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Results for “PANCREAS”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 415 records · Page 23
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice

Highlights: • Oral supplementation of pancrelipase alters composition of intestinal microbiota. • Over-represented taxa include bacteria promoting intestinal homeostasis. • Akkermansia muciniphila and Lactobacillus reuteri are over-represented. • Pro-inflammatory bacteria is inhibited by supplementation of pancrelipase. • Pancrelipase may help treat chronic pancreatitis by altering intestinal microbiota. Although pancreatic enzyme replacement therapy (PERT) is effective in the alleviation of pancreatic exocrine insufficiency (PEI)-related symptoms in patients with chronic pancreatitis, its mechanism of action is poorly understood. Recent studies suggest that the intestinal microbiota is associated with the pathogenesis of chronic pancreatitis. Therefore, we hypothesized that PERT exerts its effect by modifying the intestinal microbiota in addition to its presumed role in promoting fat and protein absorption. To explore the mechanism of action of PERT, we analyzed the intestinal microbiotas of two groups of mice treated with either pancrelipase or tap water by using 16S rRNA amplicon sequencing. The results revealed that the bacterial compositions of the pancrelipase-treated mice were significantly different from those of the control samples. Akkermansia muciniphila, a key beneficial bacterium in the intestinal tract, showed a higher relative abundance in the pancrelipase-treated samples than in the control samples. Lactobacillus reuteri, a widely used probiotic bacterium known to relieve intestinal inflammation, also showed a higher relative abundance in the pancrelipase-treated samples. These results suggested that PERT induces the colonization of beneficial bacteria, thereby contributing to the attenuation of PEI-associated symptoms in addition to improvement of the nutritional state.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Galangin enhances TGF-β1-mediated growth inhibition by suppressing phosphorylation of threonine 179 residue in Smad3 linker region

Highlights: • Galangin significantly induced apoptosis in the presence of TGF-β1. • Galangin inhibits phosphorylation of the Thr-179 site at the Smad3 linker region. • Galangin suppresses CDK4-mediated Smad3 linker phosphorylation. Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells. However, the mechanism of action of galangin in various cancers remains unclear, and there has been no report concerning regulation of Smad3 phosphorylation by galangin. In the present study, we show that galangin significantly induced apoptosis and inhibited cell proliferation in the presence of TGF-β1 in both human prostate and pancreatic cancer cell lines. Particularly, galangin effectively inhibits phosphorylation of the Thr-179 site at Smad3 linker region through suppression of CDK4 phosphorylation. Thus, galangin can be a promising candidate as a selective inhibitor to suppress phosphorylation of Smad3 linker region.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells

Highlights: • Effects of cancer cell-derived exosomes on stellate cell functions were examined. • Exosomes increased proliferation and migration in stellate cells. • Cancer cells increased miR-1246 and miR-1290 expression in stellate cells. • Exosomes and miR-1290 overexpression increased the expression of profibrogenic genes and ACTA2. • Exosome-mediated cell-to-cell communication regulates stellate cell functions. Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor β1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Chaetospirolactone reverses the apoptotic resistance towards TRAIL in pancreatic cancer

Highlights: • CSL reverses TRAIL-mediated apoptotic resistance. • DR4 is induced by CSL. • H3 lysine 27 trimethylation by EZH2 is inhibited by CSL. The pancreatic cancer is one of the most aggressive tumors. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can trigger apoptosis by interaction with death receptors. However, in TRAIL-resistant pancreatic cancer, responsiveness to TRAIL treatment is terribly poor. In current work, we have demonstrated that a natural product chaetospirolactone (CSL) isolated from an endophytic fungus Chaetomium sp. NF00754 can enhance the susceptibility of TRAIL-resistant pancreatic cancer cells to apoptosis. CSL can induce apoptosis in TRAIL-treated pancreatic cancer cells. Furthermore, combined CSL and TRAIL treatment significantly inhibits viability and migration of pancreatic cancer cells. Combinatorial TRAIL and CSL treatment repressed xenograft tumor growth without substantially toxic side effects. CSL can specifically upregulate expression of death receptor 4 (DR4). Further study revealed that CSL represses the activities of an epigenetic regulator enhancer of zeste homolog 2 (EZH2) and consistently reduces histone H3 lysine 27 trimethylation (H3K27me3) to allow DR4 transcription. Taken together, CSL treatment may reverse TRAIL resistance in pancreatic cancer cells via epigenetic regulation of DR4 implying that administration of CSL might represent a putative strategy for pancreatic cancer therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Antioxidant effects of epigallocatechin-3-gallate on the aTC1-6 pancreatic alpha cell line

Highlights: • The ability of pancreatic α-cells respond to hypoglycemia becomes impaired in diabetes patients. • EGCG has antioxidant potential on pancreatic αTC1-6 cell lines. • EGCG protected the normal function of pancreatic α-cells from H{sub 2}O{sub 2}. • EGCG inhibited cell apoptosis via the activation of Akt and suppression of P38 and JNK pathway. • Combining the conventional anti-hyperglycemia therapy and antioxidant therapy would avert hypoglycemia in diabetes treatment. Hypoglycemia is a major barrier to achieving stable metabolic control in patients with diabetes which is a serious clinical concern. With progression of diabetes, the ability of pancreatic α-cells which respond to hypoglycemia becomes impaired; However, it is not clear whether the dysfunctional responses of α-cells during hypoglycemia are related with oxidative stress. In the present study, we investigated whether epigallocatechin-3-gallate (EGCG) has antioxidant potential on pancreatic alpha TC1-6 (αTC1-6) cell lines and protect the normal function of α-cells from H{sub 2}O{sub 2} induced oxidative stress. ROS production, cell viability, glucagon secretion, and cell apoptosis were assessed. EGCG reduced ROS production and cell apoptosis, while restored cell viability and glucagon secretion within a particular concentration range. Moreover, EGCG activated Akt signaling and inhibited P38 as well as JNK mitogen-activated protein kinase (MAPK) pathway. Taken together, EGCG prevented αTC1-6 cells from H{sub 2}O{sub 2} induced oxidative stress, restored dysfunction of glucagon secretion and inhibited cell apoptosis via the activation of Akt signaling and suppression of P38 and JNK pathway. These results provide rationale for combining the conventional anti-hyperglycemia therapy and antioxidant therapy in order to avert hypoglycemia in clinical treatment of diabetes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Structural insights and binding of a natural ligand, succinic acid with serine and cysteine proteases

Highlights: • Identification of a natural ligand through structural and functional studies, which can inhibit serine and cystein proteases. • Crystallographic and ITC binding studies support the inhibition of serine protease. • This is supported by both radial diffusion assay and modelling studies with serine and cystein protease. • The ligand activity can be accounted for the anti-viral nature of plant extracts where dicarboxilic fatty acids are abundant. In the age of growing infectious diseases, there is a great demand for new inhibitors which can exhibit minimum side effects. Owing to the importance of proteases in life cycle and invasion, they have been projected as attractive targets for structure based drug designing against microbes including viruses. Here we report the inhibitory activity of a well known natural compound succinic acid against both serine and cysteine proteases. The ligand is found co-crystallized with Bovine pancreatic trypsin in one of our crystallization trials and the diffraction data up to1.9 Å reveal its interactions with the catalytic triad residues Histidine 57 and Serine 195. Binding of the ligand with these proteases have been validated using caseinolysis inhibition. With trypsin, ITC analysis showed tight binding of the ligand, resulting in change in Gibb's free energy (ΔG) by −20.31 kJ/mol. To understand the existence of succinic acid at the active site, molecular docking was performed and it revealed binding of it with trypsin and papain at corresponding active sites. This dual inhibitory activity of natural ligand, succinic acid can be accounted for the recent reports on anti-viral property of plant extracts where dicarboxilic fatty acids are normally abundant.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Angiotensin-converting enzyme 2 regulates mitochondrial function in pancreatic β-cells

Highlights: • ACE2 improved glucose stimulated insulin secretion (GSIS) and mitochondrial membrane potential in INS-1 cells. • PCR array demonstrated that ACE2 up-regulated 67 mitochondria-related genes in INS-1 cells. • ACE2 deletion suppressed mitochondrial oxidation and calcium influx in islets. • ACE2 over-expression in db/db mice promoted mitochondrial oxidation and calcium influx in islets. Mitochondrial metabolism plays an essential role in the regulation of insulin release and glucose homeostasis. Evidence demonstrated that the angiotensin-converting enzyme 2 (ACE2) participates in the regulation of glucose metabolism, however, its role in mitochondrial metabolism remains unclear. The purpose of our study was to determine if ACE2 can regulate mitochondrial function in pancreatic β-cells. We found that ACE2 over-expression restored glucose-stimulated insulin secretion (GSIS) and mitochondrial membrane potential (MMP) in the presence of H{sub 2}O{sub 2} in INS-1 cells. PCR array demonstrated that ACE2 over-expression up-regulated 67 mitochondria-related genes in INS-1 cells. In pancreatic islets, ACE2 ablation attenuated intracellular calcium influx with a decrease in GSIS. Ace2{sup −/y} mice islets exhibited impaired mitochondrial respiration and lower production of ATP, along with decreased expression of genes involved in mitochondrial oxidation. In islets from db/db mice, ACE2 over-expression increased intracellular calcium influx and restored impaired mitochondrial oxidation, potentially causing an increase in GSIS. These results shed light on the potential roles of ACE2 in mitochondrial metabolism, moreover, may improve our understanding of diabetes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Co-treatment with a C1B5 peptide of protein kinase Cγ and a low dose of gemcitabine strongly attenuated pancreatic cancer growth in mice through T cell activation

Highlights: • Co-treatment of C1B5 peptide and gemcitabine inhibits pancreatic cancer cell growth in vitro. • Co-treatment of C1B5 peptide and a low dose of gemcitabine attenuates the growth of pancreatic cancer autografts in mice. • Co-treatment of C1B5 peptide and gemcitabine increases neutrophils and granzyme B{sup +} lymphocytes in tumor microenvironment. Although gemcitabine is an effective chemotherapeutic for pancreatic cancer, severe side effects often accompany its use. Since we have discovered that locally administered C1B domain peptides effectively control tumor growth without any side effects, the efficacy of co-treatment with this peptide and a low dose of gemcitabine on the growth of pancreatic cancer was examined. Two- and three-dimensional cell culture studies clarified that a co-treatment with C1B5 peptide and gemcitabine significantly attenuated growth of PAN02 mouse and PANC-1 human pancreatic cancer cells in 2D and 3D cultures. Although treatment with the low dose of gemcitabine alone (76%) or the C1B5 peptide alone (39%) inhibited tumor growth moderately, a co-treatment with C1B5 peptide and a low dose of gemcitabine markedly inhibited the growth of PAN02 autografts in the mouse peritoneal cavity (94% inhibition) without any noticeable adverse effect. The number of peritoneal cavity-infiltrating neutrophils and granzyme B{sup +} lymphocytes was significantly higher in the co-treatment group than in the control group. A significant increase of granzyme B mRNA expression was also detected in human T cells by the co-treatment. Taken together, the current study suggests that C1B5 peptide offers a remarkably effective combination treatment strategy to reduce side effects associated with gemcitabine, without losing its tumoricidal effect.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response

Highlights: • Unbiased screening with 2320 known compounds identified 12 chemical probes for p13. • > 80% screened agents increased or decreased p13 mRNA and affected cardiac function. • Four cardiotonic agents decreased p13 levels and induced oxidative stress. • In vivo profile of p13 expression shows its importance in heart pathophysiology. • PGC1-alpha, a mitochondrial master regulator, markedly elevated p13 expression. We recently showed that a 13-kDa protein (p13), the homolog protein of formation of mitochondrial complex V assembly factor 1 in yeast, acts as a potential protective factor in pancreatic islets under diabetes. Here, we aimed to identify known compounds regulating p13 mRNA expression to obtain therapeutic insight into the cellular stress response. A luciferase reporter system was developed using the putative promoter region of the human p13 gene. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1α, a master player regulating mitochondrial metabolism, increased both reporter activity and p13 expression. Following unbiased screening with 2320 known compounds in HeLa cells, 12 pharmacological agents (including 8 cardiotonics and 2 anthracyclines) that elicited >2-fold changes in p13 mRNA expression were identified. Among them, four cardiac glycosides decreased p13 expression and concomitantly elevated cellular oxidative stress. Additional database analyses showed highest p13 expression in heart, with typically decreased expression in cardiac disease. Accordingly, our results illustrate the usefulness of unbiased compound screening as a method for identifying novel functional roles of unfamiliar genes. Our findings also highlight the importance of p13 in the cellular stress response in heart.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Role of osteopontin and its regulation in pancreatic islet

Osteopontin (OPN) is involved in various physiological processes and also implicated in multiple pathological states. It has been suggested that OPN may have a role in type 2 diabetes (T2D) by protecting pancreatic islets and interaction with incretins. However, the regulation and function of OPN in islets, especially in humans, remains largely unexplored. In this study, we performed our investigations on both diabetic mouse model SUR1-E1506K+/+ and islets from human donors. We demonstrated that OPN protein, secretion and gene expression was elevated in the diabetic SUR1-E1506K+/+ islets. We also showed that high glucose and incretins simultaneously stimulated islet OPN secretion. In islets from human cadaver donors, OPN gene expression was elevated in diabetic islets, and externally added OPN significantly increased glucose-stimulated insulin secretion (GSIS) from diabetic but not normal glycemic donors. The increase in GSIS by OPN in diabetic human islets was Ca{sup 2+} dependent, which was abolished by Ca{sup 2+}-channel inhibitor isradipine. Furthermore, we also confirmed that OPN promoted cell metabolic activity when challenged by high glucose. These observations provided evidence on the protective role of OPN in pancreatic islets under diabetic condition, and may point to novel therapeutic targets for islet protection in T2D.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ectopic serotonin production in β-cell specific transgenic mice

Highlights: • β-cell specific transgenic mice showed the ectopic serotonin production in β-cells. • hGH induced the ectopic serotonin production via PRLR-Stat5-Tph1 pathway in β-cell. • Transgenic mice containing the hGH cassette should be interpreted carefully. Genetically modified mice have been widely used in the field of β-cell research. However, analysis of results gathered using genetically modified organisms should be interpreted carefully as the results may be confounded by several factors. Here, we showed the ectopic serotonin (5-HT) production in β-cells of RIP-Cre{sup Mgn}, MIP-GFP, and MIP-Cre/ERT mice. These mice contained a human growth hormone (hGH) cassette to enhance transgene expression and hGH expression and Stat5 phosphorylation were detected in pancreatic islets of these mice. The expression level of tryptophan hydroxylase 1 (Tph1) was upregulated in pancreatic islets of transgenic mice with an hGH cassette but not in transgenic mice without an hGH cassette. Ectopic 5-HT production was not observed in β-cell-specific prolactin receptor (Prlr) knockout mice or Stat5 knockout mice crossed with RIP-Cre{sup Mgn}. We further confirmed that 5-HT production in β-cells of several transgenic mice was induced by hGH expression followed by the activation of the Prlr-Stat5-Tph1 pathway. These findings indicate that results obtained using transgenic mice containing the hGH cassette should be interpreted with care.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

High expression of diffuse panbronchiolitis critical region 1 gene promotes cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma

Highlights: • DPCR1 is overexpressed in PDAC and correlates with prognosis of PDAC patients. • Inhibition of DPCR1 suppresses PDAC cell proliferation in vitro and in vivo. • Inhibition of DPCR1 suppresses PDAC cell migration and invasion. • DPCR1 may promote tumor progression by regulating NF-κB pathway. Diffuse panbronchiolitis critical region 1 (DPCR1) is located in the major histocompatibility complex (MHC) class I. It was reported to be downregulated in invasive pituitary adenoma compared with that in non-invasive tumors, but upregulated in the precursor of gastric carcinogenesis. However, the direct effect of DPCR1 on cancer cells has rarely been reported, and the role DPCR1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The clinical sample validation and public data analysis of the present study demonstrated that DPCR1 was upregulated markedly in PDAC and this high expression was negatively correlated with the patient prognosis. Functionally, knocking down DPCR1 in PDAC cell lines inhibited cell proliferation, migration and invasion in vitro. Tumor xenograft experiments further showed that suppression of DPCR1 inhibited tumor growth in vivo. In addition, the results of RNA deep sequencing and qRT-PCR assay showed that DPCR1 participated in PADC progression by regulating nuclear factor-kappa B signaling pathway, suggesting that it might be a novel oncogene in tumor progression and a potential therapeutic target in PDAC as well.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer

Highlights: • Integrative immunomonitoring was undertaken in resected pancreatic cancer patients. • Immunomonitoring employed flow cytometry, multiplex-bead assays and RMA-Seq. • Higher NK cell % in peripheral blood are associated with better prognosis. • Type I and II IFN signatures in the tumor are associated with better prognosis. • Epithelial mesenchymal transition is associated with early recurrence. To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P = .037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P = .058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor-intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression

Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases

The cluster of differentiation 36 (CD36) is implicated in the intake of long-chain fatty acids and fat storage in various cell types including the pancreatic beta cell, thus contributing to the pathogenesis of metabolic stress and diabetes. Recent evidence indicates that CD36 undergoes post-translational modifications such as acetylation-deacetylation. However, putative roles of such modifications in its functional activation and onset of beta cell dysregulation under the duress of glucolipotoxicity (GLT) remain largely unknown. Using pharmacological approaches, we validated, herein, the hypothesis that acetylation-deacetylation signaling steps are involved in CD36-mediated lipid accumulation and downstream apoptotic signaling in pancreatic beta (INS-1832/13) cells under GLT. Exposure of these cells to GLT resulted in significant lipid accumulation without affecting the CD36 expression. Sulfo-n-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, significantly attenuated lipid accumulation under GLT conditions, thus implicating CD36 in this metabolic step. Furthermore, trichostatin A (TSA) or valproic acid (VPA), known inhibitors of lysine deacetylases, markedly suppressed GLT-associated lipid accumulation with no discernible effects on CD36 expression. Lastly, SSO or TSA prevented caspase 3 activation in INS-1832/13 cells exposed to GLT conditions. Based on these findings, we conclude that an acetylation-deacetylation signaling step might regulate CD36 functional activity and subsequent lipid accumulation and caspase 3 activation in pancreatic beta cells exposed to GLT conditions. Identification of specific lysine deacetylases that control CD36 function should provide novel clues for the prevention of beta-cell dysfunction under GLT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ro60/SSA levels are increased and promote the progression of pancreatic ductal adenocarcinoma

Highlights: • Ro60/SSA was highly expressed in the nuclei of pancreatic cancer cells. • Down-regulation of Ro60/SSA by siRNA inhibited tumorigenesis in vivo. • Down-regulation of Ro60 inhibited proliferation, migration and invasion of PDAC. Ro60/SSA is a vital auto antigen that is targeted in Sjogren's syndrome and systemic lupus erythematosus (SLE). However, its role in solid cancers has rarely been reported. The present study investigated the expression and function of Ro60/SSA in the development of pancreatic ductal adenocarcinoma (PDAC) both in vitro and in vivo. Immunohistochemistry was used to examine the expression of Ro60/SSA in PDAC and normal pancreatic tissues by using tissue microarray chips. The results showed that Ro60/SSA expression was increased in PDAC tissues compared with normal pancreatic tissues. Knockdown of Ro60/SSA by siRNA transfection significantly decreased cell proliferation and invasion in vitro. Furthermore, knockdown of Ro60/SSA inhibited the growth of subcutaneous tumors in vivo. Taken together, the current study provides evidence of new function of Ro60/SSA in the development of cancer. It facilitates pancreatic cancer proliferation, migration and invasion. Therefore, it may represent a novel molecular target for the management of pancreatic cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Amelioration of streptozotocin-induced type 2 diabetes mellitus in Wistar rats by arachidonic acid

Traditionally arachidonic acid (AA, 20:4 n-6) is considered as a pro-inflammatory molecule since it forms precursor to prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs) that have pro-inflammatory actions. Type 2 diabetes mellitus (type 2 DM) is considered as a low-grade systemic inflammatory condition in which circulating PGs and LTs are increased. Streptozotocin (STZ)-induced type 2 DM is used as a model of human type 2 DM in which peripheral insulin resistance, increased plasma interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and hyperglycemia occurs. In the present study, we observed that oral supplementation of AA prevented STZ-induced type 2 DM in Wistar rats by restoring hyperglycemia, plasma levels of TNF-α and IL-6; adipose tissue NF-kB and lipocalin 2 (LPCLN2) and pancreatic tissue NF-kB and 5- and 12- lipoxygenase enzymes to normal. AA treatment enhanced insulin sensitivity and plasma lipoxin A4 (LXA4) levels, a potent anti-inflammatory molecule derived from AA. These results are supported by our previous studies wherein it was noted that plasma phospholipid content of AA and circulating LXA4 levels are low in those with type 2 DM. In a preliminary study, we also noted that high-fat-diet (HFD)-induced type 2 DM in Wistar rats can be prevented by oral supplementation of AA. These results suggest AA has anti-inflammatory and anti-diabetic actions by enhancing the production of its anti-inflammatory metabolite LXA4.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Heterogeneity of autophagic status in pancreatic β cells under metabolic stress

Highlights: • Autophagic status was analyzed in β cells of insulin-resistant mice as well as wild-type mice. • Pancreatic β cells are heterogeneous regarding their autophagic status. • Insulin resistance promotes the increased heterogeneity of autophagic status in β cells. Autophagy in β cells has been demonstrated to play a pivotal role in cellular homeostasis and the progression of glucose intolerance. Although autophagic activity is affected by metabolic stress both in vivo and in vitro, it remains unclear as to what extent the autophagic status in each β cell is different from its neighboring cells. To address this question, GFP-LC3 reporter mice, which can visualize the autophagic status of each β cell as green-fluorescent puncta, were crossed with obese diabetic db/db mice. Imaging of green-fluorescent puncta in the islets of GFP-LC3 mice revealed that β cells are a heterogeneous population, as the density of GFP-LC3 puncta in each cell was variable. Furthermore, the variability was greater in GFP-LC3; db/db mice than in non-diabetic GFP-LC3; db/+ mice. Furthermore, when GFP-LC3 mice were treated with a low dose of S961, which antagonizes insulin signaling without inducing overt hyperglycemia, the number of β cells with a high density of GFP puncta was increased, suggesting that insulin resistance affects autophagic status independently of glucose profiles. These results suggest that pancreatic β cells under metabolic stress are heterogeneous regarding their autophagic status, which provides insights into the cellular dynamics of each β cell rather than the whole β-cell population.

60 APPLIED LIFE SCIENCES↗