Discovery of novel α2A adrenergic receptor agonists coupling to Gαi/o proteins by virtual screening / 中国药理学与毒理学杂志

Most α2-AR agonists derived from dexme-detomidine have few structure differences between them and have no selectivity for α2A/2B-AR or Gi/Gs,that can lead to the side effect of drugs.To get novel and potent α2A-AR agonists,we built the homology model for human α 2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity.Compound P300-2342 and its 3 analogs sig-nificantly decreased the locomotor activity of mice(P＜0.05).Furthermore,P300-2342 and its 3 analogs inhibited the binding of[3H]rauwolscine to α 2A-AR and α 2B-AR respectively.In α2A-AR-HEK293 cells,P300-2342 decre-ased forskolinstimulatedcAMPpruductionwithoutincreas-ing cAMP pruduction,that indicated the P300-2342 acti-vating α2A-AR coupling with Gαi/o pathway without Gαs coupling.P300-2342 had no agonistic and antagonistic activities on α 2B-AR.Similar results were shown in 3 analogs of P300-2342.The docking results showed that P300-2342 formed the π-hydrogen bonds with Y394,V114 of α2A-AR,and with V93 of α2B-AR.3 analogs of P300-2342 formed several π-hydrogen bonds with V114,Y196,F390 of α 2A-AR and with V93 of α 2B-AR.We believe that these molecules can serve as leads for fur-ther optimization of α2A-AR agonists with potentially few side effects.

Liver cell therapies: cellular sources and grafting strategies / 医学前沿

The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver's cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

Shikimic Acid Promotes Oligodendrocyte Precursor Cell Differentiation and Accelerates Remyelination in Mice / 神经科学通报·英文版

The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells (OPCs) to differentiate, since OPCs and oligodendrocyte-lineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid (SA) is mainly derived from star anise, and is reported to have anti-influenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis (EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination. Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated mTOR. Taken together, our results demonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.

Myt1L Promotes Differentiation of Oligodendrocyte Precursor Cells and is Necessary for Remyelination After Lysolecithin-Induced Demyelination / 神经科学通报·英文版

The differentiation and maturation of oligodendrocyte precursor cells (OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1L in neuron/glia antigen 2-positive (NG2) OPCs was significantly higher than that in mature CC1 oligodendrocytes. In primary cultured OPCs, overexpression of Myt1L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. ChIP assays showed that Myt1L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1L is an essential regulator of OPC differentiation, thereby supporting Myt1L as a potential therapeutic target for demyelinating diseases.

Effect of CD40 siRNA on lupus nephritis of MRL/Lpr mice / 中国免疫学杂志

Objective:To observe the effect of CD40 siRNA on the changes in kidney,urinary protein and complement C3 of MRL/Lpr mice and explore its therapy on lupus nephritis.Methods: 16 female MRL/Lpr mice were randomly divided into control group,empty vector group,CD40-siRNA1 group and CD40-siRNA2 group.The vectors expressing siRNA against CD40 were injected by tail veil into MRL/Lpr mice,while MRL/Lpr mice in control group and empty vector group were injected with the same dose of PBS and pGFP-V-RS vector respectively.There were six times injection and every one day.The 24 hours urine output was gathered 24 hours before mice were killed.Fourteen days following administration,these mice were killed,tissue sections of kidney were observed if the signal of siRNA were expressed in kidney.The expression levels of CD40 mRNA and protein in kidney tissue of MRL/Lpr mice were detected by RT-PCR and immunohistochemistry methods respectively.At the same time,the pathological changes of the kidney were observed by haematoxylin-eosin ( HE) staining method.The 24 h urinary protein content was detected using the method of coomassie brilliant blue and the expression levels of complement C3 in serum were detected by Immunoturbidimetric assays.Results:The vector of CD40-siRNA was expressed in kidney of MRL/Lpr.The expression levels of CD40 mRNA and protein in kidney were lower in CD40-siRNA1 group and CD40-siRNA2 group than control group and empty vector group on the 14th day after last injection ( P<0.05).The inflammatory cells infiltration of kidney and some glomerular volume were significantly reduced in CD40-siRNA1 group and CD40-siRNA2 group than control group and empty vector group.The renal tubular swelling was alleviated in CD40-siRNA1 group and CD40-siRNA2 group than control group and empty vector group.The levels of 24 hours urinary protein were lower and the levels of complement C3 were higher in CD40-siRNA1 group and CD40-siRNA2 group than control group and empty vector group ( P<0.05). Conclusion:CD-40 siRNA can suppress the expression levels of CD40 mRNA and protein and decrease inflammatory cells infiltration in kidney of MRL/Lpr.Meanwhile after suppressing expression of CD40 mRNA and protein, it can reduce the content of 24 hours urinary protein and elevate the level of complement C3 in serum,which CD-40 siRNA can delay progress of the disease and protect kidney,so that it has therapy effect on lupus nephritis.

Construction of TNF-αsiRNA Expression Vector and its Therapeutic Effect on TNF-αand IL-1 in TypeⅡCollagen Induced Arthritis Rat / 天津医药

Objective To investigate the therapeutic effect of tumor necrosis factor (TNF)-αsiRNA on typeⅡcolla-gen induced arthritis (CIA) in rats. Methods The expression vectors of siRNA against TNF-αgene were constructed suc-cessfully and were injected by tail veil into CIA rats. Twenty-four CIA rats were randomly divided into 4 groups including model group, empty vector group, TNF-α-siRNA1 group and TNF-α-siRNA2 group. CIA rats were injected with the same dose of phosphate buffered sodium (PBS) and pGFP-V-RS vector respectively in model group and empty vector group, while TNF-α-siRNA1 group and TNF-α-siRNA2 group were injected with TNF-α-siRNA1 eukaryotic expression vector and TNF-α-siRNA2 eukaryotic expression vector respectively. Another 6 rats, which were not established CIA model, were in-jected with PBS (blank control group). The serum expression levels of IL-1 were detected by ELISA on day 1, 5, 9 and 13 af-ter injection. The expression level of TNF-αmRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR) on day 13. Results The expression level of IL-1 was significantly higher on day 1, 5, 9 and 13 in model group than that of blank group (P＜0.05). The expression levels of IL-1 were significantly lower on day 1, 5 and 9 in TNF-α-siRNA1 group and TNF-α-siRNA2 group than that of model group and blank group (P ＜ 0.05). The expression level of TNF-αmRNA was significantly higher on day 13 in model group than that of blank group (P＜0.05). The expression levels of TNF-αmRNA were significantly lower in TNF-α-siRNA1 group and TNF-α-siRNA2 group than those of model group and emp-ty vector group (P＜0.05). Conclusion TNF-αspecific siRNA can suppress the levels of TNF-αmRNA and IL-1, which provides experimental basis for gene therapy of rheumatoid arthritis.

Tanreqing Injection in Treatment of Acute Respiratory Tract Infections in Children:A Clinical Observation of 110 Cases / 中华医院感染学杂志

OBJECTIVE To observe the clinical effect of Tanreqing injection on acute respiratory tract infections(ARTI) in children.METHODS Totally 218 children cases with ARTI were randomly divided into Tanreqing group and control group.The fever,cough,sputum volume,and the extent of expectoration of the two groups were observed.RESULTS The incidence of clinical effect in treating group was 88.0% which was more than that of control group 71.5%(P

Azithromycin in Treating Mycoplasmal pheumonia:A Clinical Observation of 100 Cases / 中华医院感染学杂志

OBJECTIVE To evaluate the effect of azithromycin on mycoplasmal pneumonia(MP). METHODS We divided 204 MP cases into treatment and control groups.In treatment group 10mg/(kg?d) ivgtt for 3-5 d,while in control group 30mg/(kg?d) erythromycin dripping iv.qd for 7-10 d and then observe the effect. RESULTS In treatment and controll groups the effective rate was 91.5% and 78%,respectively.The average days of curing for cough were 6.8 days and 8.7 days(P