Characterization and comparison of insulinoma tumor model and pancreatic damage caused by the tumor, and identification of possible markers.

Insulinoma is a neuroendocrine tumor. It arises from the uncontrolled proliferation of pancreatic ß cells. In this study, we created an insulinoma tumor model in nude mice. INS-1 cells were injected in two different ways, subcutaneously (S.C.) or intraperitoneally (I.P.). Body weight, tumor weight, and size were measured. ELISA kits were used analyze to Glucose, insulin, and CA19-9 levels in serum, pancreas, and tumor tissues. KCNN4, KCNK1, GLUT2, IR, HSP70, HSF1, and HSP90 levels were analyzed by western blotting of membrane and/or cytosolic fractions of tumor and pancreas tissue. Tumor formation occurred in nude mice, but it did not occur in Wistar albino rats. The tumor has neuroendocrine cell morphology. Insulin and CA19-9 levels increased in pancreas tissue. In tumor tissue, KCNN4 levels were higher in both membrane and cytosolic fractions, while KCNK1 levels were lower in the membrane fraction of the S.C. group. HSP70 levels were also lower in the S.C. group. In pancreas tissue, KCNK1 levels were lower in the membrane fraction of the S.C. and I.P. groups. GLUT2 levels increased in both groups according to the control group, while IR levels decreased in the S.C. group compared to the control group. However, HSF1 levels increased in the I.P. group, while HSP90 decreased in the S.C. group in pancreatic tissues. The S.C. group is a more suitable insulinoma tumor model. KCNN4, KCNK1, and HSP70 proteins may be important biomarkers in the diagnosis and treatment of insulinoma.

Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCB2, cytoplasmic Ca+2, and AKT

The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1’s role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin+ cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2+, glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin+ cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCβ2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal’s molecules T1R3, PLCβ2, cytoplasmic Ca+2, and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development. (AU)

Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCß2, cytoplasmic Ca+2, and AKT.

The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1's role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin+ cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2+, glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin+ cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCß2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal's molecules T1R3, PLCß2, cytoplasmic Ca+2, and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development.

Exendin-4 inhibits small intestinal glucose sensing and absorption through repression of T1R2/T1R3 sweet taste receptor signalling in streptozotocin diabetic mice.

The small intestine, which is the area where sugars are absorbed, should be considered in the approaches developed for the treatment of diabetes. However, studies on small intestine damage in diabetic individuals, and the effects of current treatments on the small intestine are very limited. This is the first study to investigate the effects of exendin-4, a GLP-1 receptor agonist, on small intestine injury in diabetic mice. BALB/c male mice were divided into 4 groups for this study. The first group was given citrate buffer, the second group was given exendin-4, the third group was given streptozotocin (STZ), and the fourth group was given both exendin-4, and STZ. As the results, we determined a decrease in the edema and deterioration in the integrity of the villi, disruption in continuity of the brush border, fibrosis and enterocyte apoptosis, while the TNFα level and crypt cell proliferation were increased in the small intestinal tissue of exendin-4 treated STZ diabetic mice. Furthermore, the levels of duodenal tissue glucose, SGLT1, and GLUT2 were decreased, whereas there was an increase in GIP level in diabetic mice administered with exendin-4. Moreover, we determined that the sweet taste receptors T1R2/T1R3, downstream molecules PLCß2, α-gustducin and associated secondary messengers IP3, cAMP, which were increased in the duodenal tissue of STZ-diabetic mice, decreased with exendin-4 administration. These findings were evaluated as that exendin-4 reduces glucose absorption by suppressing the T1R2/T1R3 sweet taste signal perception pathway in duodenum of STZ diabetic mice.

Zinc Prevents Ethanol-Induced Oxidative Damage in Lingual Tissues of Rats.

The current study was designed to investigate the effects of zinc sulfate on cell proliferation, metallothionein (MT) immunoreactivity and antioxidant system against acute ethanol-induced oxidative damage in tongue tissues of rats. Wistar albino male rats, 2.5 to 3.0 months, were divided into four groups: Group I (n = 8), intact control rats; group II (n = 8), control animals given only zinc sulfate (100 mg/kg/day, for 3 consecutive days); group III (n = 14), animals given 1 mL absolute ethanol; group IV (n = 11), animals given zinc sulfate and absolute ethanol at the same dose and time. Animals were sacrificed under anesthesia 2 h after ethanol administration or 4 h after the last zinc sulfate treatment. Ethanol administration caused a marked decrease in the number of MT immunopositive cells and the proliferating cells in the lingual epithelium. A statistically significant decline in reduced glutathione levels, catalase activity and superoxide dismutase activities was also observed, whereas a significant elevation of lipid peroxidation levels and lactate dehydrogenase activities was detected in the ethanol group. In contrast, these changes were reversed by administration of zinc sulfate to ethanol-treated rats. In conclusion, it shows that zinc sulfate has therapeutic effects on acute ethanol-induced oxidative damage in the tongue tissues of rats.

Vitamin U prevents valproic acid-induced liver injury through supporting enzymatic antioxidant system and increasing hepatocyte proliferation triggered by inflammation and apoptosis.

The aim of this study was to investigate the cellular mechanisms that cause valproic acid (VPA)-induced liver damage and the therapeutic effect of Vitamin U (Vit U) on these mechanisms. Female Sprague Dawley rats were randomly divided into four groups: intact control animals, animals that received Vit U (50 mg/kg/day), animals given VPA (500 mg/kg/day), and animals given both VPA and Vit U. The rats in the Vit U + VPA group were administered Vit U by gavage an hour before VPA administration every day for 15 days. Liver tissues were evaluated through histopathological, biochemical, immunohistochemical, and Western blotting techniques. Administration of Vit U with VPA resulted in (i) prevention of histopathological changes caused by VPA; (ii) blockage of the decrease in catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities; prevention of the elevation in gamma-glutamyl transferase (GGT) activity and advanced oxidation protein products (AOPP) level; (iii) increased in the levels of interleukin-1 beta (IL-1ß), active caspase-3, and cytoplasmic cytochrome c; (iv) increase in cleaved poly (ADP-ribose) polymerase (PARP) level and decrease in LC3B (II/I) ratio; (v) increase in the number of proliferating cells nuclear antigen (PCNA) positive hepatocytes. These findings show that Vit U prevents liver damage caused by VPA through increasing the antioxidant enzyme capacity and hepatocyte proliferation by triggering inflammation and apoptosis. These findings suggest that Vit U provides its protective effects against VPA-induced liver damage by stimulating homeostasis and regeneration.

Aspartame induces cancer stem cell enrichment through p21, NICD and GLI1 in human PANC-1 pancreas adenocarcinoma cells.

This study aimed to investigate the molecular effects of the common natural sugar glucose and artificial sweetener aspartame on cancer stem cell (CSC) population and cancer aggressiveness of PANC-1 human pancreas adenocarcinoma cells. According to our findings while aspartame exposure significantly increased the CSC population, high glucose had no effect on it. The epithelial-mesenchymal transition marker N-cadherin increased only in the aspartame group. The findings indicate that a high level of glucose exposure does not effect the invasion and migration of PANC-1 cells, while aspartame increases both of these aggressiveness criteria. The findings also suggest that a high concentration of glucose maintains CSC population through induction of nuclear Oct3/4 and differentiation to parental cells via increasing cytoplasmic c-myc. Aspartame exposure to PANC-1 cells activated AKT and deactivated GSK3ß by increasing levels of ROS and cytoplasmic Ca+2, respectively, through T1R2/T1R3 stimulation. Then p-GSK3ß(Ser9) boosted the CSC population by increasing pluripotency factors Oct3/4 and c-myc via NICD, GLI1 and p21. In the aspartame group, T1R1 silencing further increased the CSC population but decreased cell viability and suppressed the p21, NICD and GLI activation. The presence and amount of T1R subunits in the membrane fraction of PANC-1 cells are demonstrated for the first time in this study, as is the regulatory effect of T1R1's on CSC population. In conclusion, the present study demonstrated that long-term aspartame exposure increases CSC population and tumor cell aggressiveness through p21, NICD, GLI1. Moreover, while aspartame had no tumorigenic effect, it could potentially advance an existing tumor.

miR-375 induces adipogenesis through targeting Erk1 in pancreatic duct cells under the influence of sodium palmitate.

The goal of this study was to research long-term saturated fatty acid overexposure that can induce differentiation of pancreatic duct cells into adipocytes and also into ß-cells. The important findings can be summarized as follows: (i) adipogenesis and early stage ß-cell differentiation were stimulated in duct cells under lipotoxicity and glucolipotoxicity conditions, (ii) miR-375 expression was upregulated while its target Erk1 was downregulated and miR-375 inhibitor upregulated Erk1 while expression of adipogenesis markers was downregulated in duct cells under both conditions, (iii) apoptosis was induced in ß and duct cells under both conditions, (iv) lipotoxicity induced proliferation of co-cultured ß-cells. These findings suggest that long-term saturated fatty acid overexposure may cause intrapancreatic fat accumulation by inducing differentiation of duct cells into adipocytes and it may contributes to ß-cell compensation by stimulating the early stage of ß-cell differentiation in duct cells. In addition, miR-375 may have the potential to be a new target in the treatment of Type 2 diabetes, and NAFPD due to its role in the adipogenesis of duct cells.

Protective Effects of an Oxovanadium(IV) Complex with N2O2 Chelating Thiosemicarbazone on Small Intestine Injury of STZ-Diabetic Rats.

Vanadium compounds are being investigated as potential therapeutic agents in the treatment of many health problems, primarily diabetes. We aimed to provide the effect of N(1)-4-hydroxysalicylidene-N(4)-salicylidene-S-methyl-isothiosemicarbazidato-oxovanadium(IV) (VOL) on small intestinal injury in experimental male diabetic rats. Four groups were created of 3.0-3.5-month-old rats. The rats were made diabetic by a single dose of streptozotocin (STZ) at 65 mg/kg and grouped as follows: control animals, VOL-given control animals, STZ-induced diabetic animals and STZ-induced diabetic animals given VOL. A daily dose of 0.2 mM/kg vanadium complex was administered orally for 12 days after the inducement of diabetes. On the 12th day, small intestine tissue samples were taken. According to the data obtained from the biochemical analysis, reduced glutathione (GSH) level, catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), Na+/K+-ATPase and paraoxanase (PON) activities were increased, whereas sialic acid (SA), xanthine oxidase (XO) and disaccharidases (maltase and saccharidase) activities were decreased in the small intestine tissue of VOL-treated diabetic rats. Microscopic examinations revealed a remarkable decrease in the mucosal necrotic areas, discontinuity in the brush border, deterioration of the villi integrity and oedema inside the villi, but with a mild decrease in the inflammatory cells, deterioration and loss of integrity of the gland in the small intestine of VOL-treated diabetic rats. Moreover, VOL treatment markedly decreased the proliferation of villus cells and especially inflammatory cells in the small intestine of diabetic rats. According to the obtained data, the administration of VOL is a potentially convenient strategy to reducing small intestine injury in diabetic rats.

Investigation of cell death mechanism and activity of esculetin-loaded PLGA nanoparticles on insulinoma cells in vitro.

AIM: The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS-1 cells and to study its effect on cell death with related mechanisms in vitro. METHODS: Polylactide-co-glycolide (PLGA) nano-micelles were used for preparation of esculetin nano-formulation (nano-esculetin). The cells were treated with nano-esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS-1 cells for both free and nano-esculetin formulations. RESULTS: About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow-release behaviour was observed during release studies. Nano-esculetin bearing 25, 50 and 100 µg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 µg esculetin bearing nano-formulation and its equivalent free esculetin. CONCLUSIONS: The results revealed that esculetin is able to show its anti-tumor afficacy after loading to PLGA nano-micelles and nano-encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.

The effects of vitamins and selenium mixture or ranitidine against small intestinal injury induced by indomethacin in adult rats.

This study was aimed at investigating morphological and biochemical efficacies of antioxidants on indomethacin-induced small intestinal damage in rats. Group I: control animals (negative control) given only placebo, Group II: (positive control) are animals orally given combination of antioxidants [vitamin C (Vit C), vitamin E (Vit E), ß-carotene and sodium selenite (Se)] daily for 3 days, Group III: Rats were given only indomethacin, Group IV: animals were given of antioxidants combination for 3 days, last dose was given 2 hr before the administration of indomethacin. Group V: Animals receiving ranitidine for 3 days (second positive control). Group VI: Animals received ranitidine for 3 days, last dose was given 2 hr before to indomethacin administration. Indomethacin caused degenerative morphological and biochemical changes, which were reversed on antioxidants administration. As a result, we propose that antioxidants combination would be therapeutically beneficial for treating indomethacin-induced lesions of small intestine. PRACTICAL APPLICATIONS: Indomethacin is a widely preferred nonsteroidal anti-inflammatory drug (NSAID) but its side effects on gastrointestinal system are well known. Indomethacin also causes production of reactive oxygen species. Antioxidants and selenium has protective effects. According to the results of this study, antioxidants and selenium can be used as a food supplement for preventing NSAID-induced side effects and toxicity.

The effects of atorvastatin on the kidney injury in mice with pulmonary fibrosis.

OBJECTIVES: The present study investigated the effects of atorvastatin on kidney injury in mice with pulmonary fibrosis (PF). METHODS: Adult mice were divided into four groups: mice treated with intratracheal bleomycin (I) and their controls (II), and mice treated with atorvastatin for 10 days after 7 days from bleomycin treatment (III) and their controls (IV). Mice were dissected on the 21st day. KEY FINDINGS: Mononuclear cell infiltrations, injured proximal tubule epithelium and p-c-Jun level increased, while cell proliferation and the levels of p-SMAD2, ELK1, p-ELK1, p-ATF2 and c-Jun decreased in the kidney tissue of mice with PF. The atorvastatin treatments to mice with PF resulted in significant increases at the TGF-ß activation, cell proliferation and kidney damage and decreases in the levels of p-SMAD2, p-ELK1, p-ATF2 and p-c-Jun, but not change the p-SMAD3, ELK1 and ATF2 in kidneys. CONCLUSIONS: The depletion of MAPK signals, rather than SMAD signalling, is effective in kidney damage of mice with PF. Atorvastatin did not regress kidney damage in these mice, whereas it increases the kidney injury. The c-Jun-mediated JNK signals could help kidney repair through cell proliferation. The treatment time and doses of atorvastatin should be optimized for regression of kidney damage.

The effects of vitamins and selenium mixture against brain tissue induced by d-galactosamine.

Brain damage is a major complication of fulminant hepatic failure. d-Galactosamine (d-GalN)-induced liver toxicity causes damage to brain. The effects of vitamins and selenium mixture against d-GalN stimulated brain injury were investigated in this study. Sprague-Dawley female rats aged 2.0-2.5 months were used for the study. The rats were divided into four categories. A 0.9% NaCl solution was intraperitoneally given to the experimental rats in the first group. Using gavage technique, the second group of animals were subjected to a formulation consisting of 100 mg·kg-1 ·day-1 vitamin C, 15 mg·kg-1 ·day-1 of ß-carotene, 100 mg·kg-1 ·day-1 of α-tocopherol in addition to 0.2 mg·kg-1 ·day-1 of sodium selenate for 3 days. The third group was given a single dose of d-GalN hydrochloride at the concentration of 500 mg·kg-1 through a saline injection. The final group was given similar concentrations of both the antioxidant combination and d-GalN. Tissue samples were collected under ether anesthesia. The rats treated with d-GalN showed brain damage; increased myeloperoxidase, catalase, glutathione peroxidase, glutathione-S-transferase, lactate dehydrogenase, and superoxide dismutase activities; and decreased glutathione levels. Treatment with vitamins and selenium combination resulted in alleviation of these alterations in the rats. These findings suggest that administration of the vitamins and selenium combination suppresses oxidative stress and protects brain cells from injury induced by d-GalN.

Vitronectin, fibronectin and epidermal growth factor induce proliferation via the JNK and ERK pathways in insulinoma INS-1 cells.

An insulinoma is a tumor formed by beta cells in the Langerhans islets of the pancreas. Vitronectin (VTN), fibronectin (FN) and epidermal growth factor (EGF) are important in cell signaling. The aim of this study was to investigate the molecular mechanism that occurs in INS-1 cells with the administration of VTN, FN and EGF in proliferative doses. We determined the proliferative doses of EGF, VTN and FN. The molecular mechanism of proliferation has been investigated alone or in the combination of these proteins. It was observed that INS-1 cells did not have VTN and FN. Cell viability increased with the administration of 0.1 µg/ml VTN, 0.1 µg/ml FN and 1 mg/ml EGF. Proliferation increased with the administration of FN + EGF, and VTN + FN + EGF together when compared to the control group. The total JNK levels did not change between the groups; however, the active JNK levels increased in the VT + FN + EGF group compared to the control group. The total ERK levels increased in the VT + FN + EGF group, and the active ERK levels increased in the VTN + FN, VTN + EGF and VTN + FN + EGF groups compared to the control group. The JNK and ERK pathways are important for proliferation. The JNK and ERK pathways were activated in VTN + FN + EGF administered group. However, it was observed that the ERK pathway was more active than the JNK pathway.

Tub and ß-catenin play a key role in insulin and leptin resistance-induced pancreatic beta-cell differentiation.

The aim of this study was to investigate the molecular mechanism of pancreatic islet-derived mesenchymal stem cell (PID-MSC) differentiation into beta-cells in the presence of insulin and leptin resistance stimulators. We determined that beta-cell differentiation was stimulated by glucose, insulin, and leptin. Co-administration of insulin and leptin resulted in greater, at a further stage of differentiation but non-functional beta-cell formation. The levels of p-AKT(Ser473) did not change; SOCS3, PTP1B, p-IRS1(Ser307), PTEN levels increased and p-IRS1(Try) levels decreased due to insulin and leptin co-administration. These findings suggest that co-administration of insulin and leptin to PID-MSCs results in the development of both insulin and leptin resistance together. We showed that this differentiation signaling is mainly mediated by AKT/GSK-3ß/ß-catenin and Tub. Moreover, ß-catenin and Tub were linked to each other in the nucleus under this condition. Furthermore, we found that Tub and ß-catenin contributes to insulin production by increasing the expression of transcription factors by binding to the promoter regions of ins1, ins2, and pdx1 genes. In addition, Tub is also bound to the promoter region of the MafA gene. These findings demonstrate that when insulin and leptin resistance develop together in rat PID-MSCs beta-cell differentiation increases markedly via ß-catenin and Tub. New therapeutic agents that inhibit AKT/GSK-3ß/ß-catenin and in particular Tub may help prevent the development or retard the progression of type 2 diabetes.

4-Methylcatechol prevents streptozotocin-induced acute kidney injury through modulating NGF/TrkA and ROS-related Akt/GSK3ß/ß-catenin pathways.

Nerve growth factor (NGF) has been shown to protect the viability of kidney cells in acute phase of renal damage. However, since the half-life of NGF is very short, it is too large to pass the blood-brain barrier and rapidly transported to the liver for catabolizing its use in therapy is limited. 4-Methylcatechol (4MC) is a substance that increases NGF synthesis in many tissues. This study aimed to investigate the protective effects of 4MC against acute renal injury induced by streptozotocin (STZ). We have investigated the profibrotic, proinflammatory, oxidative changes in STZ-induced acute renal damage and the possible role of the NGF/TrkA system and Akt/GSK3ß/ß-catenin pathway in this mechanism. Experiment was designed as to be started with injection of 4MC for 10 days as a single dose (10 µg/kg) per day and to be terminated after 4 h of a single dose (75 mg/kg) STZ injection. As the result, 4MC pre-treatment decreased kidney damage, ROS production, the renal levels of TGFß1, CD68, tumor necrosis factor-α and interleukin 1ß. Moreover, 4MC pre-treatment increased levels of NGF and its receptor TrkA, p-Akt (Thr308), p-GSK3ß (Ser9) and nuclear ß-catenin. These data suggest that 4MC prevents the development of STZ-induced renal damage by suppressing ROS production and inflammation via Akt/GSK3ß/ß-catenin pathway which may be stimulated by NGF/TrkA signaling. Therefore, 4MC can be suggested as a potential agent for the prevention of acute renal injury.

The effect of plant lectins on the survival and malignant behaviors of thyroid cancer cells.

Altered or aberrant glycosylation is a common phenomenon in cancer cells and it originates from changes in the expression of the enzymes, glycosyltransferase, and glycosidase which up-regulate in response to some oncogenes in the glycan synthesis pathway. In this present study, it has been aimed to determine the alteration of sialic acid and fucose expressions in the cell surface of human thyroid carcinoma cells and investigate the changes in tumorigenic and malignant characters after treating them with specific plant lectins. Our study showed that the cell surface glycan chains of anaplastic 8305C, follicular FTC-133, and papillary K1 thyroid carcinoma cells were rich in α-2,6, α-2,3, sialic acid, and α-1,6 fucose residues. When the cells were treated with specific doses of Maackia amurensis lectin II (MAL), Sambucus nigra agglutinin (SNA), and Aleuria aurantia lectin (AAL) which have specific binding capacity for the detected glycan residues, respectively their cancerous traits changed dramatically. Remarkable findings obtained from MAL treatment leading to necrosis in 8505C cells without any toxicity for normal thyroid epithelial cells but it had proliferative effect on K1 and FCT-133 cells. Besides, MAL and SNA treatment decreased the mobility of 8505C and K1 cells. MAL and SNA lectins dramatically reduced the endothelial affinity of the cells and AAL significantly attenuated that of 8050C and K1 cells but not FTC-133. These results suggest that altered cell surface glycosylation in thyroid cancer seems to be a strong candidate for developing new therapeutic strategies.

Involvement of dying beta cell originated messenger molecules in differentiation of pancreatic mesenchymal stem cells under glucotoxic and glucolipotoxic conditions.

Beta cell mass regulation represents a critical issue for understanding and treatment of diabetes. The most important process in the development of diabetes is beta cell death, generally induced by glucotoxicity or glucolipotoxicity, and the regeneration mechanism of new beta cells that will replace dead beta cells is still not fully understood. The aim of this study was to investigate the generation mechanism of new beta cells by considering the compensation phase of type 2 diabetes mellitus. In this study, pancreatic islet derived mesenchymal stem cells (PI-MSCs) were isolated from adult rats and characterized. Then, beta cells isolated from rats were co-cultured with PI-MSCs and they were exposed to glucotoxicity, lipotoxicity and glucolipotoxicity conditions for 72 hr. As the results apoptotic and necrotic cell death were increased in both PI-MSCs and beta cells especially by the exposure of glucotoxic and glucolipotoxic conditions to the co-culture systems. Glucotoxicity induced-differentiated beta cells were functional due to their capability of insulin secretion in response to rising glucose concentrations. Moreover, beta cell proliferation was induced in the glucotoxicity-treated co-culture system whereas suppressed in lipotoxicity or glucolipotoxicity-treated co-culture systems. In addition, 11 novel proteins, that may release from dead beta cells and have the ability to stimulate PI-MSCs in the direction of differentiation, were determined in media of glucotoxicity or glucolipotoxicity-treated co-culture systems. In conclusion, these molecules were considered as important for understanding cellular mechanism of beta cell differentiation and diabetes. Thus, they may be potential targets for diagnosis and cellular or therapeutic treatment of diabetes.

Exendin-4 partly ameliorates - hyperglycemia-mediated tissue damage in lungs of streptozotocin-induced diabetic mice.

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion, - plays anti-inflammatory role in atherosclerosis, and has surfactant-releasing effects in lungs. GLP-1 analogues are used in diabetes therapy. This is the first study to investigate the effects of exendin-4, a GLP-1 receptor agonist, on lung injury in diabetic mice. BALB/c male mice were divided into four groups. The first group was given only citrate buffer, the second group was given only exendin-4, the third group was given only streptozotocin (STZ), and the fourth group was given both exendin-4 and STZ. Exendin-4 (3µg/kg) was administered daily by subcutaneous injection for 30days after mice were rendered diabetic with a single dose of STZ (200mg/kg). Structural alterations, oxidative stress, apoptosis, insulin signaling and expressions of prosurfactant-C, alpha-smooth muscle actin, collagen-I and fibronectin were evaluated in lung tissue. Diabetic mice lungs were characterized by induced oxidative stress, apoptosis, edema, and cell proliferation. They had honeycomb-like alveoli, thicker alveolar walls, and hypertrophic pneumocytes. Although exendin-4 treatment improved pulmonary edema, apoptosis, oxidative stress, and lung injury, it led to the disrupted insulin signaling and interstitial collagen accumulation in the lungs of diabetic mice. Exendin-4 ameliorates hyperglycemia-mediated lung damage by reducing glucose, -oxidative stress and stimulating cell proliferation. However, exendin-4 led to increased lung injury partly by reducing insulin signaling - and collagen accumulation around pulmonary vasculature in diabetic mice.