目的:利用快速卫生技术评估(HTA)工具对白蛋白结合型紫杉醇(nab-PTX)治疗乳腺癌的有效性、安全性及经济性进行评估,为药物选择提供循证依据.方法:检索PubMed、Cochrane Library、中国知网、万方数据库及卫生技术评估网站,纳入nab-PTX治疗乳腺癌的系统评价/Meta分析、HTA和药物经济学研究,采用描述性分析对研究结论进行分类分析.结果:共纳入5篇系统评价/Meta分析、8篇药物经济学研究.与传统紫杉类药物相比,nab-PTX可提高新辅助化疗(NAC)的乳腺癌患者的病理完全缓解率(pCR)[OR=1.39,95％CI(1.16,1.67),P<0.001]和无事件生存期(EFS)[HR=0.69,95％CI(0.57,0.85),P<0.001];但两者在转移性乳腺癌(MBC)患者的总生存期(OS)、无进展生存期(PFS)、客观缓解率(ORR)和疾病控制率(DCR)上差异则无统计学意义.安全性方面,nab-PTX提高了MBC患者3～4级感觉神经毒性的发生率[OR=1.89,95％CI(1.36,2.61),P<0.001],增加了NAC的乳腺癌患者中性粒细胞减少发生率[OR=1.52,95％CI(1.23,1.88),P<0.001]、感觉神经毒性发生率[OR=2.17,95％CI(1.38,3.40),P<0.001]、皮疹发生率[OR=1.46,95％CI(1.18,1.80),P<0.001]以及疲劳发生率[OR=1.28,95％CI(1.04,1.56),P=0.02].药物经济学研究显示,nab-PTX相对于传统紫杉类药物可提高MBC患者的质量调整生命年,更具有经济性.结论:nab-PTX可提高NAC的乳腺癌患者的pCR,但在MBC的有效性上并无显著优势,且不良反应更为多见;采用nab-PTX治疗MBC比传统紫杉类药物可能更具成本-效用优势.

Histone acetyltransferases are responsible for histone acetylation, while histone deacetylases (HDACs) counteract histone acetylation. An unbalanced dynamic between histone acetylation and deacetylation may lead to aberrant chromatin landscape and chromosomal function. HDAC2, a member of class I HDAC family, serves a crucial role in the modulation of cell signaling, immune response and gene expression. HDAC2 has emerged as a promising therapeutic target for liver disease by regulating gene transcription, chromatin remodeling, signal transduction and nuclear reprogramming, thus receiving attention from researchers and clinicians. The present review introduces biological information of HDAC2 and its physiological and biochemical functions. Secondly, the functional roles of HDAC2 in liver disease are discussed in terms of hepatocyte apoptosis and proliferation, liver regeneration, hepatocellular carcinoma, liver fibrosis and non-alcoholic steatohepatitis. Moreover, abnormal expression of HDAC2 may be involved in the pathogenesis of liver disease, and its expression levels and pharmacological activity may represent potential biomarkers of liver disease. Finally, research on selective HDAC2 inhibitors and non-coding RNAs relevant to HDAC2 expression in liver disease is also reviewed. The aim of the present review was to improve understanding of the multifunctional role and potential regulatory mechanism of HDAC2 in liver disease.

Via promoting synovitis, pannus growth and cartilage/bone destruction, fibroblast-like synovial cells (FLSs) play a significant role in the pathogenesis of rheumatoid arthritis (RA). In our study, rats were induced with complete freund's adjuvant (CFA) to be animal models for studying the RA pathogenesis. Microtubule-associated Serine/Threonine-protein kinase 3 (MAST3) has been documented to play a critical role in regulating the immune response of IBD (Inflammatory bowel disease) and involved in the process of cytoskeleton organization, intracellular signal transduction and peptidyl-serine phosphorylation, but its role in the progression of RA remains unknown and is warranted for investigation. So, we tried our best to investigate the mechanism and signaling pathway of MAST3 in RA progression. In the synovial tissue and FLSs of AA rats, we have found that MAST3 was significantly up-regulated than normal. Furthermore, MAST3 overexpression could promote proliferation and inflammatory response of FLSs. In the aspect of mechanism, we discovered that the expression of MAST3 might involve in NF-κB signaling pathway in RA. On the whole, our results suggested that MAST3 might promote the proliferation and inflammation of FLSs by regulating NF-κB signaling pathway.

Innate immunity activates the corresponding immune response relying on multiple pattern recognition receptors (PRRs) that includes pattern recognition receptors (PRRs), like NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs), which could accurately recognize invasive pathogens. In particular, NLRs belong to a large protein family of pattern recognition receptors in the cytoplasm, where they are highly correlated with activation of inflammatory response system followed by rapid clearance of invasive pathogens. Among the NLRs family, NLRC5, also known as NOD4 or NOD27, accounts for a large proportion and involves in immune responses far and wide. Notably, in the above response case of inflammation, the expression of NLRC5 remarkably increased in immune cells and immune-related tissues. However, the evidence for higher expression of NLRC5 in immune disease still remains controversial. It is noted that the growing evidence further accounts for the participation of NLRC5 in the innate immune response and inflammatory diseases. Moreover, NLRC5 has also been confirmed to exert a critical role in the control of regulatory diverse signaling pathways. Together with its broad participation in the occurrence and development of immune diseases, NLRC5 can be consequently treated as a potential therapeutic target. Nevertheless, the paucity of absolute understanding of intrinsic characteristics and underlying mechanisms of NLRC5 still make it hard to develop targeting drugs. Therefore, current summary about NLRC5 information is indispensable. Herein, current knowledge of NLRC5 is summarized, and research advances in terms of NLRC5 in characteristics, biological function, and regulatory mechanisms are reviewed.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and the pathogenesis remains unclear. Previous studies suggested that fibroblast-like synoviocytes (FLSs) play an important role in RA pathogenesis, including the injury of cartilage, the hyperplasia of the synovium and the release of inflammatory cytokines. We used complete Freund's adjuvant (CFA) induced rats as animal models for studying the RA pathogenesis. NLRC5 as the largest member of the NLR family has been reported to play a critical role in regulating immune responses. Increasing evidence suggests that NLRC5 is an pivotal negative modulator of inflammatory pathways. We investigated the mechanisms and signaling pathways of NLRC5 in RA progression. Significantly increased expression of NLRC5 was found in AA rats synovial tissues and cells. And high expression of inflammatory cytokine and cell proliferation of FLSs accompanied with NLRC5 overexpression, but inhibited in cells with NLRC5 silencing treatment. Interestingly, we found that overexpression of NLRC5 also coordinated the activation of NF-κB signaling pathway. These results suggested that NLRC5 promotes RA progression via the NF-κB signaling pathway potentially.

1. Si-Ni-San (SNS) possesses extensive therapeutic effects, however, the extent to which main components are absorbed and the mechanisms involved are controversial. 2. In this study, MDCK cell model was used to determine the permeability characteristics and interaction between the major components of Si-Ni-San, including saikosaponin a, paeoniflorin, naringin and glycyrrhizic acid. 3. The transport of the major components was concentration-dependent in both directions. Moreover, the transport of paeoniflorin, naringin and glycyrrhizic acid was significantly reduced at 4 degrees C or in the presence of NaN3. Additionally, the efflux of paeoniflorin and naringin were apparently reduced in the presence of P-gp inhibitor verapamil. The transport of glycyrrhizic acid was clearly inhibited by the inhibitors of MRP2, indicating that MRP2 may be involved in the transport of glycyrrhizic acid. However, the results indicated that saikosaponin a was absorbed mainly by passive diffusion. Furthermore, the combined incubation of four major components had a powerful sorbefacient effect than a single drug used alone which may be regulated by tight junctions. 4. Taken together, our study provides useful information for pharmacological applications of Si-Ni-San and offers new insights into this ancient decoction for further researches, especially in drug synergism.

1.Hesperetin (HDND) possesses extensive bioactivities, however, its poor solubility and low bioavailability limit its application. HDND-7, a derivative of HDND, has better solubility and high bioavailability. In this study, we investigated the intestinal absorption mechanisms of HDND-7.2.MDCK cells were used to examine the transport mechanisms of HDND-7 in vitro, and a rat in situ intestinal perfusion model was used to characterize the absorption of HDND-7. The concentration of HDND-7 was determined by HPLC.3.In MDCK cells, HDND-7 was effectively absorbed in a concentration-dependent manner in both directions. Moreover, HDND-7 showed pH-dependent and TEER-independent transport in both directions. The transport of HDND-7 was significantly reduced at 4 degrees C or in the presence of NaN3. Furthermore, the efflux of HDND-7 was apparently reduced in the presence of MRP2 inhibitors MK-571 or probenecid. However, P-gp inhibitor verapamil had no effect on the transport of HDND-7. The in situ intestinal perfusion study indicated HDND-7 was well-absorbed in four intestinal segments. Furthermore, MRP2 inhibitors may slightly increase the absorption of HDND-7 in jejunum.4.In summary, all results indicated that HDND-7 might be absorbed mainly by passive diffusion via transcellular pathway, MRP2 but P-gp may participate in the efflux of HDND-7.

MTBH, a novel hesperetin derivative, possesses in vivo hepatoprotective effects against carbon tetrachloride (CCl4)-induced acute liver injury in Institute of Cancer Research (ICR) mice.

Hesperetin, the aglycone of hesperidin, occurs naturally in citrus fruits. It exerts extensive pharmacological activities. However, hesperetin's poor solubility and low bioavailability limit its wide application. In order to overcome these limitations, recently a series of novel hesperitin derivatives containing Mannich base moieties were synthesized and the anti-inflammatory activity was evaluated, among which MTBH (8-methylene-tert-butylamine-3′,5,7-trihydroxy-4′-methoxyflavanone) showed a significantly improved water solubility, and promising anti-inflammatory activity in vitro and in vivo compared with hesperitin. Thus, the aim of this study was to investigate the permeability and transport mechanisms of MTBH, using Caco-2 cell monolayer. MTBH was effectively absorbed by Caco-2 cells in a concentration-dependent manner in both directions at 7.5–480 μM. Moreover, MTBH showed pH dependent and TEER values independent transport in both directions. Transport of MTBH was obviously decreased in the presence of sodium azide (an ATP inhibitor) or CCCP (a proton-ionophore). MTBH transport was markedly reduced by MCT inhibitors quercetin or phloretin, and the substrate analogs l-lactate or benzoic acid. We verified MCT1, MCT3, MCT4, MCT5, and MCT6 were expressed in Caco-2 cells by western blot. Silence MCT1 with siRNA resulted in significant inhibition of MTBH uptake. The verapamil, a P-gp inhibitor, and Ko143, a BCRP inhibitor, had no effect on the transport of MTBH. However, MK-571 or probenecid, MRP2 inhibitors, led to an apparently decrease in the efflux of MTBH. In summary, MTBH was absorbed by transcellular passive diffusion and a pH dependent mechanism mediated by MCT1. MRP2 but P-gp or BCRP may be involved in the transport of MTBH.

A sensitive and reliable HPLC-MS/MS method was developed and validated for the determination of free (unconjugated), glucuronidated, sulfated, and total (free and conjugated) HDND-7 in rat plasma and tissues. Plasma and tissues samples were treated prior to and after the enzyme hydrolysis. Chromatographic separation was achieved on a Phenomenex Luna C18 column (150 × 4.6mm, 3 μm), using isocratic mobile phase consisting of 0.1% formic acid-acetonitrile (50:50, v/v) at a flow rate of 300 μl/min. The detection was performed on a triple quadruple tandem mass spectrometer using positive electrospray ionization (ESI) source with a chromatographic run time of 5.0 min. The detection was operated by multiple reaction monitoring (MRM) of the transitions of m/z 429.3 → 223.9 for HDND-7 and 272.9 → 152.9 for naringenin (IS), respectively. This method was validated in terms of specificity, linearity, precision, accuracy, and stability. The calibration curves for plasma and tissues were linear over a wide concentration range of 0.02-40 μg/ml with a lower limit of quantification (LLOQ) of 0.02 μg/ml. Mean extraction recoveries in plasma and tissues ranged from 87.4 to 97.1% and from 54.2 to 70.5%, respectively. The intra- and inter-day precision values were below 15% and the accuracy was within ± 15%. The samples were stable under all the tested conditions. This method has been successfully applied to the pharmacokinetic study following oral doses of 25, 50 and 100mg/kg and intravenous dose of 25mg/kg, and tissue distribution study following oral dose of 50mg/kg.

Using a procedure of emulsification–lyophilization (PEL), adjuvant lipid A-cochleates (LACs) were prepared as a carrier for model antigen bovine serum albumin (BSA). With phosphatidylserine and lipid A as emulsifiers dissolved in oil phase (O), sucrose and CaCl2 in the inner water phase (W1), and BSA, sucrose and PEG2000 in the outer water phase (W2), the W1/O/W2 emulsions were prepared and subsequently lyophilized to form a dry product which was stable enough to be stored at room temperature. Upon rehydration of the dry products, cochleates formed with a size of 800 nm and antigen association rates of 38%. After vaccination of mice through oral mucosal (o.m.) administration, LACs showed no side effects but induced potent immune responses as evidenced by high levels of IgG in the sera and IgA in the salivary, intestinal and vaginal secretions of mice. In addition, high levels of IgG2a and IFN-γ in the sera or culture supernatants of splenocytes of the immunized mice were also detected. These results revealed that LACs induced a mixed Th1/Th2 response against the loaded antigens. Thus, the LACs prepared by PEL were able to induce both systemic and mucosal immune responses and may act as a potent cold-chain-free oral mucosal vaccine adjuvant delivery system (VADS).

To develop convenient, effective cold chain-free subunit vaccines, a mannose-PEG-cholesterol conjugate (MPC) was synthesized as a lectin binding molecule and anchored onto liposomes which entrapped lipid A and model antigen to form a vaccine adjuvant-delivery system targeting antigen presenting cells. With MPC, soy phosphatidylcholine, stearylamine and monophosphoryl lipid A as emulsifiers dissolved in oil phase (O), and sucrose and BSA in water phase (W), the O/W emulsions were prepared and subsequently lyophilized. The lyophilized product was stable enough to be stored at room temperature and, upon rehydration, formed MPC-/lipid A-liposomes (MLLs) with a size under 300 nm and antigen association rates of around 36%. The MLLs given to mice via oral mucosal (o.m.) administration showed no side effects but induced potent immune responses as evidenced by the high levels of IgG in the sera and IgA in the salivary, intestinal and vaginal secretions of mice. High levels of IgG2a and IFN-γ in treated mice revealed that MLLs via o.m. vaccination induced a mixed Th1/Th2 response against antigens, establishing both humoral and cellular immunity. Thus, the MLLs may be a potent cold chain-free oral mucosal vaccine adjuvant-delivery system.