A novel near-infrared fluorescent probe for high-sensitivity detection of butyrylcholinesterase in various pathological states.

Butyrylcholinesterase (BChE) is a crucial hydrolytic enzyme predominantly synthesized in the liver, playing a significant role in conditions like liver disorders, diabetes, Alzheimer's disease, and fat metabolism regulation. This study aims to address the current limitations in visualizing BChE activity in diseases at various states by introducing an ultra-sensitive near-infrared fluorescent probe, FDCM-BChE. The probe was engineered to have several properties, such as a large Stokes shift, rapid response time, high stability, excellent selectivity, and low detection limits. We validated the efficacy of FDCM-BChE in quantifying BChE activity in human serum and leveraged its low cytotoxicity for cellular imaging. The study revealed the downregulation of BChE activity in liver cancer and hepatic injury and the upregulation in diabetes. Thus, FDCM-BChE shows promise as a tool for specific applications, providing insights into diseases associated with BChE activity.

Will nanomedicine become a good solution for the cardiotoxicity of chemotherapy drugs?

Cancer is one of the leading causes of death worldwide, and with the continuous development of life sciences and pharmaceutical technology, more and more antitumor drugs are being used in clinics to benefit cancer patients. However, the incidence of chemotherapy-induced cardiotoxicity has been continuously increasing, threatening patients' long-term survival. Cardio-oncology has become a research hot spot, and the combination of nanotechnology and biomedicine has brought about an unprecedented technological revolution. Nanomaterials have the potential to maximize the efficacy and reduce the side effects of chemotherapeutic drugs when used as their carriers, and several nano-formulations of frequently used chemotherapeutic drugs have already been approved for marketing. In this review, we summarize chemotherapeutic drugs that are highly associated with cardiotoxicity and evaluate the role of nano-delivery systems in reducing cardiotoxicity based on studies of their marketed or R&D nano-formulations. Some of the marketed chemotherapy drugs are combined with nano-delivery systems that can effectively deliver chemotherapy drugs to tumors and cannot easily penetrate the endothelial barrier of the heart, thus decreasing their distribution in the heart and reducing the cardiotoxicity to some extent. However, many chemotherapy nanomedicines that are marketed or in R&D have not received enough attention in determining their cardiotoxicity. In general, nanomedicine is an effective method to reduce the cardiotoxicity of traditional chemotherapy drugs. However, cardiovascular complications in cancer treatment are very complex diseases, requiring the application of multiple measures to achieve effective management and prevention.

Investigation of the "Nose-to-Brain" Pathways in Intranasal HupA Nanoemulsions and Evaluation of Their in vivo Pharmacokinetics and Brain-Targeting Ability.

Purpose: While developing huperzine A (HupA) to explore new approaches to treating Alzheimer's disease (AD), intranasal administration was proposed as an alternative route to deliver drugs into the brain. This study aimed to prepare nanoemulsions (NEs) of HupA to investigate their potential "nose-to-brain" pathways and to evaluate their pharmacokinetic and brain-targeting parameters. Methods: HupA-NE and Lf-HupA-NE that underwent surface modification with lactoferrin (Lf) were characterized to determine various physicochemical properties, such as their size, PDI, zeta potential, pH, and loading efficiency; in addition, transmission electron microscopy and stability assessments were performed. We utilized an aggregation-caused quenching (ACQ) probe to monitor intact NEs in the brains of olfactory nerve transection model and normal rats. Immunohistochemistry, pharmacokinetic and targeting index analyses were performed to investigate the in vivo effects of HupA-NE and Lf-HupA-NE. Results: Based on the live imaging results, HupA-NE and Lf-HupA-NE could be transported into the brain via nerve and blood circulation pathways. Immunohistochemical staining tests demonstrated that the efflux proteins P-gp, MRP1, and BCRP were expressed in brain tissue. NEs can inhibit efflux pumps to improve drug concentrations in the brain. The findings of this study showed that NEs (especially Lf-HupA-NE) had better pharmacokinetic profiles and a better nose-to-brain drug transport efficiency than free HupA. Conclusion: The newly designed formulations might contribute to the transport and accumulation of HupA to achieve therapeutic results. The delivery system may be a promising strategy for the brain-targeted delivery of HupA.

The effect of clinical pharmacists' intervention in adverse drug reaction reporting: a retrospective analysis with a 9-year interrupted time series.

BACKGROUND: In China, 85.4% of adverse drug reactions (ADRs) are spontaneously reported by healthcare facilities. As a result, many ADRs are not reported due to lack of mandatory reporting requirements. As healthcare professionals, clinical pharmacists (CPhs) serve as a bridge between clinical work and medication and ensure rational drug use. In China, A team of CPhs implemented an intervention for ADRs reporting, with the goal of improving the number of ADRs reports, the number of unreported ADRs, and the standardized reporting rate. METHODS: On June 01, 2015, a team of CPhs implemented an intervention for ADRs reporting at a Grade A, Class 3 hospital in China. The drug review catalogue (DRC) was used to screen physician orders for having visible symptoms of ADRs across departments, pooled the ADRs, and submitted them to the Center for Advanced Drug Monitoring (CNCAM). We retrospectively analysed the effect of a CPhs ADRs reporting intervention on the number of clinical ADRs reports, the number of unreported ADRs, and the standardized reporting rate over a 9-year period by interrupted time series (ITS). The method was implemented at the hospital on June 1, 2015, and a segmented regression model was used to analyse the data from January 1, 2010, to December 31, 2019. RESULTS: After the CPhs ADRs reporting intervention, the number of inpatient ADRs reports submitted to the CNCAM immediately increased by approximately 63 (62.658, P < 0.01) and then decreased by approximately 1 (0.701, P = 0.000151 < 0.01) per month afterward; the number of unreported ADRs was immediately reduced by approximately 44 (44.091, P < 0.01) and remained largely unchanged over time (P > 0.05); the standardized ADRs reporting rate per month immediately increased by 63.634% (P < 0.01) and remained largely unchanged over time (P > 0.05). CONCLUSION: The CPhs ADRs reporting intervention had an immediate effect on improving ADRs reporting, which highlights the severity of ADRs underreporting in Chinese hospitals. The method is practical and should be used more widely in clinical practice. For example, the method can adjust and establish a DRC catalog that meets the actual situation of the implementing hospital based on the hospital's drug use habits and has the characteristics of good adaptability. However, it does have some limitations; for example, it may be difficult to detect early ADRs without visible symptoms.

Characterization and Evaluation of the Pro-Coagulant and Immunomodulatory Activities of Polysaccharides from Bletilla striata.

Bletilla striata is widely used for stanching bleeding. In this study, polysaccharides from B. striata (BSP) were extracted by hot water. Four polysaccharides named BSP-1-BSP-4 were fractionated using DEAE-52 cellulose. BSP fractions contained sulfate, and the degrees of substitution of BSP-3 and BSP-4 were 1.59 and 1.70, respectively. Analysis of monosaccharide composition showed that four polysaccharides were mainly composed of mannan and glucose. The in vitro results showed that BSP-1-BSP-4 elicited pro-coagulant capacities by shortening the activating partial thromboplastin time, prothrombin time, and thrombin time and elevating the fibrinogen content. Immunomodulatory activity was evaluated by MTT assay, the pinocytic capacity and NO production. Although BSP fractions did not affect RAW 264.7 cell viability, they, especially BSP-2, enhanced the immunomodulatory activity by increasing the pinocytic capacity and NO production. Overall, BSP may be developed as a potential coagulant with immunomodulatory effects.

The Optimization Design Of Lactoferrin Loaded HupA Nanoemulsion For Targeted Drug Transport Via Intranasal Route.

BACKGROUND: Huperzine A (HupA) is a selective acetylcholinesterase inhibitor used to treat Alzheimer's disease. The existing dosage of HupA lacks brain selectivity and can cause serious side effects in the gastrointestinal and peripheral cholinergic systems. PURPOSE: The aim of this study was to develop and characterize a HupA nanoemulsion (NE) and a targeted HupA-NE modified with lactoferrin (Lf) for intranasal administration. METHODS: The NE was formulated using pseudo-ternary phase diagrams and optimized with response surface methodology. Particle size distribution and zeta potential were evaluated, and transmission electron microscopy was performed. We investigated the transport mechanisms of HupA-NEs into hCMEC/D3 cells, an in vitro model of the blood-brain barrier. HupA-NE, Lf-HupA-NE, and HupA solution were intranasally administered to rats to investigate the brain-targeting effects of these formulations. A drug targeting index (DTI) was calculated to determine brain-targeting efficiency. RESULTS: Optimized HupA-NE had a particle size of 15.24±0.67 nm, polydispersity index (PDI) of 0.128±0.025, and zeta potential of -4.48±0.97 mV. The composition of the optimized HupA-NE was 3.00% isopropyl myristate (IPM), 3.81% Capryol 90, and 40% Cremophor EL + Labrasol. NEs, particularly Lf-HupA-NE, were taken up into hCMEC/D3 cells to a greater extent than pure drug alone. Western blot analysis showed that hCMEC/D3 cells contained P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein 1 (MRP1) transporters. The likely mechanisms resulting in higher NE transport to the brain were uptake by specific transporters and transcytosis. In vivo, intranasal Lf-HupA-NE significantly enhanced drug delivery to the brain compared to HupA-NE, which was confirmed by differences in pharmacokinetic parameters. The DTI of Lf-HupA-NE (3.2±0.75) demonstrated brain targeting, and the area under the curve for Lf-HupA-NE was significantly higher than that for HupA-NE. CONCLUSION: Lf-HupA-NE is a promising nasal drug delivery carrier for facilitating delivery of HupA to the central nervous system.

Pharmacokinetics and liver uptake of three Schisandra lignans in rats after oral administration of liposome encapsulating ß-cyclodextrin inclusion compound of Schisandra extract.

Schisandra chinensis fructus (SCF) is widely used traditional Chinese medicine, which possesses hepato-protective potential. Schisandrin (SD), schisantherin (ST), and γ-schizandrin (SZ) are the major bioactive lignans. The main problem associated with the major bioactive lignans oral administration is low oral bioavailability due to the lignans' poor aqueous solubility and taste. The aim of the present research work was to develop liposome (SCL) encapsulated ß-cyclodextrin (ß-CD) inclusion complex loaded with SCF extract (SCF-E). The SD, ST, and SZ were selected as effective candidates to perform comparisons of liver targeting among the solution (SES), ß-cyclodextrin inclusion compound (SCF-E-ß-CD), liposome (SEL), and SCL of SCF-E to characterize the pharmacokinetic behaviors and liver targeting in rats. The ß-CD inclusion complex (SCF-E-ß-CD) was used to improve the solubility. The concentrations were determined using high-performance liquid chromatography (HPLC) and analyzed by DAS3.0. The pharmacokinetic results indicate that the plasma concentration-time courses were fitted well to the one-compartment model with the first weighing factor. The half-life period (t1/2) and area under the concentration-time curve (AUC) of the three components in SCL were the largest. The SCL exhibit a relatively high liver targeting effect. The results would be helpful for guiding the clinical application of this herbal medicine.

Combination doxorubicin and interferon-α therapy stimulates immunogenicity of murine pancreatic cancer Panc02 cells via up-regulation of NKG2D ligands and MHC class I.

BACKGROUND: Pancreatic adenocarcinoma is a malignant gastrointestinal cancer with significant morbidity and mortality. Despite severe side effects of chemotherapy, the use of immunotherapy combined with chemotherapy has emerged as a common clinical treatment. In this study, we investigated the efficacy of the combined doxorubicin and interferon-α (IFN-α) therapy on murine pancreatic cancer Panc02 cells in vitro and in vivo and underlying mechanisms. MATERIALS AND METHODS: A Panc02-bearing mouse model was established to determine whether doxorubicin and interferon-α (IFN-α) could effectively inhibit tumor growth in vivo. Cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) was evaluated using a standard LDH release assay. To evaluate the relevance of NK cells and CD8 T cells to the combination therapy-mediated anti-tumor effects, they were depleted in tumor-bearing mice by injecting anti-asialo-GM-1 antibodies or anti-CD8 antibodies, respectively. Finally, the influence of doxorubicin+interferon-α (IFN-α) on the ligands of NK and T cells was assessed by flow cytometry. RESULTS: The combination therapy group demonstrated a significant inhibition of growth of Panc02 in vivo, resulting from activated cytotoxicity of NK cells and CTLs. Depleting CD8 T cells or NK cells reduced the anticancer effects mediated by immunochemotherapy. Furthermore, the doxorubicin+IFN-a treatment increased the expression of major histocompatibility complex class I (MHC I) and NKG2D ligands on Panc02 cells, suggesting that the combined therapy may be a potential strategy for enhancing immunogenicity of tumors. All these data indicate that the combination therapy using doxorubicin and interferon-α (IFN-α) may be a potential strategy for treating pancreatic adenocarcinoma.