Novel Leflunomide Analog, UTLOH-4e, Ameliorates Gouty Arthritis Induced by Monosodium Urate Via NF-κB/NLRP3 Signaling Pathway.

BACKGROUND: Gouty arthritis (GA) is a common form of inflammatory arthritis caused by intra-articular deposition of monosodium urate (MSU) crystals; however, there is a tremendous lack of safe and effective therapy in the clinic. OBJECTIVE: The goal of this work was to investigate a novel leflunomide analogue, N-(2,4- dihydroxyphenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTLOH-4e), for its potential to prevent/ treat gouty arthritis. METHODS: In this study, the anti-inflammatory activity of UTLOH-4e was evaluated by MSUinduced GA model in vivo and in vitro, and the molecular docking test was applied to estimate the affinity of UTLOH-4e/UTL-5g/b for MAPKs, NF-κB, and NLRP3. RESULTS: In vitro, UTLOH-4e (1~100 µM) treatment inhibited the inflammatory reaction with no obvious cytotoxicity in PMA-induced THP-1 macrophages exposed to MSU crystals for 24 h, involving the prominent decreased production and gene expression of IL-1ß, TNF-α, and IL-6. Western blot analyses demonstrated that UTLOH-4e (1~100 µM) significantly suppressed the activation of NLRP3 inflammasomes, NF-κB, and MAPK pathways. Furthermore, the data from the experiment on gouty rats induced by intra-articular injection of MSU crystal confirmed that UTLOH-4e markedly ameliorated rat paw swelling, articular synovium inflammation and reduced the concentration of IL-1ß and TNF-α in serum through down-regulating NLRP3 protein expression. CONCLUSION: These results manifested that UTLOH-4e ameliorates GA induced by MSU crystals, which contributes to the modulation of NF-κB/ NLRP3 signaling pathway, suggesting that UTLOH- 4e is a promising and potent drug candidate for the prevention and treatment of gouty arthritis.

Sources, morphology, phytochemistry, pharmacology of Curcumae Longae Rhizoma, Curcumae Radix, and Curcumae Rhizoma: a review of the literature.

Curcumae Longae Rhizoma (turmeric), Curcumae Radix and Curcumae Rhizoma are derived from the Curcuma species, and have gradually become three of the most commonly used medicinal herbs in China due to their different origins, processing methods and medicinal part. These three herbs have certain similarities in morphology, chemical composition, and pharmacological effects. All three of these herbs contain curcuminoids and volatile oil compounds, which exhibit anti-inflammatory, anti-tumor, antioxidant, and neuroprotective properties, although modern clinical applications have their own requirements. At present, there is no systematic guidelines for the clinical application of these three of Curcuma species; consequently, there is a high risk of unwanted phenomena associated with the mixing and indiscriminate use of these herbs. In this review, we focus predominantly on morphology, chemical composition, and the pharmacological activity of these three Curcuma herbs and summarize the current status of research in this field. Our goal is to provide a better understanding of clinical value of these Curcuma species so that we can provide reference guidelines for their further development, utilization and rational clinical application.

LC-MS-based metabolomics reveals the mechanism of anti-gouty arthritis effect of Wuwei Shexiang pill.

Wuwei Shexiang Pill (WSP) is a Tibetan traditional medicine, which has been demonstrated to exhibit potent anti-inflammatory and anti-gout effects. However, the specific pharmacological mechanism is not elucidated clearly. In the present study, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied to investigate the alteration of serum metabolites induced by WSP treatment in MSU-induced gouty rats. Subsequently, bioinformatics was utilized to analyze the potential metabolic pathway of the anti-gout effect of WSP. The pharmacodynamic data discovered that WSP could ameliorate ankle swelling and inflammatory cell infiltration, as well as downregulate the protein expression of IL-1ß, p-NF-κB p65, and NLRP3 in the synovial membrane and surrounding tissues of gouty ankles. LC-MS-based metabolomics revealed that there were 30 differential metabolites in the serum between sham-operated rats and gouty ones, which were mainly involved in the metabolism of fructose and mannose, primary bile acid biosynthesis, and cholesterol metabolism. However, compared to the model group, WSP treatment upregulated 11 metabolic biomarkers and downregulated 31 biomarkers in the serum. KEGG enrichment analysis found that 27 metabolic pathways contributed to the therapeutic action of WSP, including linoleic acid metabolism, phenylalanine metabolism, and pantothenate and CoA biosynthesis. The comprehensive analysis-combined network pharmacology and metabolomics further revealed that the regulatory network of WSP against gout might be attributed to 11 metabolites, 7 metabolic pathways, 39 targets, and 49 active ingredients of WSP. In conclusion, WSP could ameliorate the inflammation of the ankle in MSU-induced gouty rats, and its anti-gout mechanism might be relevant to the modulation of multiple metabolic pathways, such as linoleic acid metabolism, phenylalanine metabolism, and pantothenate and CoA biosynthesis. This study provided data support for the secondary development of Chinese traditional patent medicine.

Polypeptide from Moschus Suppresses Lipopolysaccharide-Induced Inflammation by Inhibiting NF-κ B-ROS/NLRP3 Pathway.

OBJECTIVE: To examine the anti-inflammatory effects and potential mechanisms of polypeptide from Moschus (PPM) in lipopolysaccharide (LPS)-induced THP-1 macrophages and BALB/c mice. METHODS: The polypeptide was extracted from Moschus and analyzed by high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Subsequently, LPS was used to induce inflammation in THP-1 macrophages and BALB/c mice. In LPS-treated or untreated THP-1 macrophages, cell viability was observed by cell counting kit 8 and lactate dehydrogenase release assays; the proinflammatory cytokines and reactive oxygen species (ROS) were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively; and protein and mRNA levels were measured by Western blot and real-time quantitative polymerase chain reaction (qRT-PCR), respectively. In LPS-induced BALB/c mice, the proinflammatory cytokines were measured, and lung histology and cytokines were observed by hematoxylin and eosin (HE) and immunohistochemical (IHC) staining, respectively. RESULTS: The SDS-PAGE results suggested that the molecular weight of purified PPM was in the range of 10-26 kD. In vitro, PPM reduced the production of interleukin 1ß (IL-1ß), IL-18, tumor necrosis factor α (TNF-α), IL-6 and ROS in LPS-induced THP-1 macrophages (P<0.01). Western blot analysis demonstrated that PPM inhibited LPS-induced nuclear factor κB (NF-κB) pathway and thioredoxin interacting protein (TXNIP)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome pathway by reducing protein expression of phospho-NF-κB p65, phospho-inhibitors of NF-κB (Iκ Bs) kinase α/ß (IKKα/ß), TXNIP, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1 (P<0.05 or P<0.01). In addition, qRT-PCR revealed the inhibitory effects of PPM on the mRNA levels of TXNIP, NLRP3, ASC, and caspase-1 (P<0.05 or P<0.01). Furthermore, in LPS-induced BALB/c mice, PPM reduced TNF-α and IL-6 levels in serum (P<0.05 or P<0.01), decreased IL-1ß and IL-18 levels in the lungs (P<0.01) and alleviated pathological injury to the lungs. CONCLUSION: PPM could attenuate LPS-induced inflammation by inhibiting the NF-κB-ROS/NLRP3 pathway, and may be a novel potential candidate drug for treating inflammation and inflammation-related diseases.

Genome-wide identification of the C2H2-Zinc finger gene family and functional validation of CsZFP7 in citrus nucellar embryogenesis.

KEY MESSAGE: Genome-wide identification of C2H2-ZF gene family in the poly- and mono-embryonic citrus species and validation of the positive role of CsZFP7 in sporophytic apomixis. The C2H2 zinc finger (C2H2-ZF) gene family is involved in plant vegetative and reproductive development. Although a large number of C2H2 zinc-finger proteins (C2H2-ZFPs) have been well characterized in some horticultural plants, little is known about the C2H2-ZFPs and their function in citrus. In this work, we performed a genome-wide sequence analysis and identified 97 and 101 putative C2H2-ZF gene family members in the genomes of sweet orange (C. sinensis, poly-embryonic) and pummelo (C. grandis, mono-embryonic), respectively. Phylogenetic analysis categorized citrus C2H2-ZF gene family into four clades, and their possible functions were inferred. According to the numerous regulatory elements on promoter, citrus C2H2-ZFPs can be divided into five different regulatory function types that indicate functional differentiation. RNA-seq data revealed 20 differentially expressed C2H2-ZF genes between poly-embryonic and mono-embryonic ovules at two stages of citrus nucellar embryogenesis, among them CsZFP52 specifically expressed in mono-embryonic pummelo ovules, while CsZFP7, 37, 44, 45, 67 and 68 specifically expressed in poly-embryonic sweet orange ovules. RT-qPCR further validated that CsZFP7 specifically expressed at higher levels in poly-embryonic ovules, and down-regulation of CsZFP7 in the poly-embryonic mini citrus (Fortunella hindsii) increased rate of mono-embryonic seeds compared with the wild type, indicating the regulatory potential of CsZFP7 in nucellar embryogenesis of citrus. This work provided a comprehensive analysis of C2H2-ZF gene family in citrus, including genome organization and gene structure, phylogenetic relationships, gene duplications, possible cis-elements on promoter regions and expression profiles, especially in the poly- and mono-embryogenic ovules, and suggested that CsZFP7 is involved in nucellar embryogenesis.

Metabolomics-based discovery of XHP as a CYP3A4 inhibitor against pancreatic cancer.

Background: Xihuang Wan (XHW), a purgative and detoxifying agent, is commonly utilized in modern medicine as a treatment and adjuvant therapy for various malignancies, including breast cancer, liver cancer, and lung cancer. A clinical study demonstrated the potential usefulness of the combination of XHW and gemcitabine as a therapy for pancreatic cancer (PC), indicating that XHW's broad-spectrum antitumor herbal combination could be beneficial in the treatment of PC. However, the precise therapeutic efficacy of XHW in treating pancreatic cancer remains uncertain. Aim: This study assessed the biological activity of XHW by optimizing the therapeutic concentration of XHW (Xihuang pills, XHP). We performed cell culture and developed an animal test model to determine whether XHP can inhibit pancreatic cancer (PC). We also applied the well-known widely targeted metabolomics analysis and conducted specific experiments to assess the feasibility of our method in PC therapy. Materials and Methods: We used UPLC/Q-TOF-MS to test XHP values to set up therapeutic concentrations for the in vivo test model. SW1990 pancreatic cancer cells were cultured to check the effect the anti-cancer effects of XHP by general in vitro cell analyses including CCK-8, Hoechst 33258, and flow cytometry. To develop the animal model, a solid tumor was subcutaneously formed on a mouse model of PC and assessed by immunohistochemistry and TUNEL apoptosis assay. We also applied the widely targeted metabolomics method following Western blot and RT-PCR to evaluate multiple metabolites to check the therapeutic effect of XHP in our cancer test model. Results: Quantified analysis from UPLC/Q-TOF-MS showed the presence of the following components of XHP: 11-carbonyl-ß-acetyl-boswellic acid (AKBA), 11-carbonyl-ß-boswellic acid (KBA), 4-methylene-2,8,8-trimethyl-2-vinyl-bicyclo [5.2.0]nonane, and (1S-endo)-2-methyl-3-methylene-2-(4-methyl-3-3-pentenyl)-bicyclo [2.2.1heptane]. The results of the cell culture experiments demonstrated that XHP suppressed the growth of SW1990 PC cells by enhancing apoptosis. The results of the animal model tests also indicated the suppression effect of XHP on tumor growth. Furthermore, the result of the widely targeted metabolomics analysis showed that the steroid hormone biosynthesis metabolic pathway was a critical factor in the anti-PC effect of XHP in the animal model. Moreover, Western blot and RT-PCR analyses revealed XHP downregulated CYP3A4 expression as an applicable targeted therapeutic approach. Conclusion: The results of this study demonstrated the potential of XHP in therapeutic applications in PC. Moreover, the widely targeted metabolomics method revealed CYP3A4 is a potential therapeutic target of XHP in PC control. These findings provide a high level of confidence that XHP significantly acts as a CYP3A4 inhibitor in anti-cancer therapeutic applications.

Mechanism Investigation of Wuwei Shexiang Pills on Gouty Arthritis via Network Pharmacology, Molecule Docking, and Pharmacological Verification.

Background: Gout is a common crystal-related arthritis caused by the deposition of monosodium urates (MSU). Tibetan medicine Wuwei Shexiang Pills (WSP) has been demonstrated to exhibit anti-inflammatory, antihyperuricemia, and antigout activities. However, the underlying mechanism is unknown. Objectives: To explore the mechanisms of Wuwei Shexiang Pills on gouty arthritis via network pharmacology, molecule docking, and pharmacological verification. Methods: The ingredients and targets of WSP were obtained by searching and screening in BATMAN-TCM and SwissADME. The targets involving the gout were acquired from public databases. The shared targets were put onto STRING to construct a PPI network. Furthermore, Metascape was applied for the GO and KEGG enrichment analysis to predict the biological processes and signaling pathways. And molecular docking was performed to validate the binding association between the key ingredients and the relative proteins of TNF signaling. Based on the serum pharmacology, the predicted antigout mechanism of WSP was validated in MSU-induced THP-1 macrophages. The levels of inflammatory cytokines and mRNA were measured by ELISA and qRT-PCR, respectively, and MAPK, NF-κB, and NLRP3 signaling-associated proteins were determined by western blot and immunofluorescence staining. Results: 48 bioactive ingredients and 165 common targets were found in WSP. The data showed that 5-Cis-Cyclopentadecen-1-One, 5-Cis-Cyclotetradecen-1-One, (-)-isoshyobunone, etc. were potential active ingredients. TNF signaling, HIF-1 signaling, and Jak-STAT signaling were predicted to be the potential pathways against gout. The molecule docking analysis found that most ingredients had a high affinity for p65, NLRP3, IL-1ß, TNF-α, and p38. The data from in vitro experiment showed that WSP suppressed the production and gene expression of inflammatory cytokines. Furthermore, WSP could inhibit the activation of MAPK, NF-κB, and NLRP3 signaling pathways. Conclusion: Our finding suggested that the antigout effect of WSP could be achieved by inhibiting MAPK, NF-κB, and NLRP3 signaling pathways. WSP might be a candidate drug for gouty treatment.

The gut-lung axis: Gut microbiota changes associated with pulmonary fibrosis in mouse models induced by bleomycin.

The main objective of this study was to investigate the alterations in the gut microbiota (GM) of pulmonary fibrosis (PF) mice induced by bleomycin (BLM) with its underlying mechanisms. BLM was docked with the targets of TGF-ß/SMAD and caspase-3 pathways using the molecular docking technique. HE staining and Masson staining were applied to observe the histopathological changes in the pulmonary tissues. Detection of the apoptotic signals was conducted by flow cytometry and TUNEL staining. The mRNA expression of targets involved in the TGF-ß/SMAD and caspase-3 signaling pathways in lungs was determined by qPCR. Immunohistochemistry (IHC) assay was used to detect the expression levels of cleaved caspase-3 and BAX proteins in mice lung tissues. 16S rDNA sequencing analysis was used to investigate the changes of GM in the fecal samples of mice in each group. The results showed that the apoptosis rate of pulmonary cells in the BLM group distinctly increased, with the expression levels of crucial target pro-apoptotic gene caspase-3, BAX with the corresponding protein, cleaved caspase-3, BAX were apparently elevated. This was accompanied by a significant increase in pro-fibrotic targets level such as TGF-ß, fibronectin, collagen I, and collagen III. The mechanisms of PF induced by BLM were related to apoptosis of lung tissue cells such as alveolar epithelial cells and destroyed alveolar structure and excessive production of extracellular matrix (ECM), which may be bound up with activating TGF-ß/SMAD and caspase-3 pathways. As for the GM, it was found that, after BLM induced PF in mice, the micro ecological balance of the GM was destroyed; the distance of PCo1 and Pco2 was significantly elongated, and the relative abundance of some intestinal probiotics like Catenibacterium and Lactobacillus (L. johnsonii and L. gasseri) dramatically lowered while the relative abundance of Verrucomicrobiales and Enterobacteriales substantially increased. Therefore, GM changes associated with PF in mouse models induced by BLM and the concept of "gut-lung axis" might provide an optional therapeutic strategy for PF.

[Mystery of Yiyin decoction theory: rule discovery and evaluation strategy of atypical pharmacological effects of Chinese medicinal prescription].

Yi Yin, a famous medical scientist and culinary master in the late Xia Dynasty and early Shang Dynasty, developed the Chinese medicinal liquids and Chinese medicinal prescriptions emerged after that. Chinese medicinal prescriptions have attracted much attention because of their unique advantages in the treatment of chronic multifactorial diseases, representing an important direction of drug discovery in the future. Yiyin decoction theory is the superior form of personalized combined medication with advanced consciousness. It is different from not only the magic bullet theory of single component action but also the connotation of modern multi-target drugs. The core of Yiyin decoction theory can be summarized as compound compatibility, multiple effects, and moderate regulation. Compound compatibility refers to that the formulation of Chinese medicinal prescriptions involves the complex synergy and interactions between sovereign, minister, assistant, and guide medicinal materials. Multiple effects mean that the prescriptions employ a variety of mechanisms to exert comprehensive pharmacological effects of nonlinear feedback. Moderate regulation reflects that the prescriptions can accurately regulate the multiple points of the disease biological network as a whole. To solve the mystery of Yiyin decoction theory, we should not only simply study the known active substances(components) and their independent target effects in the mixture, but also mine the "dark matter" and "dark effect" of Chinese medicinal prescriptions. That is, we should learn the neglected atypical pharmacological effects of Chinese medicinal prescriptions and the multi-point nesting mechanism that plays a precise regulatory function in the body. Yiyin decoction theory focuses on the overall pharmacological effect to reflect the comprehensive clinical value of Chinese medicinal prescriptions, which is of great significance for the development of a new model for the evaluation and application of new Chinese medicinal prescriptions in line with the theory of traditional Chinese medicine.

Berberine prevents diabetic retinopathy through inhibiting HIF-1α /VEGF/ NF-κ B pathway in db/db mice.

Our paper investigated the effect of berberine on the diabetic retinopathy (DR) in db/db transgenic mice and explored its possible mechanisms. During chronic intragastric administration for ten weeks, berberine could decrease the levels of fasting blood glucose, TC and TG without hepatotoxicity. Moreover, berberine could protect the retinal morphology against the hyperglycemic insults and decrease glycogen accumulation, the contents of TNF-α and IL-1ß in the retinas, as demonstrated by HE staining, PAS staining and ELISA kits, respectively. Immunofluorescence assay revealed that the protein expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, hypoxia-inducible factor-1α(HIF-1α), and nuclear factor-κ B (NF-κB) p65 was upregulated in db/db retinas compared with wild type ones, whereas berberine treatment could suppress their expression. Berberine prevent DR development through modulating the glucolipid metabolism and inhibiting the HIF-1α /VEGF/NF-κ B pathway, suggesting that berberine maybe a potential agent for the treatment of DR.

Bulbus Fritillariae Cirrhosae as a Respiratory Medicine: Is There a Potential Drug in the Treatment of COVID-19?

Bulbus fritillariae cirrhosae (BFC) is one of the most used Chinese medicines for lung disease, and exerts antitussive, expectorant, anti-inflammatory, anti-asthmatic, and antioxidant effects, which is an ideal therapeutic drug for respiratory diseases such as ARDS, COPD, asthma, lung cancer, and pulmonary tuberculosis. Through this review, it is found that the therapeutic mechanism of BFC on respiratory diseases exhibits the characteristics of multi-components, multi-targets, and multi-signaling pathways. In particular, the therapeutic potential of BFC in terms of intervention of "cytokine storm", STAT, NF-κB, and MAPK signaling pathways, as well as the renin-angiotensin system (RAS) that ACE is involved in. In the "cytokine storm" of SARS-CoV-2 infection there is an intense inflammatory response. ACE2 regulates the RAS by degradation of Ang II produced by ACE, which is associated with SARS-CoV-2. For COVID-19, may it be a potential drug? This review summarized the research progress of BFC in the respiratory diseases, discussed the development potentiality of BFC for the treatment of COVID-19, explained the chemical diversity and biological significance of the alkaloids in BFC, and clarified the material basis, molecular targets, and signaling pathways of BFC for the respiratory diseases. We hope this review can provide insights on the drug discovery of anti-COVID-19.

Tetrahydrocurcumin ameliorates diabetes profiles of db/db mice by altering the composition of gut microbiota and up-regulating the expression of GLP-1 in the pancreas.

Diabetes is a worldwide healthy concern, which affects approximately 9% of the population. Tetrahydrocurcumin (THC) is the main metabolite of curcumin, which exerts the anti-diabetic activity. However, the underlying mechanism has not been clarified. In the research, we investigated whether THC could improve diabetes by regulating the gut microbiota and the expression of pancreatic glucagon-like peptide-1 (GLP-1) in the db/db mice. After 8-week THC administration (ig., once a day, THCH group: 200 mg/kg, THCL group: 100 mg/kg), the fasting blood glucose (FBG) was measured every two weeks. Serum insulin levels, the expression of GLP-1 in the pancreas, the histopathology of pancreas and the composition of gut microbiota were evaluated at the end of the experiment. Compared to the diabetic group, THC treatment decreased significantly blood glucose, increased the secretion of insulin and the expression of GLP-1 in the pancreas. Histomorphological analysis revealed that THC could protect pancreatic islet cells against hyperglycemic insult. Furthermore, the data from the sequencing of the 16S rDNA genes in gut microbiome displayed that THC could restore the intestinal dysbiosis, including the lowered relative abundance of Proteobacteria, Actinobacteria and the ratio of Firmicutes to Bacteroidetes. The linear regression analysis showed a close correlation between the GLP-1 expression and the proportion of the intestinal microflora. Altogether, these results demonstrated that THC might have a direct regulatory effect on gut microflora, which indirectly decrease the FBG levels by modulating GLP-1 expression in the pancreas.

Comparative Analysis of the Transcriptome of Latent Autoimmune Diabetes in Adult (LADA) Patients from Eastern China.

Latent autoimmune diabetes in adults (LADA) is characterized as a slow-progressing form of autoimmune diabetes. LADA resembles some phenotypes of type 1 diabetes (T1D) and type 2 diabetes (T2D), frequently leading to misdiagnosis and inappropriate therapeutic strategies. Understanding its transcriptome profiles aids in revealing the detailed molecular mechanisms of LADA and its therapy. In the present study, we performed RNA-seq analysis of LADA patients from Eastern China and showed that LADA exhibited 277 differentially expressed genes (DEGs) with 199 upregulated and 78 downregulated. Gene ontology and KEGG pathway enrichment analysis revealed that these DEGs were mainly related to immune function and cell death and growth. Furthermore, a comparison of DEGs in LADA with those in T1D and T2D identified from the online databases showed that there are very few overlapped genes between LADA and T1D or T2D, confirming LADA to be a distinct type of diabetes from T1D or T2D. In summary, our comprehensive analysis may aid in the understanding and treatment of LADA patients in Eastern China.

Baicalin Reverses Depressive-Like Behaviours and Regulates Apoptotic Signalling Induced by Olfactory Bulbectomy.

Apoptosis is thought to be involved in neurological disorders including major depression. In this study, we examined whether the polyphenolic compound baicalin could decrease apoptosis in the olfactory bulbectomy (OBX) depression rat model. OBX rats exhibited decreased performance in depression-like behavioural tests and showed evidence of increased oxidative stress, decreased synaptophysin expression, and hippocampal apoptosis. Treatment with baicalin (20 and 40 mg/kg) significantly reversed all of these changes. Baicalin modulated the levels or activity of malondialdehyde, superoxide dismutase, and glutathione peroxidase and prevented apoptotic protease-activating factor-1 expression, effectively suppressing caspase-mediated apoptosis signalling cascades. Our results demonstrate that baicalin has potent antidepressant activity, likely because of its ability to suppress apoptosis.

Asiaticoside attenuates diabetes-induced cognition deficits by regulating PI3K/Akt/NF-κB pathway.

Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy", has been confirmed in a great deal of literature. Current evidence support that oxidative stress, inflammation, energy metabolism imbalance, and aberrant insulin signaling are associated with cognition deficits induced by diabetes. The present study explore the effect of asiaticoside on the cognition behaviors, synapses, and oxidative stress in diabetic rats. Asiaticoside could markedly ameliorate the performance in the Morris Water Maze (decreased latency time and path length, and increased time spent in the target quadrant), which was correlated with its capabilities of suppressing oxidative stress, restoring Na(+)-K(+)-ATPase activity and protecting hippocampal synapses. In vitro, asiaticoside could up-regulate synaptic proteins expression via modulating Phosphoinositide 3-kinase (PI3K)/Protein Kinase B(AKT)/Nuclear Factor -kappa B (NF-κB)-mediated inflammatory pathway in SH-SY5Y cells incubated with high glucose chronically. In conclusion, asiaticoside had beneficial effects on the prevention and treatment of diabetes-associated cognitive deficits, which was involved in oxidative stress, PI3K/Akt/NF-κB pathway and synaptic function in the development of cognitive decline induced by diabetes.

Baicalin reverse AMPA receptor expression and neuron apoptosis in chronic unpredictable mild stress rats.

Changes of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression could impacts the viability of neurons and brain levels of brain-derived neurotrophic factor (BDNF) expression in the key brain structures in the pathophysiology of depressive disorder. In the present study, chronic unpredictable mild stress (CUMS) degraded performance decreased AMPA receptor expression and increased neuron apoptosis. Treatment with baicalin (20, 40mg/kg) significantly reversed these changes. This study demonstrates that baicalin has potent antidepressant effect, likely through up-regulated the expression of AMPA receptor and suppression neuron apoptosis in CUMS-treated rats.

Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism.

Asiaticoside (AS) is isolated from Centella asiatica (L.) which has been using for a long time as a memory enhancing drug in India. This study was to investigate the effects of AS on memory impairment and inflammatory cytokines expression induced by transient cerebral ischemia and reperfusion in mice, as well as the potential signaling pathway. Transient bilateral common carotid artery occlusion (tBCCAO) induced severe memory deficits in mice according to the Morris water maze task and the step-down passive avoidance test. Meanwhile the microglial activation and the gene expression of inflammatory cytokines including interleukin (IL)-1ß, interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased in the hippocampus of the mice with cerebral ischemia and reperfusion. Oral administration of AS (40 and 60 mg/kg, once per day, started the day after surgery and lasted for 7 days) significantly ameliorated the memory impairment and the inflammation. Moreover, AS (20, 40 and 60 mg/kg) markedly reduced the microglial overactivation and the phosphorylation of p38 MAPK in hippocampus compared with the transient cerebral ischemia and reperfusion group. These results suggested that AS showed the neuroprotective effect against transient cerebral ischemia and reperfusion in mice, and this effect might be associated with the anti-inflammation effect of AS via inhibiting overactivation of p38 MAPK pathway.