Identification and quantification of compounds with Angiotensin-converting enzyme inhibitory activity in licorice by UPLC-MS.

Licorice is a famous medicine-food herb for treating cardiovascular diseases in many compound prescriptions. Angiotensin-converting enzyme (ACE) is a key target of cardiovascular diseases. Despite its significance, there is limited scientific investigation regarding the ACE inhibitory effects of licorice. In this study, we used an activity-guided approach with an aggregation-induced emission (AIE) fluorescent probe to identify compounds with ACE-inhibitory activity in licorice. Nine components of licorice were found to have ACE inhibitory activity, in which 46 compounds were identified by using UPLC-QTOF-MS. Seven active compounds were found in this study. Among them, licochalcone B had best ACE inhibitory activity (IC50 = 0.24 µM). Finally, an UPLC-Q-MS method was established to quantify the five major active compounds in three batches of licorice. The findings of this study offer valuable insights into the potential of licorice as a source of ACE inhibitors and its relevance in the development of related products.

Surfactant-stripped J-aggregates of azaBODIPY derivatives: All-in-one phototheranostics in the second near infrared window.

Development of multifacted phototheranostics with bright fluorescence and absorbance in the second near infrared (NIR-II) window is very appealing for precise cancer diagnosis and treatment, but still challenging nowadays. Herein, we synthesize a hydrophobic annularly fused azaBODIPY (termed as HBP) molecule with sharp NIR absorbance peaked at 878 nm and bright NIR-II fluorescence. With Pluronic F127 as the surfactant and hydrophobic paclitaxel (PTX) as the spacer, such HBP molecule would self-assemble to form surfactant-stripped HBP/PTX micelles with absorption peak red-shifted to 1012 nm and intrinsic NIR-II fluorescence negligibly disturbed. We found that such HBP/PTX micelles can be utilized as a bimodal NIR-II nano-probe to enable real-time tracking of lymph nodes and tumors under an NIR-II fluorescence imaging system, as well as clear visualization of tumor microvasculatures under an NIR-II photoacoustic imaging system. Furthermore, together with 1064 nm laser exposure, such HBP/PTX micelles would synergistically suppress the growth of tumors grown on the mice upon tumor accumulation. This work highlights the concise preparation of a type of all-in-one NIR-II phototheranostics from the newly synthesized HBP molecules, thereby enables NIR-II fluorescence/photoacoustic bimodal imaging guided synergistic cancer treatment via the NIR-II laser boosted photothermal therapy and chemotherapy.

Surfactant-Stripped Micelles of Near Infrared Dye and Paclitaxel for Photoacoustic Imaging Guided Photothermal-Chemotherapy.

Development of nanoagents with strong near-infrared (NIR) absorbance and high photothermal conversion capacity is highly desired for efficient photoacoustic (PA) imaging and photothermal therapy of cancers. Herein, surfactant-stripped micelles with photostable near-infrared dye, ß-thiophene-fused BF2 -azadipyrromethene (aza-BDTP), are prepared in the presence of paclitaxel (PTX) with Pluronic F127 as the surfactant. Distinct from hydrophobic aza-BDTP and PTX, the obtained surfactant-stripped micelles aza-BDTP/PTX show excellent solubility, physiological stability, and high loading efficiencies for corresponding aza-BDTP and PTX. Intriguingly, these aza-BDTP/PTX micelles exhibit high photothermal conversion efficiency at 33.9%, significantly higher than 16.9% for bare aza-BDTP molecules, owing to aggregation-induced quenching of aza-BDTP fluorescence. With excellent photostability, aza-BDTP/PTX micelles appear to be a highly stable photoacoustic imaging probe and show efficient tumor accumulation as visualized under photoacoustic imaging upon intravenous injection. After being irradiated with a 785 nm laser, 4T1 tumors on the mice with systemic administration of aza-BDTP/PTX micelles are fully eradiated without any recurrences within 60 d. This work presents a general method for efficient encapsulation of hydrophobic aza-BDTP and PTX, obtaining hybrid aza-BDTP/PTX micelles as promising nanotheranostics for imaging guided cancer combination therapy.

Sensitivity of myeloid leukemia cells to calcium influx blockade: application to bone marrow purging.

OBJECTIVE: The aim of this study was to assess the potential of store-operated Ca(2+) channel (SOC) antagonists as purging agents for leukemia cells. MATERIALS AND METHODS: Clonogenic, limiting dilution, and nuclear condensation assays were used to evaluate SOC antagonist efficacy. SOC activity and endoplasmic reticulum Ca(2+) content were measured by flow cytometry. Murine bone marrow transplantation was used to determine purging efficacy and effects on hemopoietic reconstitution. RESULTS: Econazole (Ec) and ketotifen (Ke) were variably effective against human and murine leukemia cell lines after 24 hours of incubation. However, a 2-hour serum and bovine serum albumin-free treatment protocol with Ec was found to maximize differential sensitivity between leukemic cells and normal hemopoietic progenitors. Primary acute myelogenous leukemia blast cell viability was reduced 4.2 to 5.1 logs by 2-hour Ec treatment as measured by limiting dilution. An inverse relationship between endoplasmic reticulum Ca(2+) content and Ke sensitivity in leukemia and untransformed cells was observed. Nuclear condensation, an index of apoptosis, which occurred after 24-hour treatments with either Ec or Ke, was not observed after 2-hour serum- and bovine serum albumin-free Ec exposures; however, condensed nuclei were observed after an additional 10-hour incubation in growth medium without drug. Using bone marrow deliberately contaminated with 1% P815 cells, we showed that highly effective in vitro purging can be accomplished using Ec with no adverse effects on bone marrow reconstitution in mice. CONCLUSIONS: These studies suggest that SOC antagonists have potential as purging agents for residual leukemia cells present in bone marrow in the context of high-dose chemotherapy and autologous transplantation for leukemia.

Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death.

Activation enhanced cell death (AECD) involves stimulating cells with growth or activation signals while concurrently blocking calcium influx. In this study, we have evaluated the effect of AECD on human breast cancer cells. MCF-7 or MDA-MB-231 cells treated with Ca2+ influx blockers econazole or ketotifen for 24 h underwent a dose-dependent, irreversible loss of viability, and clonogenicity. Two-hour treatment of these cells with higher concentrations of the drugs also resulted in loss of clonogenicity, but morphological indicators of cell death were apparent only after longer incubation. Loss of clonogenicity could be enhanced almost 10-fold by co-stimulation of the cells with the agonists EGF or bombesin. Econazole was also effective in inducing cell death in multi-drug resistant MCF-7adr cells. Human hemopoietic progenitor cell sensitivity to econazole or ketotifen was evaluated by colony assay. Under conditions resulting in 2.5-3 logs of breast cancer cell loss, 60-70% of hemopoietic progenitors could be recovered. We further evaluated the effect of econazole on breast cancer cells present in mobilized hemopoietic cells obtained from patients undergoing high dose chemotherapy with autologous stem cell support. In six of eight samples evaluated, cytokeratin-positive breast cancer cells could be detected by immunofluorescence microscopy and colony formation. Breast cancer colonies were reduced 60-500-fold or more after exposure to econazole while hemopoietic colonies were typically reduced only 2-fold. In all cases, addition of EGF as an activator either had no evaluable effect or enhanced breast cancer cell loss. We conclude that Ca2+ influx blockade with concurrent EGF stimulation is a promising approach for purging breast cancer cells from hemopoietic progenitor cell preparations.