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. 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. 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. Proximal intestinal glucose sensing and metabolism play an important role in blood glucose homeostasis by DJB.

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.

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.

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.

Duodenojejunal bypass (DJB) is an experimental procedure to study the mechanism of metabolic surgery in type 2 diabetes (T2DM),independent of weight changes. The aim of this study was to evaluate the role of Gastrointestinal (GI) glucose sensing and glucose transportation in DJB regulated glucose metabolism using T2DM rat model. T2DM was induced in Wistar rats with 2 months of high-fat diet and one low-dose streptozocin (STZ) injection. T2DM rats were randomly divided into sham operation group (T2DM-Sham, n=8) and DJB group (T2DM-DJB, n=8). Eight Wistar rats were used as wild type control group(Control, n=8). The results showed that DJB surgery significantly improved blood glucose homeostasis in T2DM rats. The hematoxylin-eosin staining results revealed that DJB operation thickened the wall of small intestine comparing to Sham operation. DJB also increased the length of villus in small intestine. Western Blot and qRT-PCR results showed that DJB significantly increased the expression of sodium-glucose co-transporter-1 (SGLT1) while reducing the expression of glucose transporter-2 (GLUT2) in the alimentary limb of DJB rats. The results also showed the expression of intestinal sweet receptors (T1R2/T1R3), Glucagon-like peptide 1/2 (GLP1/2) and its receptor (GLP1/2R) increased significantly in the alimentary limb after DJB surgery. Here we describe a new observation that DJB surgery lowers blood glucose level via intestinal glucose transport and glucose sensing regulation in the alimentary limb. Disclosure B. Jiang: None. H. Wang: None. W. Wang: None. Q. Yan: None. M. Qu: None. Z. Gao: None. Funding National Natural Science Foundation of China (81871892); Natural Science Foundation of Shandong Province (ZR2019BH036); Technology Development Plan of Weifang (2018YX027)

This study was focused on the effect of duodenal-jejunal bypass (DJB) on brain inflammation, activation brain insulin signaling and POMC positive neurons in type 2 diabetic (T2DM) rats. T2DM rats were induced by high-fat diet (HFD) and low dose streptozotocin (STZ) injection. Twelve T2DM rats were randomly divided into 2 groups, DJB group (T2DM-DJB, n=6) and T2DM group (T2DM-Sham, n=6). Six health Wistar rats were used as normal control rats (Wistar-Control, n=6). The results showed DJB group was significantly reduced the HOMA-IR and increased HOMA-ISI of T2DM rats 6 weeks after surgery. The Q-RT-PCR and Western-blot results showed DJB intervene significantly decreased the expression of inflammatory factors IL-6, TNF-α, IL-1β and NF-κB in the brain. Our data also showed that DJB activated the brain insulin by increasing the expression of insulin, IRS1 and IRS2 in the brain of T2DM rats. Immunohistochemical assay showed that DJB increased the number of POMC positive neurons in brain, and increased the expression of BDNF in neurons. Those results indicated that DJB might fulfill the antidiabetic effect by increasing POMC positive neurons and decreasing the brain inflammation in T2DM rats. Disclosure H. Wang: None. B. Jiang: None. J. Li: None. W. Wang: None. N. Li: None. Q. Yan: None. Z. Gao: None. M. Qu: None. Funding National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)

Glucagon-like peptide-1 (GLP-1) is a peptide with multiple functions in regulating blood glucose with the mechnism still not throughly understand. AMP-activated protein kinase (AMPK) plays an important role in glucose and energy homeostasis, especially in type 2 diabetes mellitus (T2DM) pathophysiology. This study explores GLP-1 analogue exendin-4 (Ex-4) regulating glucose balance by activating AMPK and regulation gluconeogenesis in insulin-resistant cell model (IR/ HepG2). IR/HepG2 cells were treated with Ex-4, AMPK activator or Ex-4 pretreated with AMPK inhibitor Compound C. The change of cell morphology, glucose consumption and lipid content in IR/HepG2 cells were examined. The expression of AMPK and p-AMPK in IR/HepG2 treated by Ex-4 were determined by Western blot and immunochemisthistology (IHC) assay. Key enzymes of glucose metabolism, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) in IR/HepG2 cells treated by Ex-4 were detected by Western blot, immunohistochemistry and qRT-PCR. The results showed that Ex-4 treatment increased the expression of p-AMPK and reduced the expression of G-6-Pase and PEPCK in IR/HepG2 cells. Pretreatment with AMPK inhibitor Compound C counteracts the effect of Ex-4. These findings suggest that Ex-4 fulfilled it glucose regulation effect by phosphorylation of AMPK and decreased the expression of enzymes involving gluconeogenesis.

Duodenal-Jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction, while the mechanism underlying remains unclear. The most important characteristic of diabetes is hyperglycemia due to impaired glucose homeostatic regulation, increasing evidences have demonstrated that the brain can directly initiate behavioral and metabolic responses to control energy and peripheral glucose homeostasis. This study mainly focused on exploring the role of brain insulin signaling activation and brain glucose utilization in the antidiabetic mechanism of DJB. The diabetic rats that induced by Streptozotocin (STZ) injection were grouped and proceeded with DJB or Sham operation, respectively. Basal glycemic parameters, such as fasting glucose, fasting plasmid insulin, OGTT, HOMA-IR and Hb1Ac, were detected by ELISA kits. In different treated (DJB, Sham or Control) rats models, 18F-FDG PET scanning was used to detect the glucose uptake in different organs, and of the level of insulin as well as insulin signaling pathway related proteins (InsR, IRS1/2, PI3K, AKT) and glucose utilization related proteins (HK1, PFK2) was evaluated by Q-RT-PCR, Western blot or IHC in the brain. Results showed that DJB surgery significantly improved basal glycemic parameters (Blood glucose, Insulin, HOMA-IR, HbA1c and OGTT) and reversed the decreased glucose uptake in the brain which was caused by type 2 diabetes. DJB surgery not only induced the gene expression of the brain insulin as well activated the insulin related signals, but also increased the expression of glucose utilization enzymes, such as HK1 and PFK2 in the brain. These results indicated that activation of brain insulin signaling and elevation of brain glucose metabolism might play an important role in the antidiabetic effect of DJB. Disclosure Q. Yan: None. N. Li: None. R. Pan: None. H. Wang: None. B. Jiang: None. W. Wang: None. Z. Gao: None. M. Qu: None. Funding National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)

BACKGROUND:Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization.METHODS:A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed.RESULTS:The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain.CONCLUSION:These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.

Aim To prepare hyaluronic acid nanoparti-cles(Ade/GA-HA) using glycyrrhetinic acid modified hyaluronic acid as the carrier and adenine as a model drug, and analyze their physicochemical property and proliferation effect on Bel-7402 cells. Methods Gly-cyrrhetinic acid and hyaluronic acid were combined by chemical cross-linking method, dialysis and freeze-dr-ying,based on which Ade/GA-HA was prepared using ultrasonic method, and the particle size and Zeta po-tential were determined by Malvern laser particle analy-zer,and the morphology was observed by transmission electron microscopy, and the absorbance was deter-mined by ultraviolet-visible spectrophotometer, high performance liquid chromatograph and microplate read-er to caculate drug load, encapsulation efficiency and in vitro release. MTT assays were utilized to determine the proliferation of nanoparticles treated Bel-7402 cells. Results GA-HA nanoparticles had spherical shape with a good dispersion, at diameters of 398.1 nm, of which Zeta potential was - 34.2 mV, and presented good short term stability. The drug load and encapsulation efficiency of Ade/GA-HA nanoparticles were (22.5 ± 5.8)% and (87.27 ± 0.33) %, re-spectively. Burst release was observed in Ade/GA-HA nanoparticles within 4 h, while controlled release 4 h later. Compared with free adenine,Ade/GA-HA nano-particles had a stronger inhibitory effect on cell prolif-eration with statistically significant difference. Conclu-sion GA-HA nanoparticles has excellent physico-chemical properties and meet the design requirement.

Liver cancer is one of the most common human malignancies worldwide. Currently, chemotherapy remains the cornerstone for liver cancer treatment. However, chemotherapy often causes many side effects, such as leukopenia, digestive reaction, hepatic and renal dysfunction and hair loss. Recently, great advances in nanoparticles-based liver-targeting drug delivery systems have been developed to overcome these problems. Glycyrrhetinic acid (GA), a pentacyclic triterpenoid extracted from the root of licorice, and has been widely used in liver cancer therapy. GA is capable of binding to hepatocytes via the specific site of GA-R on the surface of hepatic parenchymatous cells. From this prospective, this review highlights GA-mediated nanoparticles liver-targeting drug delivery systems from different polymer materials.

Liver cancer is one of the most common human malignancies worldwide. Currently, chemotherapy remains the cornerstone for liver cancer treatment. However, chemotherapy often causes many side effects, such as leukopenia, digestive reaction, hepatic and renal dysfunction and hair loss. Recently, great advances in nanoparticles-based liver-targeting drug delivery systems have been developed to overcome these problems. Glycyrrhetinic acid (GA), a pentacyclic triterpenoid extracted from the root of licorice, and has been widely used in liver cancer therapy. GA is capable of binding to hepatocytes via the specific site of GA-R on the surface of hepatic parenchymatous cells. From this prospective, this review highlights GA-mediated nanoparticles liver-targeting drug delivery systems from different polymer materials.

Duodenal-jejunal bypass surgery (DJB) is a experimental surgical procedure to study the mechanism of gastric surgery in T2DM treatment. Methods: T2DM rats induced by high glucose high fat food and low dose streptozotocin (STZ) injection were randomly divided into 2 groups: T2DM group and DJB surgery group (T2DM-DJB).Wistar rats were used as normal control. The fasting blood glucose and HbA1C were measured. Glucose utilizationin the brain was detected by small animal positron emission tomography (PET) using [18F]-fluorodeoxyglucose ([18F]-FDG).GLUT1, GLUT3 expression in the brain were measured by Q-RT-PCR. Results:DJB surgery significantly decreased the fasting blood glucose and Hb1Ac of the T2DM rats. [18F]-FDG uptake (standardized uptake values (SUV)mean)in the brain was elevated siginificantly 4 weeks after DJB (Wistar vs. T2DM vs. T2DM-DJB: SUVmean value 1.30±0.27 vs. 0.59±0.10 vs. 1.55±0.31, P<0.001). Q-RT-PCR showed that GLUT3 expression in the brain significantly increased 4 weeks after DJB while T2DM rats decreased. This study indicates that the improvement of glucose utilization in the brain plays an pivotal role in DJB treatment of T2DM. Disclosure R. Pan: None. N. Li: None. T. Zhao: None. H. Wang: None. B. Jiang: None. Q. Yan: None. Z. Gao: None. M. Qu: None.