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Danshen has been widely used for the treatment of central nervous system diseases. We investigated the effect of dihydroisotanshinone I (DT), a compound extracted from Danshen, as well as the corresponding mechanisms in an in vitro-based 6-OHDA-induced Parkinson’s disease (PD) model. SH-SY5Y human neuroblastoma cell lines were pretreated with 6-hydroxydopamine (6-OHDA) and challenged with DT. Subsequently, the cell viability and levels of reactive oxygen species (ROS) and caspase-3 were analyzed. The effect of DT on the 6-OHDA-treated SH-SY5Y cells and the expression of the core circadian clock genes were measured using a real-time quantitative polymerase chain reaction. Our results indicated that DT attenuated the 6-OHDA-induced cell death in the SH-SY5Y cells and suppressed ROS and caspase-3. Moreover, DT reversed both the RNA and protein levels of BMAL1 and SIRT1 in the 6-OHDA-treated SH-SY5Y cells. Additionally, the SIRT1 inhibitor attenuated the effect of DT on BMAL1 and reduced the cell viability. The DT and SIRT1 activators activated SIRT1 and BMAL1, and then reduced the death of the SH-SY5Y cells damaged by 6-OHDA. SIRT1 silencing was enhanced by DT and resulted in a BMAL1 downregulation and a reduction in cell viability. In conclusion, our investigation suggested that DT reduces cell apoptosis, including an antioxidative effect due to a reduction in ROS, and regulates the circadian genes by enhancing SIRT1 and suppressing BMAL1. DT may possess novel therapeutic potential for PD in the future, but further in vivo studies are still needed.

Bi2Te3-based materials are the most commonly used materials in commercial thermoelectric devices. There are many joints in thermoelectric devices, thus knowledge of interfacial reactions with Bi2Te3 substrate is important. Interfacial reactions are examined in the following couples, Sn/Bi2Te3 at 160 °C, In/Bi2Te3 at 140 °C and Cu/Bi2Te3 at 350 °C. The reaction temperatures are all lower than the melting points of the respective reaction substrates, so all these couples are solid/solid couples; however, liquation phenomena are observed in these couples. A reaction zone composed of two regions is formed in the Sn/Bi2Te3 couple reacted at 160 °C. The phase region adjacent to Sn is liquid phase and that adjacent to Bi2Te3 is SnTe with Bi solubility. The liquid phase is of near Bi-Sn eutectic composition and is formed due to alloying between Sn and Bi. The reaction path is Sn/liquid/SnTe/Bi2Te3. In the In/Bi2Te3 couple reacted at 140 °C, a liquid phase is formed among various reaction phases. The reaction path is In/In4Te3/liquid/Bi/(Bi2)m(Bi2Te3)n/Bi2Te3. Te atoms diffuse toward In and an In4Te3 phase is formed. Liquid phase is formed due to the alloying between In and remaining Bi. A metastable CuxBi2Te3, an oversaturated Bi2Te3 phase, is formed adjacent to the Bi2Te3 substrate in the Cu/Bi2Te3 couple reacted at 350 °C. The oversaturated phase decomposes, and a stable Cu2Te phase is formed. The remaining Bi adjacent to CuxBi2Te3 phase is molten at 350 °C, and the remaining Bi in contact with Cu, alloying with Cu and is also molten. Once the liquid phase is formed, the reaction rates become very fast. The reaction paths in the couples are illustrated with the proposed related phase equilibria isothermal sections.

In this descriptive, retrospective study, we analyzed the types of questions posed by healthcare professionals to drug counselors at a medical center and the types of provision of pharmaceutical advice solicited to improve pharmaceutical care quality and establish clear directions for clinical pharmacist training. We collected 8,558 questions posed by healthcare professionals (physicians, 38%; pharmacists, 39%; nurses, 23%) from the electronic drug information record system from May 2013 to April 2015 in one medical center. Overall, 52% and 45% of calls came from outpatient and inpatient departments, respectively. Telephone was the main route of provision of pharmaceutical advice (total, 6,035 questions; 72%), and hospital/electronic formulary was the main reference type (43%). The top 10 topics were dosage, alternatives, drug name, usage, adverse drug reactions, medication suggestion, drug compatibility, national health insurance criteria, mechanism, and indications. Pharmacological classification inquiries most frequently addressed antimicrobial agents (20%), and vancomycin was the top single drug. Finally, 67% of calls were completed in 5 minutes. Our results suggest that the systematic organization of issues into a searchable database would reduce inquiry durations and improve work efficiency. Furthermore, the availability of various search tools and methods would quickly provide healthcare professionals with provision of drug information needed to improve patient medication safety.

The transitional stage of B-cell development is a formative stage in the spleen where autoreactive specificities are censored as B cells gain immune-competence, but the intrinsic and extrinsic factors regulating survival of transitional stage 1 (T1) B cells are unknown. We report that B-cell expression of IFNβ is required for optimal survival and TLR7 responses of transitional B cells in the spleen and was over-expressed in T1 B cells from BXD2 lupus-prone mice. Single-cell gene expression analysis of B6 Ifnb+/+ vs. B6 Ifnb−/− T1 B cells revealed heterogeneous expression of Ifnb in WT B cells and distinct gene expression patterns associated with endogenous IFNβ. Single cell analysis of BXD2 T1 B cells revealed that Ifnb is expressed in early T1 B-cell development with subsequent upregulation of Tlr7 and Ifna1. Together these data suggest that T1 B-cell expression of IFNβ plays a key role in regulating responsiveness to external factors.

Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) TFH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra(-/-) mice, the majority of CXCR5(+) TFH cells from BXD2-Il17ra(-/-) mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra(-/-), disrupted TFH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.

The pathogenic connection of type I IFN and its role in regulating the migration response of Ag delivery by B cells into lymphoid follicles in an autoimmune condition has not been well-identified. Here, we show that there was a significantly larger population of marginal zone precursor (MZ-P) B cells, defined as being IgM(hi)CD1d(hi)CD21(hi)CD23(hi) in the spleens of autoimmune BXD2 mice compared with B6 mice. MZ-P B cells were highly proliferative compared with marginal zone (MZ) and follicular (FO) B cells. The intrafollicular accumulation of MZ-P B cells in proximity to germinal centers (GCs) in BXD2 mice facilitated rapid Ag delivery to the GC area, whereas Ag-carrying MZ B cells, residing predominantly in the periphery, had a lower ability to carry Ag into the GCs. IFN-alpha, generated by plasmacytoid dendritic cells, induced the expression of CD69 and suppressed the sphingosine-1-phosphate-induced chemotactic response, promoting FO-oriented Ag transport by MZ-P B cells. Knockout of type I IFN receptor in BXD2 (BXD2-Ifnalphar(-/-)) mice substantially diffused the intrafollicular MZ-P B cell conglomeration and shifted their location to the FO-MZ border near the marginal sinus, making Ag delivery to the FO interior less efficient. The development of spontaneous GCs was decreased in BXD2-Ifnalphar(-/-) mice. Together, our results suggest that the MZ-P B cells are major Ag-delivery B cells and that the FO entry of these B cells is highly regulated by type I IFN-producing plasmacytoid dendritic cells in the marginal sinus in the spleens of autoimmune BXD2 mice.