Role of Proximal Intestinal Glucose Sensing and Metabolism in the Blood Glucose Control in Type 2 Diabetic Rats After Duodenal Jejunal Bypass Surgery.

BACKGROUND: Although gastric surgery can significantly improve blood glucose homeostasis in type 2 diabetes mellitus (T2DM), its mechanism remains unclear. This study evaluated the role of intestinal glucose sensing, glucose transport, and metabolism in the alimentary limb (A limb) of T2DM rats after duodenal jejunal bypass (DJB) surgery. METHODS: A T2DM rat model was induced via a high-glucose high-fat diet and low-dose streptozotocin injection. The diabetic rats were divided into two groups: the DJB surgery (T2DM-DJB) group and the sham surgery (T2DM-Sham) group. Wistar rats were used as wild-type control (Control). Small animal PET was used to assess the change in glucose metabolic status in the intestine. The intestinal villi height and the number of EECs after DJB were evaluated. The expressions of sweet taste receptors (T1R2/T1R3), glucose transporters (SGLT1/GLUT2), and key enzymes involved in glucose metabolism (HK2, PFK2, PKM2, G6Pase, and PCK1) in the A limb after DJB was detected by Western blot and qRT-PCR. RESULTS: Small animal PET analysis showed the intestinal glucose metabolism increased significantly 6 weeks after DJB surgery. The intestinal villi height and the number of EECs in the A limb 6 weeks after surgery increased significantly in T2DM-DJB rats comparing to T2DM-Sham rats. The mRNA and protein expression of T1R1/T1R3 and SGLT1/GLUT2 were downregulated in DJB-T2DM rats, while enzymes involved in glucose metabolism was upregulated in the A limb in T2DM-DJB rats. CONCLUSION: Proximal intestinal glucose sensing and metabolism play an important role in blood glucose homeostasis by DJB.

Preparation of docetaxel-loaded, glycyrrhetinic acid-modified nanoparticles and their liver-targeting and antitumor activity.

Liver cancer is one of the most common malignancies worldwide and poses a serious threat to human health. The most important treatment method, liver cancer chemotherapy, is limited due to its high toxicity and poor specificity. Targeted drug delivery systems have emerged as novel therapeutic strategies that deliver precise, substantial drug doses to target sites via targeting vectors and enhance the therapeutic efficacy. In the present study, glycyrrhetinic acid-modified hyaluronic acid (GA-HA) was used as a carrier for the model drug docetaxel (DTX) to prepare DTX-loaded GA-HA nanoparticles (DTX/GA-HA-NPs). The results indicated that the DTX/GA-HA-NPs exhibited high monodispersity (particle dispersity index, 0.209±0.116) and desirable particle size (208.73±5.0 nm) and zeta potential (-27.83±3.14 mV). The drug loading capacity and encapsulation efficiency of the NPs were 12.59±0.68 and 85.38±4.62%, respectively. Furthermore, it was determined that FITC-GA-HA was taken up by cells and distributed in the cytoplasm. DTX and DTX/GA-HA (just the DTX delivered by the nanoparticle) aggregated and altered the structure of cellular microtubules. Compared with DTX alone, DTX/GA-HA-NPs had a stronger inhibitory effect on HepG2 cell proliferation and promoted apoptosis of HepG2 cells. All experimental results indicated that DTX/GA-HA-NPs were successfully prepared and had liver-targeting and antitumor activities in vitro, which provided a foundation for future in vivo studies of the antitumor effects of DTX/GA-HA-NPs.

Enhanced targeted delivery of adenine to hepatocellular carcinoma using glycyrrhetinic acid-functionalized nanoparticles in vivo and in vitro.

Hepatocellular carcinoma (HCC), a common malignancy in China and globally, is primarily treated through surgical resection and liver transplantation, with chemotherapy as a significant synergistic option. Adenine (Ade), a nucleobase, exhibits antitumor effects by blocking human hepatic carcinoma cells in S phase and inhibiting tumor cell proliferation. However, its use is limited owing to its low solubility, poor targeting ability, and nephrotoxicity. Therefore, liver-targeting drug delivery systems have attracted considerable attention for the treatment of HCC. In this study, we explored the liver-targeting efficacy and antitumor effect of adenine-loaded glycyrrhetinic acid-modified hyaluronic acid (Ade/GA-HA) nanoparticles in vitro and in vivo. The GA-HA nanoparticles possessed obvious targeting specificity toward liver cancer cells, which was mainly achieved by the specific binding of the GA ligand to the GA receptor that was highly expressed on the liver cell membrane. In vitro and in vivo results showed that Ade/GA-HA nanoparticles could inhibit liver cancer cell proliferation and migration, promote apoptosis, and significantly inhibit the growth of tumor tissues. Altogether, this study is the first to successfully demonstrate that the targeting activity and antitumor effect of Ade against HCC are enhanced by using GA-HA nanoparticles in vitro and in vivo.

Improved efficacy of doxorubicin delivery by a novel dual-ligand-modified liposome in hepatocellular carcinoma.

Liposomes have been widely used as drug carriers in both biomedical research and for clinical applications, allowing the stabilisation of therapeutic compounds and overcoming obstacles to cellular and tissue uptake. However, liposomes still have low targeting efficiency, resulting in insufficient killing of tumour cells and unnecessary damage to normal cells. In this study, glycyrrhetinic acid (GA) and peanut agglutinin (PNA) were used as ligands to prepare dual-ligand-modified doxorubicin-loaded liposomes (DOX-GA/PNA-Lips) to enhance the targeting accuracy and efficacy of drug delivery against malignant liver cancer. PNA and GA modification enhanced the binding ability of liposomes to liver cancer cells, leading to excellent tissue and cell targeting of DOX-GA/PNA-Lips. DOX-GA/PNA-Lips showed an effective anti-tumour effect in vivo and in vitro, with its targeted delivery facilitating attenuation of the toxic side effects of DOX. These results demonstrated that dual-ligand-modified liposomes may provide an effective strategy for the treatment of hepatocellular carcinoma.