The behavioral, pathological and therapeutic features of the triple transgenic Alzheimer's disease (3 × Tg-AD) mouse model strain.

As a classic animal model of Alzheimer's disease (AD), the 3 × Tg-AD mouse not only recapitulates most of anatomical hallmarks observed in AD pathology but also displays cognitive alterations in memory and learning tasks. The 3 × Tg-AD can better show the two characteristics of AD, amyloid ß (Aß) and neurofibrillary tangles (NFT). Therefore, 3 × Tg-AD strain is widely used in AD pathogenesis research and new drug development of AD. In this paper, the construction methods, pathological changes, and treatment characteristics of 3 × Tg-AD mouse models commonly used in AD research are summarized and commented, hoping to provide reference for researchers to choose and establish experimental patterns.

The role of signaling crosstalk of microglia in hippocampus on progression of ageing and Alzheimer's disease.

Based on single-cell sequencing of the hippocampi of 5× familiar Alzheimer's disease (5× FAD) and wild type mice at 2-, 12-, and 24-month of age, we found an increased percentage of microglia in aging and Alzheimer's disease (AD) mice. Blood brain barrier injury may also have contributed to this increase. Immune regulation by microglia plays a major role in the progression of aging and AD, according to the functions of 41 intersecting differentially expressed genes in microglia. Signaling crosstalk between C-C motif chemokine ligand (CCL) and major histocompatibility complex-1 bridges intercellular communication in the hippocampus during aging and AD. The amyloid precursor protein (APP) and colony stimulating factor (CSF) signals drive 5× FAD to deviate from aging track to AD occurrence among intercellular communication in hippocampus. Microglia are involved in the progression of aging and AD can be divided into 10 functional types. The strength of the interaction among microglial subtypes weakened with aging, and the CCL and CSF signaling pathways were the fundamental bridge of communication among microglial subtypes.

Qi-fu-yin attenuated cognitive disorders in 5xFAD mice of Alzheimer's disease animal model by regulating immunity.

Introduction: Cognitive impairment is the main symptom of Alzheimer's disease (AD). Accumulating evidence implicate that immunity plays an important role in AD. Here, we investigated the effect of Qi-fu-yin (QFY) on cognitive impairment and cytokine secretion of 5xFAD mice. Methods: We used 2.5-month-old 5xFAD transgenic mice for behavioral tests to observe the changes in cognitive function after QFY treatment. After the behavioral experiment, the whole brain, cortex and plasma of each mouse were collected for soluble Aß analysis, immunohistochemical experiment and cytokine analysis. Results: Here we found that the treatment of QFY ameliorated the ability of object recognition, passive avoidance responses and the ability of spatial learning and memory in 5xFAD mice. The deposits of ß1 - 42 and Aß1 - 40 were alleviated and the ration of Aß1 - 42/Aß1 - 40 was decrease in the plasma and brain of 5xFAD mice administrated with QFY. The administration of QFY promoted the secretion of anti-inflammatory cytokines, IL-5, IL-10 and G-CSF, and reduced the content of proinflammatory cytokines IFN-γ in plasma of 5xFAD mice. Notably, we found that the treatment of QFY decreased the concentration of CCL11 in the brain and plasma of 5xFAD mice. Conclusion: This suggested that QFY improved cognition and reduced Aß deposits in 5xFAD mice by regulating abnormal immunity in 5xFAD mice. QFY may be as a potential therapeutic agent for AD.

The Mechanisms Underlying the Pharmacological Effects of GuiPi Decoction on Major Depressive Disorder based on Network Pharmacology and Molecular Docking

BACKGROUND AND AIM: Major Depressive Disorder (MDD) is a common affective disorder. GuiPi decoction (GPD) is used to treat depression in China, Japan, and Korea. However, its effective ingredients and antidepressant mechanisms remain unclear. We attempted to reveal the potential mechanisms of GPD in the treatment of MDD by network pharmacology and molecular docking. In addition, we conducted an enzymatic activity assay to validate the results of molecular docking. METHODS: GPD-related compounds and targets, and MDD-related targets were retrieved from databases and literature. The herb-compound-target network was constructed by Cytoscape. The protein- protein interaction network was built using the STRING database to find key targets of GPD on MDD. Enrichment analysis of shared targets was analyzed by MetaCore database to obtain the potential pathway and biological process of GPD on MDD. The main active compounds treating MDD were screened by molecular docking. The PDE4s inhibitors were screened and verified by an enzyme activity assay. RESULTS: GPD contained 1222 ingredients and 190 potential targets for anti-MDD. Possible biological processes regulated by GPD were neurophysiological processes, blood vessel morphogenesis, Camp Responsive Element Modulator (CREM) pathway, and Androgen Receptor (AR) signaling crosstalk in MDD. Potential pathways in MDD associated with GPD include neurotransmission, cell differentiation, androgen signaling, and estrogen signaling. Fumarine, m-cresol, quercetin, betasitosterol, fumarine, taraxasterol, and lupeol in GPD may be the targets of SLC6A4, monoamine oxidase A (MAOA), DRD2, OPRM1, HTR3A, Albumin (ALB), and NTRK1, respectively. The IC50 values of trifolin targeting Phosphodiesterase (PDE) 4A and girinimbine targeting PDE4B1 were 73.79 µM and 31.86 µM, respectively. The IC50 values of girinimbine and benzo[a]carbazole on PDE4B2 were 51.62 µM and 94.61 µM, respectively. CONCLUSION: Different compounds in GPD may target the same protein, and the same component in GPD can target multiple targets. These results suggest that the effects of GPD on MDD are holistic and systematic, unlike the pattern of one drug-one target.

Identification of the molecular subgroups in Alzheimer's disease by transcriptomic data.

Background: Alzheimer's disease (AD) is a heterogeneous pathological disease with genetic background accompanied by aging. This inconsistency is present among molecular subtypes, which has led to diagnostic ambiguity and failure in drug development. We precisely distinguished patients of AD at the transcriptome level. Methods: We collected 1,240 AD brain tissue samples collected from the GEO dataset. Consensus clustering was used to identify molecular subtypes, and the clinical characteristics were focused on. To reveal transcriptome differences among subgroups, we certificated specific upregulated genes and annotated the biological function. According to RANK METRIC SCORE in GSEA, TOP10 was defined as the hub gene. In addition, the systematic correlation between the hub gene and "A/T/N" was analyzed. Finally, we used external data sets to verify the diagnostic value of hub genes. Results: We identified three molecular subtypes of AD from 743 AD samples, among which subtypes I and III had high-risk factors, and subtype II had protective factors. All three subgroups had higher neuritis plaque density, and subgroups I and III had higher clinical dementia scores and neurofibrillary tangles than subgroup II. Our results confirmed a positive association between neurofibrillary tangles and dementia, but not neuritis plaques. Subgroup I genes clustered in viral infection, hypoxia injury, and angiogenesis. Subgroup II showed heterogeneity in synaptic pathology, and we found several essential beneficial synaptic proteins. Due to presenilin one amplification, Subgroup III was a risk subgroup suspected of familial AD, involving abnormal neurogenic signals, glial cell differentiation, and proliferation. Among the three subgroups, the highest combined diagnostic value of the hub genes were 0.95, 0.92, and 0.83, respectively, indicating that the hub genes had sound typing and diagnostic ability. Conclusion: The transcriptome classification of AD cases played out the pathological heterogeneity of different subgroups. It throws daylight on the personalized diagnosis and treatment of AD.

Effects of Qi-Fu-Yin on aging of APP/PS1 transgenic mice by regulating the intestinal microbiome.

Introduction: Alzheimer's disease is the most common form of dementia and closely related to aging. Qi-Fu-Yin is widely used to treat dementia, but its anti-aging effects is unknown. Methods: We used 11-month-old APP/PS1 transgenic mice for behavioral tests to observe the changes in cognitive function and age-related symptoms after Qi-Fu-Yin treatment. Fecal samples were collected for 16sRNA sequencing and metagenomic sequencing. Differences among the groups of intestinal microbiota and the associations with aging and intestinal microbiota were analyzed based on the results. Results: Here we found that Qi-Fu-Yin improved the ability of motor coordination, raised survival rate and prolonged the survival days under cold stress stimulation in aged APP/ PS1 transgenic mice. Our data from 16sRNA and metagenomic sequencing showed that at the Family level, the intestinal microbiota was significantly different among wild-type mice, APP/PS1 transgenic mice and the Qi-Fu-Yin group by PCA analysis. Importantly, Qi-Fu-Yin improved the functional diversity of the major KEGG pathways, carbohydrate-active enzymes, and major virulence factors in the intestinal flora of APP/PS1 transgenic mice. Among them, the functions of eight carbohydrate-active enzymes (GT2_Glycos_transf_2, GT4, GT41, GH2, CE1, CE10, CE3, and GH24) and the functions of top three virulence factors (defensive virulence factors, offensive virulence factors and nonspecific virulence factors) were significantly and positively correlated with the level of grasping ability. We further indicated that the Qi-Fu-Yin significantly reduced the plasma levels of IL-6. Conclusion: Our results indicated that the effects of Qi-Fu-Yin anti-aging of APP/PS1 transgenic mice might be through the regulation of intestinal flora diversity, species richness and the function of major active enzymes.

A network pharmacology-based study on key pharmacological pathways and targets of Qi Fu Yin acting on Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a central nervous system (CNS) disease characterized by progressive cognitive dysfunction and memory loss. Qi Fu Yin is mainly used to treat dementia, particularly AD, in the clinic, but its comprehensive mechanisms are not known. OBJECTIVE: In this research, we aimed to investigate the mechanisms of Qi Fu Yin in AD by network pharmacology and molecular docking. METHODS: First, the chemical constituents in Qi Fu Yin were obtained from five databases and classified according to their structure. Targets of chemical constituents and AD-related targets were also collected from the databases. Then, overlapping genes between Qi Fu Yin and AD were identified by intersection analysis. MetaCore was used to gather enrichment information. Combination synergy analysis was performed by Cytoscape. After ligand-receptor docking, the binding affinity was verified by ADP-Glo™ kinase assay and fluorescence resonance energy transfer (FRET) assay. RESULTS: We found 12 classes with 977 components in Qi Fu Yin. A total of 511 compounds and 577 potential target proteins in Qi Fu Yin were found to be related to AD. The pathways of Qi Fu Yin in AD included oxidative stress and immune response. There was the best binding affinity between 11 pairs of genes and compounds. Furthermore, CDK5 was inhibited by nepetin with an IC50 of 3.172 µM and kaempferol with an IC50 of 2.659 µM. Ceanothic acid and 18 beta-glycyrrhetinic acid inhibited GSK3ß, and the IC50 values were 8.732 µM and 8.06 µM, respectively. CONCLUSION: Qi Fu Yin might alleviate Tau hyperphosphorylation by nepetin, kaempferol, ceanothic acid and 18 beta-glycyrrhetinic acid.

Shuxuening injection protects against myocardial ischemia-reperfusion injury through reducing oxidative stress, inflammation and thrombosis.

BACKGROUND: Shuxuening injection (SXNI) has a good effect on cardiovascular and cerebrovascular diseases. Here, our study aims to investigate whether SXNI have the protective effect on myocardial ischemia-reperfusion injury (MIRI) and elucidate the mechanism of SXNI's cardiac protection. METHODS: In this experiment, the coronary arteries of Sprague-Dawley (SD) rats were ligated for the induction of a MIRI model. TTC staining and haematoxylin-eosin (HE), as well as troponin I (TnI), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), creatine kinase (CK) and CK-MB levels, were used to detect the protective effect of SXNI. In rat cardiac tissue, superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) activities and glucose-regulated protein 78 (GRP78), calreticulin (CRT), CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 expression levels were detected. In rat serum, the levels of inflammatory factors, including high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, tumour necrosis factor-α, interleukin-6 (IL-6) and IL-1ß, were measured by Elisa. In the rat arterial tissue, Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) expression was measured by western blot. In the rat plasma, ELISA was used to assay the levels of coagulation and plasmin system indicators, including platelet activating factor, endothelin, tissue factor (TF), plasminogen inhibitor, thromboxane B2, plasma fibrinogen. RESULTS: The results showed that SXNI can reduce the infarct size of myocardial tissue, decrease the myocardial enzyme and TnI levels and decrease the degree of myocardial damage compared with the model group. Additionally, SXNI can increase the activity of antioxidant enzymes, reduce the MDA level and decrease the GRP78, CRT, CHOP and caspase-12 expression levels. SXNI also decreased the levels of inflammatory cytokines in rat serum, lowered the level of procoagulant molecules in plasma and reduced the TLR4/NF-κB expression. CONCLUSIONS: SXNI has protective effect on MIRI mainly by inhibiting oxidative stress and endoplasmic reticulum stress (ERS), thereby regulating TLR4/NF-κB pathway to reduce inflammation, and lowing procoagulant-related factors levels to reduce the risk of thrombosis.

Antidepressant-like effects of the Guanxin Danshen formula via mediation of the CaMK II-CREB-BDNF signalling pathway in chronic unpredictable mild stress-induced depressive rats.

BACKGROUND: Depression is a chronic and recurrent syndrome of mood disorder causing immense social and economic burden; thus, treatment should be improved. Guanxin Danshen formula (GXDSF), a natural botanical drug composition prescription, has significant cardiovascular protective effects and is widely used in the clinical treatment of myocardial ischaemic diseases. However, it is still unclear and seldom studied whether GXDSF has neuroprotective effects against depressive disorders. This study explored whether GXDSF has antidepressant-like effects in rats exposed to chronic unpredictable mild stress (CUMS) and analysed the possible underlying neurotrophic expression and psychotropic mechanisms. METHODS: The present study was designed to investigate the antidepressant effects of GXDSF treatment in a CUMS-induced rat model. Based on the clinical doses, the drug-treated group was intragastrically administered GXDSF for 30 days, and rats were simultaneously exposed to CUMS stimulation for 30 days. After induction and drug administration, the depression-like behaviours were determined via the sucrose preference test (SPT), the open field test (OFT), the tail suspension test (TST), and the forced swim test (FST). ELISA kits were used to examine the monoaminergic neurotransmitters, monoamine oxidase (MAO) and Ca2+ levels in the hippocampus. Moreover, we measured and analysed the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels and the upstream regulation and signal pathways of BDNF and NGF to explore their related mechanisms in this animal model of depression, including calcium-calmodulin dependent protein kinase-II (CaMKII) and cAMP response element-binding (CREB). RESULTS: The results revealed that GXDSF may possess significant antidepressant-like effects via improving body weight, raising the sucrose preference in the SPT, increasing the total distance, the number of upright stands, and the residence time of the central zone in the open field test (OPF) and reducing the immobility time in the TST and FST. In addition, GXDSF significantly upregulated the relative levels of neurotransmitters, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in a dose-dependent manner and inhibited MAO activities in the hippocampus. Moreover, GXDSF reversed the decline in intracellular CREB and p-CREB expression induced by CUMS, downregulated the phosphorylation levels of intracellular CaMKII and its two subunits CaMKIIα and CaMKIIß in the hippocampus, and thus, clearly upregulated the downstream effector protein expression levels of BDNF, NGF, and synitaxine-1 in the hippocampus. These data suggest that the antidepressant effects of GXDSF have a potential relationship with regulating changes in the CaMKII-CREB-BDNF pathway. CONCLUSIONS: Despite several limitations of this study, the results have suggested that GXDSF administration possesses antidepressant-like effects in CUMS-treated rats and provide the first in vivo demonstration of a possible mechanism of GXDSF via regulating changes in the CaMKII-CREB-BDNF signalling pathway. These findings provide a novel potential substrate by which herbal antidepressants may exert therapeutic effects in the treatment of depression.

Ginsenoside Rb1 mitigates oxidative stress and apoptosis induced by methylglyoxal in SH-SY5Y cells via the PI3K/Akt pathway.

Diabetic encephalopathy is a severe diabetic complication characterized by cognitive dysfunction and neuropsychiatric disability. Methylglyoxal (MGO), a highly reactive metabolite of hyperglycemia, serves as a major precursor of advanced glycation end products that play key roles in diabetic complications. Ginsenoside Rb1 (abbreviated as Rb1) has received extensive attention due to its potential therapeutic effects on diabetes and neurodegeneration. Therefore, this study aimed to investigate the effects of Rb1 on MGO-induced damage in SH-SY5Y cells and the related mechanism. SH-SY5Y cells were pretreated with Rb1 for 8 h and then exposed to MGO (0.5 mM) for 24 h. Cell survival was assessed by the MTT assay. Cell apoptosis was assessed using Hoechst 33342/propidium iodide (PI) staining and an Annexin-V/PI kit. The activities of oxidative stress markers were examined using commercial kits. Reactive oxygen species (ROS) staining and JC-1 staining were used to evaluate mitochondria injury. In addition, protein levels were measured by Western blot analysis. As a result, Rb1 alleviated the injury induced by MGO by increasing the activities of superoxide dismutase, catalase and total glutathione, decreasing the level of malondialdehyde, and alleviating mitochondrial damage and ROS production. Furthermore, Rb1 could enhance the Bcl-2/Bax ratio, inhibit the expression of cleaved caspase-3 and cleaved caspase-9, and enhance the levels of phosphorylated Akt. Moreover, the protective effects of Rb1 against MGO-induced apoptosis were partly abolished by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) phosphorylation. Our results demonstrated that Rb1 ameliorated MGO-induced oxidative stress and apoptosis in SH-SY5Y cells via activating the PI3K/Akt signaling pathway.

Herb-Induced Liver Injury: Phylogenetic Relationship, Structure-Toxicity Relationship, and Herb-Ingredient Network Analysis.

Currently, hundreds of herbal products with potential hepatotoxicity were available in the literature. A comprehensive summary and analysis focused on these potential hepatotoxic herbal products may assist in understanding herb-induced liver injury (HILI). In this work, we collected 335 hepatotoxic medicinal plants, 296 hepatotoxic ingredients, and 584 hepatoprotective ingredients through a systematic literature retrieval. Then we analyzed these data from the perspectives of phylogenetic relationship and structure-toxicity relationship. Phylogenetic analysis indicated that hepatotoxic medicinal plants tended to have a closer taxonomic relationship. By investigating the structures of the hepatotoxic ingredients, we found that alkaloids and terpenoids were the two major groups of hepatotoxicity. We also identified eight major skeletons of hepatotoxicity and reviewed their hepatotoxic mechanisms. Additionally, 15 structural alerts (SAs) for hepatotoxicity were identified based on SARpy software. These SAs will help to estimate the hepatotoxic risk of ingredients from herbs. Finally, a herb-ingredient network was constructed by integrating multiple datasets, which will assist to identify the hepatotoxic ingredients of herb/herb-formula quickly. In summary, a systemic analysis focused on HILI was conducted which will not only assist to identify the toxic molecular basis of hepatotoxic herbs but also contribute to decipher the mechanisms of HILI.

An In Silico Model for Predicting Drug-Induced Hepatotoxicity.

As one of the leading causes of drug failure in clinical trials, drug-induced liver injury (DILI) seriously impeded the development of new drugs. Assessing the DILI risk of drug candidates in advance has been considered as an effective strategy to decrease the rate of attrition in drug discovery. Recently, there have been continuous attempts in the prediction of DILI. However, it indeed remains a huge challenge to predict DILI successfully. There is an urgent need to develop a quantitative structure-activity relationship (QSAR) model for predicting DILI with satisfactory performance. In this work, we reported a high-quality QSAR model for predicting the DILI risk of xenobiotics by incorporating the use of eight effective classifiers and molecular descriptors provided by Marvin. In model development, a large-scale and diverse dataset consisting of 1254 compounds for DILI was built through a comprehensive literature retrieval. The optimal model was attained by an ensemble method, averaging the probabilities from eight classifiers, with accuracy (ACC) of 0.783, sensitivity (SE) of 0.818, specificity (SP) of 0.748, and area under the receiver operating characteristic curve (AUC) of 0.859. For further validation, three external test sets and a large negative dataset were utilized. Consequently, both the internal and external validation indicated that our model outperformed prior studies significantly. Data provided by the current study will also be a valuable source for modeling/data mining in the future.

Investigation on Cf/PyC Interfacial Properties of C/C Composites by the Molecular Dynamics Simulation Method.

In this paper, a molecular dynamics (MD) simulation model of carbon-fiber/pyrolytic-carbon (Cf/PyC) interphase in carbon/carbon (C/C) composites manufactured by the chemical vapor phase infiltration (CVI) process was established based on microscopic observation results. By using the MD simulation method, the mechanical properties of the Cf/PyC interphase under tangential shear and a normal tensile load were studied, respectively. Meanwhile, the deformation and failure mechanisms of the interphase were investigated with different sizes of the average length L ¯ a of fiber surface sheets. The empirical formula of the interfacial modulus and strength with the change of L ¯ a was obtained as well. The shear properties of the isotropic pyrolysis carbon (IPyC) matrix were also presented by MD simulation. Finally, the mechanical properties obtained by the MD simulation were substituted into the cohesive force model, and a fiber ejection test of the C/C composite was simulated by the finite element analysis (FEA) method. The simulation results were in good agreement with the experimental ones. The MD simulation results show that the shear performance of the Cf/PyC interphase is relatively higher when L ¯ a is small due to the effects of non-in-plane shear, the barrier between crystals, and long sheet folding. On the other hand, the size of L ¯ a has no obvious influence on the interfacial normal tensile mechanical properties.

The Cardiotoxicity Induced by Arsenic Trioxide is Alleviated by Salvianolic Acid A via Maintaining Calcium Homeostasis and Inhibiting Endoplasmic Reticulum Stress.

Arsenic trioxide (ATO) has been verified as a breakthrough with respect to the management of acute promyelocytic leukemia (APL) in recent decades but associated with some serious adverse phenomena, particularly cardiac functional abnormalities. Salvianolic acid A (Sal A) is a major effective component in treating ATO-induced cardiotoxicity. Therefore, the objective of our study was to assess whether Sal A had protective effects by the regulation of calcium homeostasis and endoplasmic reticulum (ER) stress. For the in vivo study, BALB/c mice were treated with ATO and/or Sal A via daily tail vein injections for two weeks. For the in vitro study, we detected the effects of ATO and/or Sal A in real time using adult rat ventricular myocytes (ARVMs) and an IonOptix MyoCam system. Our results showed that Sal A pretreatment alleviated cardiac dysfunction and Ca2+ overload induced by ATO in vivo and vitro. Moreover, Sal A increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity and expression, alleviated [Ca2+]ER depletion, and decreased ER stress-related protein expression. Sal A protects the heart from ATO-induced injury and its administration correlates with the modulation of SERCA, the recovery of Ca2+ homeostasis, and the down-regulation of ER stress-mediated apoptosis.

Gastrodin Alleviates Cognitive Dysfunction and Depressive-Like Behaviors by Inhibiting ER Stress and NLRP3 Inflammasome Activation in db/db Mice.

Patients with diabetes mellitus (DM) suffer more risks from diabetic encephalopathy such as cognitive dysfunction and depressive-like behaviors. Numerous studies show that ER (endoplasmic reticulum) stress and inflammation play important roles in the development of diabetic encephalopathy. Gastrodin (Gas), one major component of Gastrodia elata, is traditionally used in central nervous system disorders and is believed to possess anti-inflammatory, anti-apoptotic, and other neuroprotective effects. This present study aims to explore the protective effects of Gas on diabetic encephalopathy. Gas was administrated daily (70 and 140 mg/Kg) for 12 weeks. Meanwhile, the fasting blood glucose and body weight of db/db mice were measured every two weeks. After Gas treatment, the Morris water maze (MWM) test and novel object recognition (NOR) test were performed to assess the learning and memory functions of db/db mice, and the forced swim test was performed to evaluate depressive-like behaviors of db/db mice. Additionally, the expression of ER stress and Nucleotide binding and oligomerization domain-like (Nod) receptor family pyrin domain-containing 3 (NLRP3) inflammasome related proteins were evaluated by using Western blot. Our study suggested that Gas attenuated blood glucose levels and dyslipidemia of db/db mice. It has been shown that Gas could improve learning and memory function and depressive-like behaviors of db/db mice. Moreover, Gas inhibited ER stress and NLRP3 inflammasome activation in the hippocampus. Taken together, this study demonstrates that Gas attenuates the diabetic encephalopathy by inhibiting ER stress and NLRP3 inflammasome activation.

Gastrodin Ameliorates Cognitive Dysfunction in Diabetes Rat Model via the Suppression of Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation.

Patients with diabetes mellitus (DM) are at high risk for cognitive dysfunction. Endoplasmic reticulum stress (ERS) and inflammation play crucial roles in DM. Gastrodin (Gas), the main component of Gastrodia elata, possesses anti-oxidative stress, anti-inflammatory, and neuroprotective effects. This present study aims to investigate whether Gas could ameliorate cognitive dysfunction in DM and to explore its underlying mechanisms. Rats with streptozotocin-induced type 2 DM were used in this study. After administration of Gas for 5 weeks, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in serum, TNF-α, IL-1ß, MDA and SOD in the hippocampus were measured. Morris water maze, hematoxylin and eosin (HE) and Nissl staining were performed to assess the effects of Gas on cognitive function and hippocampal neuronal apoptosis. Protein levels of GLUT3, brain derived neurotrophic factor (BDNF), GRP78, PERK, P-PERK, TXNIP, ASC, NLRP3, CHOP, Bcl-2 and Bax were measured by using Western blot. The results showed that Gas could improve hyperglycemia and dyslipidemia in DM rats, as the levels of TC, TG LDL-C in serum were decreased. TNF-α, IL-1ß, MDA contents in the hippocampus were decreased, and SOD contents was increased in the hippocampus of DM rats. Inflammation, oxidative stress, ERS, and apoptosis were observed in the hippocampus of DM rats, accompanied with decreased expression of BDNF and GLUT3. Gas improved the cognitive deficits caused by diabetes and inhibited inflammation, oxidative stress, ERS, and apoptosis in the hippocampus. Furthermore, Gas substantially increased the expression of GLUT3, and inhibited hippocampal ERS and ERS-mediated apoptosis. Additionally, Gas increased the expression of BDNF and decreased the activation of NLRP3 inflammasome. These results suggested that by inhibiting ERS and NLRP3 inflammasome activation and increasing the expression of BDNF and GLUT3, Gas exhibits neuroprotective effects against cognitive dysfunction in DM.

Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology.

Panax notoginseng (Burk) F. H. Chen, as traditional Chinese medicine, has a long history of high clinical value, such as anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, regulation of blood glucose and blood pressure, inhibition of neuronal apoptosis, and neuronal protection, and its main ingredients are Panax notoginseng saponins (PNS). Currently, Panax notoginseng (Burk) F. H. Chen may improve mental function, have anti-insomnia and anti-depression effects, alleviate anxiety, and decrease neural network excitation. However, the underlying effects and the mechanisms of Panax notoginseng (Burk) F. H. Chen and its containing chemical constituents (PNS) on these depression-related or anxiety-related diseases has not been completely established. This review summarized the antidepressant or anxiolytic effects and mechanisms of PNS and analyzed network targets of antidepressant or anxiolytic actions with network pharmacology tools to provide directions and references for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development. The review showed PNS and its components may exert these effects through regulating neurotransmitter mechanism (5-HT, DA, NE), modulation of the gamma-amino butyric acid (GABA) neurotransmission, glutamatergic system, hypo-thalamus-pituitary-adrenal (HPA) axis, brain-derived neurotrophic factor (BDNF), and its intracellular signaling pathways in the central nervous system; and produce neuronal protection by anti-inflammatory, anti-oxidation, or inhibition of neuronal apoptosis, or platelet aggregation and its intracellular signaling pathways. Network target analysis indicated PNS and its components also may have anti-inflammatory and anti-apoptotic effects, which leads to the preservation of brain nerves, and regulate the activity and secretion of nerve cells, exerting anti-depression and anxiolytic effects, which may provide new directions for further in-depth researches of related mechanisms.

Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice.

Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1ß is regulated by the NLRP3 inflammasome. Obese and type 2 diabetic db/db mice show anxiety- and depression-like behaviors and cognitive disorders associated with hippocampal inflammation. The purpose of this study was to explore the role of NLRP3 inflammasome in DEP. Results showed that expression levels of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as IL-1ß in the hippocampus of diabetic db/db mice were higher than those of non-diabetic db/m mice. Treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1ßexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice. These results demonstrate that inhibition of NLRP3 inflammasome activation may prove to be a potential therapeutic approach for DEP treatment.

Notoginsenoside R1 ameliorates diabetic encephalopathy by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation.

Numerous researches supported that oxidative stress and inflammation play important roles in the development of diabetic encephalopathy (DEP). Notoginsenoside R1 (NGR1), one major component of Panax notoginseng, is believed to have anti-oxidative, anti-inflammatory and neuroprotective properties. However, its neuroprotective effects against DEP and underlying mechanisms are still unknown. In this study, db/db mice as well as high-glucose (HG)-treated HT22 hippocampal neurons were used as in vivo and in vitro models to estimate NGR1 neuroprotection. NGR1 administration for 10 weeks could ameliorate cognitive dysfunction, depression-like behaviors, insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation in db/db mice. NGR1 markedly decreased the oxidative stress induced by hyperglycemia in hippocampal neurons. NGR1 significantly activated the protein kinase B (Akt)/nuclear factor-erythroid 2-related factor2 (Nrf2) pathway, and inhibited NLRP3 inflammasome activation in hippocampal neurons, which might be essential for the neuroprotective effects of NGR1. Further supporting these results, we observed that pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 abolished NGR1-mediated neuroprotective effects against oxidative stress and NLRP3 inflammasome activation in HG-treated HT22 hippocampal neurons. In conclusion, the present study demonstrates the neuroprotective effects of NGR1 on DEP by activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome activation. This study also provides a novel strategy for the application of NGR1 as a therapeutic agent for patients with DEP.

Study on active ingredient and mechanism in preventing vascular dementia of Tianzhusan coming from Tujia medicine.

To make clear of the absorbed components of Tianzhusan (TZS) and its possible mechanism in preventing vascular dementia (VD), the rats' models of VD were prepared by a permanent ligation of the bilateral common carotid arteries. After 60 days, rats were administrated with TZS for 0.1 g x kg(-1), and the volume is 0.02 mL x g(-1). After 3 days, the medicated serum was prepared and detected by UPLC, and then we predicted the possible chemical structure of the absorbed components of TZS. According to the absorbed components, the potential targets of TZS were found by ligand profiling of Discovery Studio 3.5. All of these target genes were submitted to DAVID onine for gene set enrichment analysis (GSEA). The 5 absorbed components of TZS have been predicted, and four of them have been identified as parishin B, parishin C, parishin, pennogenin-3-O-alpha-L-rhamnopyranosy-(1-->2)-beta-D-glucoside. Through reverse finding targets, we got 861 pharmacophore models and 9 pathways from KEGG, BIOCARTA after document verification. These results showed that the efficacy mechanism of TZS on VD perhaps were be related with these absorbed components and pathways. If the traditional herbs could be proved effective by efficacy tests, the serum pharmacochemistry, computer-aided drug design, system biology and other technologies can be used in the next experiments, which will be beneficial to fast discovery of material basis and mechanisms of traditional medicine coming form ethnic minorities.