objective:To investigate the effects of different doses of Didangtang on myocardial inflammatory lesions in diabetic mice. Method:Sixty C57BL/6J mice were randomly divided into normal group （<italic>n</italic>=10） and model group （<italic>n</italic>=50）. The diabetic mice in the model group were established by intraperitoneal injection of high-fat diet combined with streptozotocin （STZ）. After model reproducing， the mice were fed with high-fat diet. After 8 weeks， the cardiac function of the mice was detected by using an ultrasound imaging platform. If the cardiac function decreased， the diabetic cardiomyopathy mice were modeled successfully. The nonmodel mice were eliminated， and finally 40 model mice were modeled. The rats in the model group were randomly divided into model group， low， medium and high dose of Didangtang group（1.5，3，6 g·kg^-1） and simvastatin group（0.001 5 g·kg^-1） according to heart function， with 8 rats in each group. The cardiac function of mice was detected by ultrasound imaging platform， fiber bragg grating（FBG）， triglyceride（TG） and total cholesterol（TC） were detected by automatic biochemical analyzer， hematoxylin-eosin （HE） staining was used to observe the pathological changes of myocardium， and the levels of NOD-like receptor3（NLRP3）， thiomdoxin interaction protein（TXNIP）， cysteinyl aspartate specific proteinase-1（Caspase-1） and Interleukin-1<italic>β</italic>（IL-1<italic>β</italic>） in myocardial tissue， as well as the content of reactive oxygen species（ROS） were detected by Western blot. Result:Compared with the normal control group， the levels of FBG， TC and TG in the model group significantly increased （<italic>P</italic><0.01）； the values of EF and FS significantly decreased （<italic>P</italic><0.01）； the expression of ROS significantly increased （<italic>P</italic><0.05）， and the expressions of NLRP3， TXNIP， Caspase-1 and IL-1<italic>β</italic> in the myocardial tissue significantly increased （<italic>P</italic><0.05）. Compared with the model group， the levels of FBG， TC and TG in the middle and high dose groups of Didangtang and simvastatin groups significantly decreased （<italic>P</italic><0.05）； the EF and FS in each dose group and simvastatin group improved （<italic>P</italic><0.05）， and the change in the middle dose group was more obvious （<italic>P</italic><0.05）. HE staining showed that Didangtang could improve the pathological changes of myocardial tissue in mice， the ROS expression levels of mice in each dose group of Didangtang and simvastatin group significantly reduced， especially in the middle dose group， the expression levels of NLRP3， TXNIP， Caspase-1 and IL-1<italic>β</italic> in each dose group significantly decreased， and the effect of middle dose of Didangtang on reducing expressions of NLRP3， TXNIP and Caspase-1 in myocardial tissue was more obvious， the effect of high dose of Didangtang on reducing the expression of IL-1<italic>β</italic> in myocardial tissue was more obvious. Conclusion:Didangtang can improve myocardial inflammatory lesions in diabetic cardiomyopathy mice by inhibiting the activation of NLRP3 inflammasome.