Paeoniflorin loaded liposomes modified with glycyrrhetinic acid for liver-targeting: preparation, characterization, and pharmacokinetic study.

OBJECTIVE: To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. SIGNIFICANCE: The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. METHODS: This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. RESULTS: The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. CONCLUSION: These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug.

Construction and Biological Evaluation of Multiple Modification Hollow Mesoporous Silicone Doxorubicin Nanodrug Delivery System.

The combination of functionalized nanoparticles and chemotherapy drugs can effectively target tumor tissue, which can improve efficacy and reduce toxicity. In this article, pPeptide-PDA@HMONs-DOX nanoparticles (phosphopeptide-modified polydopamine encapsulates doxorubicin-loaded hollow mesoporous organosilica nanoparticles) were constructed that based on multiple modification hollow mesoporous organosilica nanoparticles (HMONs). The pPeptide-PDA@HMONs-DOX nanoparticles retain the biological functions of phosphorylated peptide while exhibiting biological safety that are suitable for effective drug delivery and stimulus responsive release. The degradation behaviors showed that pPeptide-PDA@HMONs-DOX has dual-responsive to drug release characteristics of pH and glutathione (GSH). In addition, the prepared pPeptide-PDA@HMONs-DOX nanoparticles have good biological safety, and their anti-tumor efficacy was significantly better than doxorubicin (DOX). This provided new research ideas for the construction of targeted nanodrug delivery systems based on mesoporous silicon. Scheme 1 The preparation of pPeptide-PDA@HMONs-DOX and the process of drug release under multiple responses. (A) Schematic diagram of the synthesis process of pPeptide-PDA@HMONs-DOX. (B) The process in which nanoparticles enter the cell and decompose and release DOX in response to pH and GSH.

PEGylated liposomes as delivery systems for Gambogenic acid: Characterization and in vitro/in vivo evaluation.

Gambogenic acid (GNA), which possesses diverse anti-tumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. However, the excessive irritation to the blood vessel, short elimination half-life and poor aqueous solubility restricted its clinical application. In this study, Gambogenic acid-loaded PEGylated liposomes (GNA-PEG-LPs) were developed to reduce toxicity, prolong the half-life and enhance anticancer efficacy both in vitro and in vivo. The average particle size of GNA-PEG-LPs was 90.13 ± 0.16 nm and their polydispersity index (PDI) was 0.092 ± 0.003. The encapsulation efficiency, drug loading and zeta potential of GNA-PEG-LPs were 88.13 ± 1.31%, 3.72 ± 0.04%, -22.10 ± 0.20 mV, respectively. Compared to free GNA, GNA-PEG-LPs showed enhanced cytotoxicity and apoptosis induction effect against A549, SGC-7901 and HepG2 cells. Mechanistically, western blot analysis revealed that up-regulation of Bax, down-regulation of Bcl-2 and activation of caspase-3 contributed to apoptosis. In addition, the blood vessel irritation test showed that the vascular irritation of GNA could be reduced by liposomal encapsulation. The hemolysis assay revealed that good hemocompatibility of the liposomes. Furthermore, pharmacokinetic study showed that the t1/2 and the AUC of GNA-PEG-LPs were higher than GNA solution approximately 2.84-fold and 2.97-fold, respectively. In vivo antitumor efficacy demonstrated that GNA-PEG-LPs significantly inhibited the tumor growth in LLC tumor-bearing C57BL/6 mouse model. Results of Immunohistochemistry indicated that GNA-PEG-LPs significantly suppressed the expression of Bcl-2 and increased the expression of Bax and caspase-3 compared with free GNA. Collectively, PEGylated liposomes could be a potential nanocarrier to prolong half-life, reduce toxicity and enhance anticancer efficacy both in vitro and in vivo.

Reversal effect of quercetin on multidrug resistance via FZD7/ß-catenin pathway in hepatocellular carcinoma cells.

BACKGROUND: Chemotherapy has been widely used to treat cancer, but the appearance of multidrug resistance (MDR) is the biggest obstacle to successful chemotherapy. One of the conventional mechanisms of MDR is overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated proteins (MRPs/ABCCs) that limits the prolonged and efficient use of chemotherapeutic drugs. To enhance the chemosensitivity of tumor cells, attentions have been focused on effective MDR modulators. PURPOSE: This study aimed to investigate the reversal effect of quercetin on MDR, and explored its mechanism of action in vitro. STUDY DESIGN/METHODS: The effect and mechanism of quercetin on MDR was examined by using MTT assay, flow cytometry, real-time PCR and western blot analysis in human hepatocellular carcinoma cells. RESULTS: Our data found that the intracellular accumulation of rhodamine-123 (Rh123) and doxorubicin (ADR) were increased, the sensitivity of BEL/5-FU cells to chemotherapeutic drugs were increased, and the expressions of ABCB1, ABCC1 and ABCC2 were all down-regulated, which indicated that the functions and expressions of ABCB1, ABCC1 and ABCC2 efflux pump were inhibited by quercetin treatment. Moreover, the suppression of ABCB1, ABCC1 and ABCC2 by quercetin was dependent on the FZD7 through the Wnt/ß-catenin pathway. Further research revealed that reduction of FZD7 by RNA interference (siFZD7) enhanced the sensitivity to chemotherapeutic drugs, increased the cellular accumulation of Rh123 and ADR, and induced inhibitory effects on the expression of FZD7, ABCB1, ABCC1, ABCC2 and ß-catenin, similar to quercetin. In the meanwhile, overexpression of FZD7 showed the inversely effect on the expressions. Interesting, it was confirmed that quercetin could inhibit the expression levels of FZD7, ABCB1, ABCC1, ABCC2 and ß-catenin in BEL-7402 cells; furthermore, treatment by quercetin combined with siFZD7 in BEL/5-FU cells, the expressions of these genes were effectively decreased in comparison to quercetin combined with siRNA negative control (sncRNA). CONCLUSION: Overall, these data suggested the effectiveness of using quercetin, at least in part, via inhibiting FZD7 to combat chemoresistance and showed that quercetin could be developed into an efficient natural sensitizer for resistant human hepatocellular carcinoma.

Propofol in combination with remifentanil for cesarean section: Placental transfer and effect on mothers and newborns at different induction to delivery intervals.

OBJECTIVE: This study aims to describe the administration of propofol in combination with remifentanil for the induction of general anesthesia during cesarean section (CS). Our aim was to evaluate its impact on the drug concentrations of the maternal and neonatal blood at different induction of anesthesia to delivery (I-D) intervals as well as its effect on newborns. MATERIALS AND METHODS: In this double-blind randomized controlled study, patients undergoing elective CS were administered anesthesia at short (n = 20) or long (n = 20) I-D intervals. Anesthesia was induced with 1 mg/kg propofol and 1 µg/kg remifentanil and maintained by continuous infusion of 3 mg/kg/h propofol and 7 µg/kg/h remifentanil. RESULTS: The mean plasma propofol concentrations at delivery in the maternal arterial (MA) blood and the fetal umbilical arterial (UA) and venous (UV) blood in the short I-D interval group were 1.91, 1.17, and 0.51 µg/mL, respectively, while those in the long I-D interval group were 1.57, 1.07, and 0.61 µg/mL, respectively. The mean plasma remifentanil concentrations at delivery in the MA, UA, and UV in the short I-D interval group were 2.25, 1.43, and 0.65 ng/mL, respectively, and those in the long I-D interval group were 1.96, 1.25, and 0.75 ng/mL, respectively. There were no statistically significant differences in the neonatal Apgar scores and neurological adaptive capacity scores between the two groups. CONCLUSIONS: It is safe to administer propofol in combination with remifentanil by continuous infusion after the bolus dose for the induction of anesthesia during cesarean section. Prolonging the I-D interval within a certain limit will not have any significant influence on the fetus.

Renoprotective effects of berberine and its potential effect on the expression of ß-arrestins and intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in streptozocin-diabetic nephropathy rats.

BACKGROUND: Berberine has been shown to exert protective effects against diabetic nephropathy (DN), but the mechanisms involved have not been fully characterized. The aim of the present study was to explore the effects of berberine on the expression of ß-arrestins, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in DN rat kidneys and investigate the underlying molecular mechanisms. METHODS: To create the DN model, rats fed a high-fat and high-glucose diet were injected with a single dose of streptozotocin (35 mg/kg, i.p.). Then, DN rats were either treated or not with berberine (50, 100, 200 mg/kg per day, i.g., 8 weeks). Periodic acid-Schiff staining was used to evaluate renal histopathological changes. Renal tissue levels of ß-arrestin 1 and ß-arrestin 2 were determined by Western blot analysis, whereas immunohistochemistry was used to determine renal ICAM-1 and VCAM-1 levels. RESULTS: Berberine (100, 200 mg/kg) ameliorated the histopathological changes in the diabetic kidney. Western blot analysis revealed significant increases in ICAM-1 and VCAM-1 levels in the kidneys of DN rats, which were reversed by treatment with 100 and 200 mg/kg berberine. In addition, berberine treatment (50, 100, 200 mg/kg) increased diabetic-induced decreases in ß-arrestin 1 and ß-arrestin 2. CONCLUSIONS: Berberine exhibited renoprotective effects in DN rats. The underlying molecular mechanisms may be associated with changes in the levels and regulation of ß-arrestin expression, as well as ICAM-1 and VCAM-1 levels in the rat kidney.

[Effect of berberine on expression of transforming growth factor-beta1 and type IV collagen proteins in mesangial cells of diabetic rats with nephropathy].

OBJECTIVE: To explore the effect and mechanism of berberine on diabetic nephropathy in experimental rats. METHOD: The rat model of diabetic nephropathy was induced by injection of streptozocin (STZ). The rats were divided into 6 groups: control group, model group, 3 berberine treatment groups and Xiaoke Wan (XKW) treatment group. The fasting blood glucose (FBG), kidney weight/body weight (KW/BW), blood urea nitrogen (BUN), creatinine (Cr) and urinary protein (Upro) were tested 8 weeks later. The expression of transforming growth factor-beta1 (TGF-beta1) and type IV collagen (IV-C) proteins in renal tissue of diabetic rats with nephropathy were observed by optical micrography. RESULT: Berberine could reduce the levels of FBG, KW/BW, BUN, Cr, Upro and the expression of TGF-beta1 and IV-C proteins in renal tissue of diabetic rats with nephropathy. CONCLUSION: Berberine may protect renal function and slow down the progression of diabetic nephropathy in rats by suppressing the expression of TGF-beta1 and IV-C proteins in renal tissue.

[Effect of compound Rhizoma Coptidis capsule on expression of transforming growth factor-beta1 and type IV collagen proteins in renal tissue of diabetic rats with nephropathy].

OBJECTIVE: To explore the effect and mechanism of compound Rhizoma Coptidis capsule (CRCC) on diabetic nephropathy in experimental rats. METHOD: The rat model of early diabetic nephropathy was induced by injection of streptozotocin (STZ). The rats were divided into 6 groups: normal control group, model group, 3 CRCC treatment groups and XKW treatment group. The fasting blood glucose (FBG), blood urea nitrogen (BUN), creatinine (Cr), insulin (Ins) and urinary protein (Upro) were tested 30 days later. The expression of transforming growth factor-beta1 (TGF-beta1) and type IV collagen (IV-C) proteins and the pathological changes in renal tissue of diabetic rats with nephropathy were observed by optical micrography. RESULT: CRCC could reduce the levels of FBG, BUN, Cr, Upro and the expression of TGF-beta1 and IV-C proteins, and alleviate pathological lesion in renal tissue of diabetic rats with nephropathy. CONCLUSION: CRCC may protect the renal function and slow down the progression of diabetic nephropathy in rats by suppressing the expression of TGF-beta1 and IV-C proteins in renal tissue.