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.

Alzheimer's disease (AD) is a type of common neurodegenerative disease.The main clinical symptom of the disease is progressive cognitive dysfunction, which has no effective therapy yet.With the in-depth immunology study in the central nervous system, studies in different fields such as preclinical phase, genetics and bioinformatics have shown that immune dysfunction contribute to the pathogenesis of AD, including the beginning, maintenance and deterioration stage in AD.China has a wealth of natural medicine resources and clinical experiences.A large number of natural drugs and effective components both can regulate the immune function and ameliorate the symptoms in AD.This review summarizes the researches of ameliorating the symptoms in AD through immunization regulation in recent years with an aim to provide new ideas and clues in the study of new anti-AD drugs using natural medicines.

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.

Alzheimer'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.

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.

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 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.

The discussion on pathophysiological of multiple sclerosis (MS) mainly focuses on T and B cells in adaptive immune response, but less involve in the myeloid cells (dendritic cells, monocytes, macrophages and microglia) in the innate immune system, which also play an important role in the pathogenesis of MS. The myeloid cell population acts as antigen-presenting cells and effector cells in neuroinflammation in the innate immune system. The interactions between T cells and myeloid cells form a vicious cycle which makes the disease continuous deterioration. At present, the studies on the therapeutic drugs for MS mainly are focused on the adaptive immune system, but pay less attention to myeloid cells. In this article, we reviewed the sub-types and functions of myeloid cells, their changes in MS patients and animal models, as well as the effects of some therapeutic drugs for MS on myeloid cells, in the purpose of finding new targets and strategies for development for MS therapy.

ABC transporters (ATP-binding cassette transporters) are a family of trans-membrane transport proteins, which are ubiquitous in prokaryotes and eukaryotes. They are functionallyinvolved in the transport and accumulation of plant secondary metabolites, phytohormone transport, lipid metabolism, exogenous toxins detoxification, plant disease and other aspects. Based on the genome and transcriptome data of Dendrobium officinale, 88ABC transporters were preliminarily identified in D. officinale and their functions and subcellular localization were predicted. These proteins are divided into seven subfamilies, ABCA-ABCI, including 4 ABCA, 19 ABCB, 12 ABCC, 3ABCD, 9 ABCF, 37ABCG and 4 ABCI, which are mainly located in plasma membrane, vacuole and Golgi apparatus. Comparative transcriptomic analysis of ABC protein expression profile between asymbiotic and symbiotic germination of D. officinale show that some members of ABCB and ABCG proteins are highly expressed during seed germination inoculated fungi. qPCR validated that 2 ABCB11 and 2 ABCG-PDR are significantly up-regulated in symbiotic assay compared to asymbiotic germination (fold change ≥ 10.0). These proteins are mainly involved in abscisic acid and auxin transport, suggesting that these proteins play an important role in the germination of D. officinale seed and in the interaction with microorganisms.

This study was designed to study the chemical constituents from bulbil of Dioscorea opposite Thunb.. Four compounds were isolated by silica gel column chromatography. On the basis of physic-chemical characters and spectroscopic data analysis, these compounds were identified as lyzalkaloid (3, 4-dihydro-6-hydroxy-4-methyl-6H-pyrido[6, 5-b]indol-5(1H)-one) (1), anoectochine (2), ginsenine (3), and 2-hydroxy-3-(1H-indol-3-yl) propanoic acid methyl ester (4). Compound 1 is a new indole alkaloid, named as lyzalkaloid. Compounds 2-4 were isolated from this plant for the first time. The cytotoxic activities were assessed by MTT assay. All compounds exhibited the cytotoxic activity against HepG2 and MDA-231 with IC₅₀ values of over 100 μmol·L^-1, respectively. All compounds show no significant cytotoxic activities against HepG2, MDA-231 cancer cell.