Objective To observe the effect of electroacupuncture on improvement of learning and memory ability and the expression of connective tissue growth factor(CTGF)mRNA and protein in hippocampus in diabetic rats with cognitive impairment.Methods The rat diabetes model was induced by injecting streptozotocin(20 g/L),and then the rats were randomly divided into three groups:electro-acupuncture group(EA),diabetes-mellitus-untreated group(DM)and control group(CN).After four weeks of electroacupuncture treatment,blood glucose level was determined and the effect of electroacupuncture on learning and memory was examined with the device of Morris water maze.RT-PCR was used to detect CTGF mRNA level,and immunohistochemistry was used to detect CTGF protein expression.Results Blood glucose level and the latency period in DM group were increased compared with those in EA and CN groups(P

This article was aimed to study the preparation process of glycyrrhetinic acid (GA)-tanshinone IIA (TSN)-salvianolic acid B (SalB) compound liposomes with 3-succinic-30-stearyl glycyrrhetinic acid (18-GA-Suc) which is one of amphiphilicglycyrrhetinic acid derivatives as targeting molecule. The structure of the targeting molecule was validated by 1H-NMR and 13C-NMR methods. The feed ratio of 18-GA-Suc was optimized through single factor test and the incorporation ratio of 18-GA-Suc was determined by low-speed centrifugation. Meanwhile, physicochemi-cal properties between Suc-GTS-Lip and GTS-Lip were compared. In vitro release studies of three components in Suc-GTS-Lip were conducted by equilibrium dialysis method. The results showed that the optimum conditions were when the feed ratio of 18-GA-Suc was 10%lipid liposomal membrane (mol·mol-1). It revealed that the incorpora-tion ratio of 18-GA-Suc was 96.58%, and the encapsulation efficiencies of GA, TSN, and SalB were about 86.15%, 81.70%, and 91.05%, respectively. In addition, the Suc-GTS-Lip was spherical and uniformly dispersed with parti-cle size of 128.7 nm and zeta potential of-15.5 mV. The release model of GA and TSN was fitted well with Higuchi equation, while SalB was fitted well with Hixon-crowell equation. It was concluded that Glycyrrhetinic acid deriva-tives (18-GA-Suc) can be successfully expressed in the liposome membrane, and the optimal preparation method of Suc-GTS-Lip was stable. All three components encapsulated into liposomes had sustained-release effects, which laid a good foundation for its further study about liver-targeting.

Objective To study how to design the treatment plan to reduce the influence of respiratory movement and the dose of heart and lung as few as possible,to improve the dosage distribution in the target area after radical mastectomy of breast cancer.Methods Twelve patients with breast cancer after radical mastectomy were selected.A dose of 50 Gy with 2 Gy every day and 5 times per week was prescribed.Based on the treatment planning system (TPS),4-field intensity modulated radiotherapy (4FIMRT) and hybrid intensity modulated treatment planning 2-field conformal radiotherapy (2FCRT) + 4FIMRT were designed respectively.The two plans were compared from the aspects of target conformity index (CI),the homogeneity index (HI) and exposure dose volume delivered to organ at risk.Results According to the hybrid plan of 2FCRT + 4FIMRT,HI was 1.08±0.01,which was superior to that from 4FIMRT (1.11±0.01,t =9.587,P ＜ 0.05).While CI was 0.74±0.08,based on the plan of 2FCRT+4FIMRT,which was slightly lower than that from 4FIMRT (0.80±0.03,t =2.497,P ＜ 0.05).Considering the dose volumes on ipsilateral lung in two plans,the values of V5,V10,Dmean of 2FCRT+4FIMRT plan were significantly less than those of 4FIMRT plan.V5,V10,Dmean from the former plan were 13 ％,23 ％,7 ％ less than those from the latter plan (t =6.002,P ＜ 0.05;t =6.826,P ＜ 0.05;t =3.645,P ＜ 0.05).Meanwhile,Dmean of contralateral lung,Dmean of heart,Dmean and V5 of contralateral breast from the 2FCRT +4FIMRT plan were all lower than those of 4FIMRT plan.Those differences between two plans were statistically significant (P ＜ 0.05).Differences of V20 and V30 of ipsilateral lung,and V30 of heart between two plans did not make sense by the statistics analysis (P ＞ 0.05).Conclusion Hybrid radiotherapy theoretically reduces the influence of respiratory movement,improves the uniformity of target dose and lowers the risk of complications of radiation therapy on breast cancer.

BACKGROUNDTo compare the effect and toxicity between gemcitabine and cisplatin (GP) with vinorelbine, ifosfamide and cisplatin (NIP) combined chemotherapy in the treatment of patients with advanced non-small cell lung cancer (NSCLC).

METHODSEighty patients received either gemcitabine 1 000 mg/m² on days 1, 8, or 15 plus cisplatin 70-80 mg/m² on day 1, or vinorelbine 25 mg/m² on days 1, 8, ifosfamide 1.2 g/m² on days 1-4 plus cisplatin 70-80 mg/m² on day 1, every 28 days as a cycle.

RESULTSThe objective response rate was 40.0% in GP goup, compared with 52.5% in NIP group (P > 0.05). Median survival time of GP and NIP groups was 13.68 and 15.34 months respectively, and 1-year survival rates were 54.29% and 59.46% respectively (P > 0.05). Leukopenia at grade III+IV was significantly lower in GP arm (27.5%) than that in NIP arm (55.0%) (P < 0.05). Non-hematological toxicities were less frequent in GP group than those in NIP group (P < 0.05).

CONCLUSIONSAlthough the response rate tends to be higher in three-drug than in two-drug combined chemotherapy, but no significant difference is observed. Three-drug combinations often result in more toxicities. Two-drug combination GP may be the standard protocol for chemotherapy of advanced NSCLC. Three-drug combination NIP should be given to young patients with good performance status.

OBJECTIVETo investigate the role of glycogen synthase kinase 3β (GSK-3β) in the maturation and function of murine bone marrow-derived dendritic cells (BMDCs).

METHODSMature DCs (mDCs) induced by LPS were examined for GSK-3β phosphorylation level with Western blotting before and after LPS exposure. To explore the role of GSK-3β in maturation and function of DCs, we added SB216763, a selective inhibitor of GSK-3β, in the cell culture of immature DCs (iDCs), and examined CD40 and CD86 expressions in the cells by flow cytometry and the expression of IL-6, IL-12 and IL-10 mRNA by real-time PCR; the changes of the immunogenicity of the cells was evaluated by mixed lymphocyte reaction. The expression of GSK-3β and RelB was examined by Western blotting in DC2.4 cells transfected with a lentiviral vector over-expressing murine GSK-3β gene.

RESULTSLPS exposure significantly lowered GSK-3β activity in iDCs as demonstrated by increased Ser9 phosphorylation and reduced Tyr216 phosphorylation. GSK-3β inhibition induced DC maturation by increasing the expression of surface costimulatory molecules CD40 and CD86, lowered the expressions of IL-6 and IL-12 while enhanced the expression of IL-10 in iDCs, and impaired mixed lymphocyte reaction of the cells. In DC2.4 cells, lentivirus-mediated over-expression of GSK-3β obviously down-regulated the expression of RelB.

CONCLUSIONSGSK-3β is a crucial enzyme involved in the differentiation and maintenance of an immature phenotype of DCs. GSK-3β is constitutively active in iDCs to inhibit their spontaneous maturation. DCs become phenotypically mature after inhibition of GSK-3β, which also executes a proinflammatory task in DC activation. The reduction of RelB protein levels as a result of GSK-3β overexpression supports GSK-3β as a new target for inducing tolerogenic DCs.

Animals ; B7-2 Antigen ; metabolism ; CD40 Antigens ; metabolism ; Cell Differentiation ; Cells, Cultured ; Culture Media ; chemistry ; Dendritic Cells ; enzymology ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Indoles ; chemistry ; Interleukin-10 ; metabolism ; Interleukin-12 ; metabolism ; Interleukin-6 ; metabolism ; Lentivirus ; Lymphocyte Culture Test, Mixed ; Maleimides ; chemistry ; Mice ; Myeloid Cells ; enzymology ; Phosphorylation ; RNA, Messenger ; Real-Time Polymerase Chain Reaction ; Signal Transduction

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.