微量元素与艾滋病相关标志物

人类免疫缺陷病毒（HIV）感染病程监督是防治艾滋病的重要措施和手段。阐述了微量元素在HIV病变进程中的变化及与其它相关标志物的关系,内容包括：微量元素与HIV病变、微量元素与CD4淋巴细胞、微量元素与谷胱甘肽、微量元素与HIV消瘦综合征,以及微量元素与炎性反应标志等5个方面。迄今的研究表明,微量元素可以作为反映HIV感染疾病进展的一种新的替代标志物。     

JNK inhibitor SP600125 promotes the formation of polymerized tubulin, leading to G2/M phase arrest, endoreduplication, and delayed apoptosis

The JNK inhibitor SP600125 strongly inhibits cell proliferation in many human cancer cells by blocking cell-cycle progression and inducing apoptosis. Despite extensive study, the mechanism by which SP600125 inhibits mitosis-related effects in human leukemia cells remains unclear. We investigated the effects of SP600125 on the inhibition of cell proliferation and the cell cycle, and on microtubule dynamics in vivo and in vitro. Treatment of synchronized leukemia cells with varying concentrations of SP600125 results in significant G₂/M cell cycle arrest with elevated p21 levels, phosphorylation of histone H3 within 24 h, and endoreduplication with elevated Cdk2 protein levels after 48 h. SP600125 also induces significant abnormal microtubule dynamics in vivo. High concentrations of SP600125 (200 µM) were required to disorganize microtubule polymerization in vitro. Additionally, SP600125-induced delayed apoptosis and cell death was accompanied by significant poly ADP-ribose polymerase (PARP) cleavage and caspase-3 activity in the late phase (at 72 h). Endoreduplication showed a greater increase in ectopic Bcl-2-expressing U937 cells at 72 h than in wild-type U937 cells without delayed apoptosis. These results indicate that Bcl-2 suppresses apoptosis and SP600125-induced G₂/M arrest and endoreduplication. Therefore, we suggest that SP600125 induces mitotic arrest by inducing abnormal spindle microtubule dynamics.     

Interleukin-1�� promotes the expression of monocyte chemoattractant protein-1 in human aorta smooth muscle cells via multiple signaling pathways

Monocyte chemoattractant protein-1 (MCP1) plays a key role in monocyte/macrophage infiltration to the sub-endothelial space of the blood vessel wall, which is a critical initial step in atherosclerosis. In this study, we examined the intracellular signaling pathway of IL-1β-induced MCP1 expression using various chemical inhibitors. The pretreatment of a phosphatidylcholine (PC)-specific PLC (PC-PLC) inhibitor (D609), PKC inhibitors, or an NF-κB inhibitor completely suppressed the IL-1β-induced MCP1 expression through blocking NF-κB translocation to the nucleus. Pretreatment with inhibitors of tyrosine kinase or PLD partially suppressed MCP1 expression and failed to block nuclear NF-κB translocation. These results suggest that IL-1β induces MCP1 expression through activation of NF-κB via the PC-PLC/PKC signaling pathway.     

Sensitive label-free electrochemical immunoassay by electrocatalytic amplification

A label-free electrochemical immunosensor for the detection of protein analytes without redox-active centers is for the first time developed based on the combination of gold nanoparticles and the mediated charge transport through the multilayer films that is related to an electrocatalytic process. Given the low detection limit, high sensitivity and selectivity, the success achieved here seems plausibly to serve as a significant step toward the development of versatile label-free immunoassay.     

Therapeutic targets in the ASK1-dependent stress signaling pathways

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family that activates downstream MAP kinases (MAPKs), c-Jun N-terminal kinases (JNKs) and p38 MAPKs, in response to various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide, and calcium overload. Activation of the JNK and p38 pathways induces stress responses such as cell death, differentiation, and the production of inflammatory cytokines. A series of studies using ASK1-deficient mice have indicated that ASK1 plays important roles in many stress-related diseases, including cardiovascular and neurodegenerative diseases, suggesting that small compounds that inhibit ASK1 activity could possibly be used for the amelioration of the development and/or progression of these diseases. In this review, we provide an overview of the pathophysiological roles of ASK1-dependent signaling pathways and discuss the mechanistic basis for how these could serve as potential therapeutic targets.     

A High-Throughput Clinical Laboratory Methodology for the Therapeutic Monitoring of Ibrutinib and Dihydrodiol Ibrutinib

Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography–mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR + DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR.     

QSAR‐based targeting anaplastic lymphoma kinase (ALK) variants with noncognate inhibitors in pediatric acute lymphoblastic leukemia

Human anaplastic lymphoma kinase (ALK) is a potential target for the treatment of pediatric acute lymphoblastic leukemia. However, a number of residue mutations in ALK kinase domain have been observed to cause drug resistance in pediatric acute lymphoblastic leukemia chemotherapy. Here, a chemometrics quantitative structure‐activity relationship predictor was developed using a structure‐based panel of kinase‐inhibitor activity data. The predictor was validated rigorously through internal cross‐validation and external blind test to ensure its statistical reliability, which was then used to computationally construct a systematic activity profile of 13 noncognate kinase inhibitors against both wild‐type ALK^wt and cancer‐related variants ALK^vt. It is revealed that most noncognate inhibitors exhibit weak potency on ALK^wt, but some of them are able to selectively target ALK^vt over ALK^wt. The chemometrics findings were then evaluated by using a kinase inhibition protocol; results showed that few noncognate inhibitors are 2‐ to 5‐fold higher potent against ALK variant than wild‐type kinase.     

Enhanced skin anti-inflammatory and moisturizing action of gold nanoparticles produced utilizing Diospyros kaki fruit extracts

Inflammatory skin diseases (ISD) cause very severe itchy skin and dryness which is now a days an important issue which has to be taken care. Nanotechnology plays a main role in manufacturing cosmetic ingredients at a nanoscale size. Among different nanoparticles, gold (Au) is one of the non-toxic materials synthesized organically or inorganically. For synthesizing nanoparticles (NPs), using inorganic methods may cause some toxicity to cells, but using organic synthesis like plant extract is less toxic and environmentally friendly. Therefore, we synthesized DK-AuNPs using Diospyros kaki fruit extract. UPLC-MS/MS was used to evaluate phytochemicals responsible for converting salt into nanoparticles. The DK-AuNPs were characterized to confirm the formation of NPs. Furthermore, we analyzed the activity of DK-AuNPs on human keratinocytes (HaCaT cells). The DK-AuNPs showed 98.2 % cell survival upto 200 µg/mL against HaCaT cells. Additionally, compared to DK treatment, DK-AuNPs therapy decreased ROS production in TNF-α/IFN-γ (T + I) stimulated HaCaT cells by 68.7 %, whereas DK treatment reduced ROS generation by 27.8 %. Moreover, the skin anti-inflammatory potential and moisturizing effect of DK-AuNPs were analyzed using HaCaT cells. Furthermore, skin inflammatory activity biomarkers were downregulated through the MAPK/NFκB signaling pathway and showed significant inhibition by DK-AuNPs. Also, the skin moisturizing biomarkers such as HAS (1–3) were upregulated and HYAL (1–2) were downregulated by PI3K/AKT/NFκB through HAS2 regulation. Therefore, skin anti-inflammatory and moisturizing activity were enhanced by treatment with DK-AuNPs. In summary, we conclude that the DK-AuNPs could be a new alternative for skin disease.