Latest ArticlesAlzheimer's disease (AD) is the most common neurodegenerative disease in the aging population.Abnormal hyperphosphorylation of tau is the main cause of AD.Protein phosphatases 2A (PP2A) can increase the hyperphosphorylation of tau.Cornel iridoid glycoside (CIG) is one of the main components extracted from Cornus of ficinalis.The aim of the present study was to investigate the effects and the underlying mechanisms of CIG on enhancing PP2A activity.SK-N-SH cells were exposed to 20 nmol·L-1 okadaic acid (OA, an inhibitor of PP2A) for 6 h to induce the hyper-phosphorylation of tau, in order to define the effect of CIG on the activity of PP2A and posttranslational modification of PP2A catalytic subunit C (PP2Ac).We found that OA significantly decreased PP2A activity, increased the phosphorylation of PP2Ac, and enhanced tau hyper-phosphorylation.Pre-incubation of CIG significantly attenuated the OA-induced tau hyper-phosphorylation at Ser 199/202 and Ser 396, and recovered the activity of PP2A.CIG inhibited PP2Ac phosphorylation at Tyr 307 and increased Src phosphorylation.In conclusion, the mechanism of CIG inhibition of tau hyper-phosphorylation was activation of PP2A to reduce the level of p-Src for a reduction of PP2Ac phosphorylation at Tyr307.
The main ingredient of extractable petroleum ether of Polyrhachis vicina Roger (EPPR) is octadecene unsaturated fatty acids.Mounting evidence supports that N-3 polyunsaturated fatty acids can attenuate neuroinflammation, reduce oxidative stress, then protect neurons.In order to explore the effect of EPPR on the inflammatory response of depressed rats, the model of depression was established by chronic unpredictable mild stress (CUMS).Sucrose preference test, forced swimming test were employed to investigate the anti-depressive effect of EPPR in rat.The activation of glial cells and astrocytes in the prefrontal cortex of depressed rats was observed by immunofluorescence.The levels of inflammatory factors were measured by Quantitative Real-time PCR.NF-κB was detected by immunoblotting.EPPR could significantly improve the depressive behavior of rats, decrease NF-κB translocation to the compartment of nucleus, down-regulate the pro-inflammatory cytokines IL-1β, TNF-α and indoleamine 2, 3-dioxygenase (IDO) gene expression levels, inhibit the activation of microglia and astrocytes in depressed rats.These results suggest that EPPR could notably ameliorate inflammation induced by chronic stress, and the protective effect might be linked to the regulation of NF-κB p65.
Drug-resistance is a challenge in the treatment of epilepsy, and traditional Chinese medicine (TCM) prescription may have a potential in therapy of the epilepsy.Here we established a modified 6 Hz corneal kindled mouse model of epilepsy, and verified its drug-resistance to four commonly used western medicines.We evaluated the efficacy of three classical TCM prescriptions in this drug-resistant epilepsy model.The results showed that:① most C57BL/6J mice with stimulation current intensity at 44 mA (8 out of 10) were fully kindled, while none ICR mice with stimulation current intensity at 44 mA or C57BL/6J mice with stimulation current intensity at 24 mA were fully kindled.Fully kindled mice exhibited epileptic electroencephalograms after 44 mA and 6 Hz corneal kindling stimulation and increased activation of astrocytes in the hippocampus (by staining the glial fibrillary acidic protein); ② 50 mg·kg-1 phenytoin sodium, 100 mg·kg-1 valproic acid sodium and 15 mg·kg-1 lamotrigine had no significant effects on the drug-resistant seizures in 6 Hz corneal kindled C57BL/6J mice, while 100 mg·kg-1 levetiracetam significantly reduced the seizure stage (P < 0.05) and incidence of generalized seizure (P < 0.05) in it; ③ TCM prescriptions, Chai-Hu Plus Long-Gu Mu-Li decoction (9.36 or 28.08 g·kg-1) and Tian-Ma Gou-Teng decoction (14.82 or 44.46 g·kg-1), had no significant effects on the drug-resistant seizures in 6 Hz corneal kindled C57BL/6J mice, while TCM prescription Feng-Yin decoction (19.11 g·kg-1) significantly reduced both the seizure stage (P < 0.01) and incidence of generalized seizure (P < 0.05) in it.Thus, the modified 6 Hz corneal kindled C57BL/6J mouse model is an excellent drug-resistant epilepsy model, Feng-Yin decoction have antiepileptic effects on it, suggesting Feng-Yin decoction may be an effective TCM prescription for clinical treatment of drug-resistant epilepsy.
Stroke is the leading cause of death in Chinese currently, characterized by high incidence, high morbidity and high mortality, of which ischemic stroke accounted for 87%.However, it still lacks the ideal treatment.Stem cells are a class of cells with self-renewal ability and high differentiation potential.Stem cell transplantation breaks the irreversibility of nerve injury to post-stroke infarct area.However, stem cells also requiring specific chemokines to promote their directional migration to the injured tissue site after transplanted.Stromal cell-derived factor-1α (SDF-1α) is one of the typical chemokines.SDF-1α and its specific receptor CXCR4 can induce its migration, increase its proliferation and promote angiogenesis.In this paper, the role of SDF-1α/CXCR4 axis in the treatment of ischemic stroke in stem cells is reviewed in order to provide a theoretical basis for enhancing the efficacy of stem cell transplantation in the treatment of ischemic stroke.
Progressive accumulation of the amyloid-β peptide (Aβ) in the brain plays a central role in the pathogenesis of Alzheimer's disease (AD).The animal model of intracerebral injection of Aβ oligomers not only provides a method for further exploring the mechanism of Aβ in AD, but also can be used to screen drug candidates targeting Aβ oligomers.This animal model has been widely used in the study of anti-AD drugs and mechanism of AD.In this paper, we summarize the research progress in the animal model of intracerebral injection of soluble Aβ oligomers, including experimental animals, the types of Aβ, the preparation of Aβ oligomers in vitro, injection sites and doses, the duration of modeling, animal behavioral changes, and the pathological mechanisms relating to this animal model, which will contribute to the application of the animal model to various conditions.
The orexin system was discovered in 1998 with two G-protein coupled receptors (GPCRs):orexin-1 (OX1R) and orexin-2 (OX2R) receptors that bind the neuropeptides orexin-A (OX-A) and orexin-B (OX-B).The causal link between the orexin system and obesity, anxiety, and sleep/wake disorders as a potential therapeutic target has drawn much attention in the field of pharmaceuticals.The developments of dual antagonism of the receptors by small molecules are clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has been approved by FDA in August, 2014.The small molecule orexin receptor antagonists (ORA) between January 2010 and August 2017 are summarized in this review and we focus on their chemical structures, mechanism and human clinical trials.
Nonribosomal peptide synthetases (NRPS) catalyze the synthesis of nonribosomal peptide (NRP) compounds with structural and functional diversities, including more than 20 marketed drugs. This review focuses on the recent advances in the functional domains of NRPS and their mechanisms of action, as well as the unconventional assembly patterns such as iterative NRPS, module skipping, in trans aminoacylation and tandem adenylation domains. This review provides the theoretical basis for exploring new nonribosomal peptide compounds and the development of new drugs.
Pancreatic cancer is a highly-malignant digestive system neoplasm. The anticancer efficacies of the chemotherapeutic drugs for pancreatic cancer treatment, such as gemcitabine, are greatly limited by their poor targetability to tumor and low drug concentration in the tumor tissue. Drug delivery system plays an important role in improvement of therapeutic efficacy and reduction of adverse effects. Enhancement of the tumor targeting capacity of nanomedicine and promotion of the delivery efficiency are the key issues in the research field of pharmaceutics. In this review article, we survey recent progress in targeted drug delivery nanosystems for treatment of pancreatic cancer by targeting cancer cells, pancreatic tumor stroma, pancreatic cancer-associated cells, and pancreatic cancer stem-like cells, which will provide a new insight into clinical treatment of pancreatic cancer.
This study was designed to investigate the effects of icariin on bone metabolism in osteoprotic mice induced by iron overload, the model of iron overload mice was established by intraperitoneal injection of iron dextran (100 mg·kg-1). Sixty 2-month-old C57/BL6 male mice were randomly divided into six groups, including normal control group, model group, N-acetyl-L-cysteine (NAC)-treated group, icariin (50, 100 and 200 mg·kg-1)-treated group. Except for the mice in control group, the mice were intraperitoneal injected weekly with iron dextran (100 mg·kg-1) to establish the model of iron overload mice. The NAC and icariin were suspended in 0.5% CMC-Na solution, and administered orally for six times one week according to body weight. The mice in normal group and model group were given the same volume of 0.5% CMC-Na solution. Three months later, the organs, serum and femurs of mice were collected. Serum biochemical parameters were detected with an ELISA kit, the distal femur bone density and trabecular bone microstructure were analyzed by Micro-CT, and the mechanical properties of femur were measured by universal mechanical analyzer. Compared with the normal control group, iron overload decreased the bone mineral density and deteriorated the micro-architecture structure and bone mechanical properties in femur of mice, increased the level of iron, phosphorus and activity of tartrate resistant acid phosphatase-5b (TRACP-5b), reduced the level of osteocalcin (OCN) in serum, decreased the activity of superoxide dismutase (SOD) of liver tissues, increased the content of malondialdehyde (MDA) of liver tissues. Icariin increased bone mineral density, improved the micro-architecture and mechanical properties of bone tissue, reduced the levels of iron and phosphorus, decreased the activity of TRACP-5b and enhanced the levels of OCN in serum, and also decreased the activity of MDA in liver tissue of iron overload mice. These results suggest that icariin is able to reduce bone loss and improve bone microstructure and mechanical properties in iron overload mice through regulation of bone metabolism via anti-oxidation.
This study is designed to investigate the effect of triptolide on the function and expression of P-glycoprotein (P-gp) in HNE1 nasopharyngeal cancer cells. MTT assay was used to test cell viability. Intracellular doxorubicin content was evaluated with flow cytometry. Rhodamine 123 (Rh) was used to detect the excretion function of P-gp. The expression of P-gp was analyzed by Western blot. ATP levels were evaluated. JC-1 staining was used to determining mitochondrial membrane potential (MMP). Triptolide, doxorubicin and the combination treatment all had the inhibitory effect to HNE1 cells, and the combination treatment had the best effect. Triptolide increased intracellular concentration of doxorubicin and Rh (P < 0.05 or P < 0.01), inhibited the excretion function of P-gp. The expression of P-gp was reduced greatly in the middle and high dose group of triptolide. The ATP levels were decreased significantly (P < 0.05). JC-1 staining showed that triptolide mediated the down-regulation of MMP in HNE1 cells. Triptolide could increase intracellular drug content and enhance cytotoxicity of chemotherapeutics by inhibition of the expression and the excretion function of P-gp.
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