Molecules
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Microglia mediate multiple facets of neuroinflammation. They can be phenotypically divided into a classical phenotype (pro-inflammatory, M1) or an alternative phenotype (anti-inflammatory, M2) with different physiological characteristics and biological functions in the inflammatory process. Betaine has been shown to exert anti-inflammatory effects. ⋯ It promoted the conversion of the microglia from M1 to M2 phenotype by decreasing the expression of inducible nitric oxide synthase and CD16/32 and by increasing that of CD206 and arginase-1. Betaine treatment inhibited the TLR4/NF-κB pathways by attenuating the expression of TLR4-Myd88 and blocking the phosphorylation of IκB and IKK. In conclusion, betaine could significantly alleviate LPS-induced inflammation by regulating the polarisation of microglial phenotype; thus, it might be an effective therapeutic agent for neurological disorders.
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'Biased' ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent μ-opioid-receptor (μOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. ⋯ Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased μOR agonists for treating pain.
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Review
Application of Molecular Methods in the Identification of Ingredients in Chinese Herbal Medicines.
There are several kinds of Chinese herbal medicines originating from diverse sources. However, the rapid taxonomic identification of large quantities of Chinese herbal medicines is difficult using traditional methods, and the process of identification itself is prone to error. ⋯ This article reviews the applicability and limitations of biochip and DNA barcoding technology in the identification of Chinese herbal medicines. Furthermore, the future development of the two technologies of interest is discussed.
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Lipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects against LPS-caused damage of BBB permeability and the underlying mechanism remain to be delineated. Prophylactic protection with catalpol (5 mg/kg, i.v.) consecutively for three days reversed the LPS-induced damage of BBB by decreased Evans Blue (EB) leakage and restored tight junctions in C57 mice. ⋯ Fluorescence staining displayed that catalpol reversed the rearrangement of the cytoskeleton protein F-actin and upregulated the tight junction protein of claudin-5 and ZO-1, which have been further demonstrated by the mRNA and protein expression levels of ZO-1, ZO-2, ZO-3, claudin-5, and occludin. Moreover, catalpol concurrently downregulated the mRNA and protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 signaling pathway. This study thus indicated that catalpol, via inhibition of the RhoA/ROCK2 signaling pathway, reverses the disaggregation of cytoskeleton actin in BMECs and prevents down-regulation of junctional proteins, such as claudin-5, occludin, and ZO-1, and decreases endothelin-1 and inflammatory cytokine secretion, eventually alleviating the increase in LPS-induced BBB permeability.
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Sinomenine is a nonaddictive alkaloid used to prevent morphine dependence, even thoughits mechanism isnot fully understood. Astrocytes aggravate the pathological process in their neighboring cellsthrough exosomes in central nervous system diseases. However, the effect of sinomenine on astrocyte-derived exosomes for the amelioration of morphine dependence has not been reported yet. ⋯ Results showed that Sino-exo reduced the level of cAMP, intracellular Ca2+, and the expression of p-CAMKII/CAMKII and p-CREB/CREB in morphine-treated SH-SY5Y cells. In conclusion, we demonstrated that sinomenine exhibited protective effects against morphine dependencein vivo and in vitro through theNMDAR1/CAMKII/CREB pathway. Sinomenine-induced alterationof the function of astrocyte-derived exosomes may contribute to the antidependence effects of sinomenine in morphine dependence.