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Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth., (© 2021. The Author(s).)

We previously reported that dye was effective to prevent the leakage of enzyme solutions from pancreatic glands during an islet isolation procedure. However, the dye used for islet isolation has not yet been optimized. In this study, we focused on pyoktanin blue (PB), diagnogreen (DG), and indigo carmine (IC) as potential candidates among clinically established dyes. A serial dilution assay was performed to determine minimal effective concentrations of each dye for detecting damaged pancreatic tissues. According to the outcome of serial dilution assays, double minimum effective concentrations of each dye were used for in vitro toxicity assays on islets and used in the isolation procedure to investigate whether they adversely affect islet isolation efficiency. The evaluations included islet yield, ADP/ATP, ATP/DNA, glucose stimulation test, and insulin/DNA assays. Islet viability cultured with PB contained medium was significantly lower than the other dyes. DG and IC appeared to be non-toxic to the islets. In isolation experiments, the islet yield in the DG group was considerably lower than that in the Control group, suggesting that DG might inhibit enzyme activity. The present study demonstrates that IC could be a promising candidate for an effective dye to detect damaged pancreatic tissues without affecting the enzyme activity and islet quality., Competing Interests: The authors have declared that no competing interests exist.

Nuclear protein 1 (NUPR1) is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1's well-established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely debated. In this study, we uncover a new role for NUPR1, participating in the unfolded protein response (UPR) and the integrated stress response. Biochemical results and ultrastructural morphological observations revealed alterations in the UPR of acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein synthesis after stress induction. Bioinformatic analysis of NUPR1-interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2α. Co-immunoprecipitation and proximity ligation assays confirmed the interaction between NUPR1 and eIF2α and its phosphorylated form (p-eIF2α). Furthermore, our data suggest loss of NUPR1 in cells results in maintained eIF2α phosphorylation and evaluation of nascent proteins by click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower poststress protein synthesis recovery when compared to wild-type. Combined, these data propose a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK branch activity and resolution through a unique interaction with eIF2α., (© 2021 Federation of European Biochemical Societies.)

Due to the limited number of organ donors, 3D printing of organs is a promising technique. Tissue engineering is increasingly using xenogeneic material for this purpose. This study was aimed at assessing the safety of decellularized porcine pancreas, together with the analysis of the risk of an undesirable immune response. We tested eight variants of the decellularization process. We determined the following impacts: rinsing agents (PBS/NH 3 ·H 2 O), temperature conditions (4 °C/24 °C), and the grinding method of native material (ground/cut). To assess the quality of the extracellular matrix after the completed decellularization process, analyses of the following were performed: DNA concentration, fat content, microscopic evaluation, proteolysis, material cytotoxicity, and most importantly, the Triton X-100 content. Our analyses showed that we obtained a product with an extremely low detergent content with negligible residual DNA content. The obtained results confirmed the performed histological and immuno-fluorescence staining. Moreover, the TEM microscopic analysis proved that the correct collagen structure was preserved after the decellularization process. Based on the obtained results, we chose the most favorable variant in terms of quality and biology. The method we chose is an effective and safe method that gives a chance for the development of transplant and regenerative medicine.

Acute pancreatitis (AP) is an inflammatory, complicated pancreatic disease, carrying significant morbidity and mortality. However, the molecular and cellular mechanisms involved in AP pathogenesis remain to be elucidated. Here, we explore the role of FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) in AP progression. Caerulein with or without LPS- induced or taurolithocholic acid 3-sulfate (TLC-S)-induced AP mouse models and cell models were performed for the validation of FENDRR expression in vivo and in vitro, respectively. Histopathological examinations of pancreatic tissues were performed to evaluate the severity of AP. Transmission electron microscopy was utilized to visualize the autophagic vacuoles. siRNA specifically targeting FENDRR was further applied. Flow cytometry was employed to assess cell apoptosis. ELISA, immunoflureoscence, and western blotting analysis were also performed to determine the levels of inflammatory cytokines and autophagy activity. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays were carried out to reveal the epigenetic regulation of FENDRR on ATG7. Additionally, silencing FENDRR was also verified in AP mouse models. Higher FENDRR and impaired autophagy were displayed in both AP mouse models and cell models. FENDRR knockdown dramatically attenuated caerulein- or TLC-S-induced AR42J cells apoptosis and autophagy suppression. Further mechanistic experiments implied that the action of FENDRR is moderately attributable to its repression of ATG7 via direct interaction with the epigenetic repressor PRC2. Moreover, the silencing of FENDRR significantly induced the promotion of ATG7, thus alleviating the development of AP in vivo. Our study highlights FENDRR as a novel target that may contribute to AP progression, suggesting a therapeutic target for AP treatment.

Acute pancreatitis (AP) is an inflammatory reaction of pancreatic tissue self-digestion, edema, hemorrhage, and even necrosis after the activation of pancreatic enzymes in the pancreas caused by a variety of etiologies. This study was aimed to explore the functions and mechanism of Wip1 in AP. Twenty male SD rats were randomly assigned into 2 groups (control group: saline treatment; AP group: cerulein treatment). And cerulein-treated AR42J cells were conducted as AP model in vitro. The levels of amylase were detected by using the Beckman biochemical analyzer. The levels of IFNβ and TNFα were analyzed by ELISA. The autophagosomes were observed by transmission electron microscopy. The Wip1-specific shRNAs were transfected to AR42J cells to silence the expression of Wip1. The levels of Wip1 were measured by qRT-PCR and Western blot. The levels of STING/TBK1/IRF3 and LC3 were measured by Western blot. The AP model was successfully constructed by cerulein administration. Wip1 was notably upregulated in AP models. Autophagy and STING pathway activation were involved in the development of AP. Wip1 inhibition counteracts the promotion effect on inflammatory response induced by cerulein in AR42J Cells. Wip1 inhibition inhibited the activity of the STING/TBK1/IRF3 and reduced LC3 levels in AP. This study preliminarily explored that Wip1 could regulate autophagy and participate in the development of AP through the STING/TBK1/IRF3 signaling pathway.

In recent years, the rapid development of deep neural networks has made great progress in automatic organ segmentation from abdominal CT scans. However, automatic segmentation for small organs (e.g., the pancreas) is still a challenging task. As an inconspicuous and small organ in the abdomen, the pancreas has a high degree of anatomical variability and is indistinguishable from the surrounding organs and tissues, which usually leads to a very vague boundary. Therefore, the accuracy of pancreatic segmentation is sometimes below satisfaction. In this paper, we propose a 2.5D U-net with an attention mechanism. The proposed network includes 2D convolutional layers and 3D convolutional layers, which means that it requires less computational resources than 3D segmentation models while it can capture more spatial information along the third dimension than 2D segmentation models. Then We use a cascaded framework to increase the accuracy of segmentation results. We evaluate our network on the NIH pancreas dataset and measure the segmentation accuracy by the Dice similarity coefficient (DSC). Experimental results demonstrate a better performance compared with state-of-the-art methods., Competing Interests: The authors have declared that no competing interests exist.

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues of human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 1-2 mm explants and cultured on gelatin sponges for 12 days. Immunohistochemistry revealed that human PDAC explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC explants were treated with Abraxane and we observed different levels of response between patients. PDAC explants were also transfected with polymeric nanoparticles + Cy5-siRNA and we observed abundant cytoplasmic distribution of Cy5-siRNA throughout the PDAC explants. Overall, our novel model retains the 3D architecture of human PDAC and has advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis, and no tissue manipulation, digestion, or artificial propagation of organoids. This provides unprecedented opportunity to study PDAC biology including tumour-stromal interactions and rapidly assess therapeutic response to drive personalised treatment.

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment. However, the sample preparations for such imaging are often onerous, and their capability for antigen detection is limited. Here, we describe FLASH (fast light-microscopic analysis of antibody-stained whole organs), a simple, rapid, fully customizable technique for molecular phenotyping of intact tissue volumes. FLASH utilizes non-degradative epitope recovery and membrane solubilization to enable the detection of a multitude of membranous, cytoplasmic and nuclear antigens in whole mouse organs and embryos, human biopsies, organoids and Drosophila. Retrieval and immunolabeling of epithelial markers, an obstacle for previous clearing techniques, can be achieved with FLASH. Upon volumetric imaging, FLASH-processed samples preserve their architecture and integrity and can be paraffin-embedded for subsequent histopathological analysis. The technique can be performed by scientists trained in light microscopy and yields results in <1 week.

Although gold-standard histological assessment is subjective it remains central to diagnosis and clinical trial protocols and is crucial for the evaluation of any preclinical disease model. Objectivity and reproducibility are enhanced by quantitative analysis of histological images but current methods require application-specific algorithm training and fail to extract understanding from the histological context of observable features. We reinterpret histopathological images as disease landscapes to describe a generalisable framework defining topographic relationships in tissue using geoscience approaches. The framework requires no user-dependent training to operate on all image datasets in a classifier-agnostic manner but is adaptable and scalable, able to quantify occult abnormalities, derive mechanistic insights, and define a new feature class for machine-learning diagnostic classification. We demonstrate application to inflammatory, fibrotic and neoplastic disease in multiple organs, including the detection and quantification of occult lobular enlargement in the liver secondary to hilar obstruction. We anticipate this approach will provide a robust class of histological data for trial stratification or endpoints, provide quantitative endorsement of experimental models of disease, and could be incorporated within advanced approaches to clinical diagnostic pathology.

Islet transplantation (ITx) has the potential to become the standard of care in beta cell replacement medicine but its results remain inferior to those obtained with whole pancreas transplantation. The protocols currently used for human islet isolation are under scrutiny because they are based on the enzymatic digestion of the organ, whereby the pancreas is demolished, its connections to the body are lost and islets are irreversibly damaged. Islet damage is characterized by critical factors such as the destruction of the extracellular matrix (ECM), which represents the 3D framework of the islet niche and whose loss is incompatible with islet euphysiology. Researchers are proposing the use of ECM-based scaffolds derived from the mammalian pancreas to address this problem and ultimately improve islet viability, function, and lifespan. Currently available methods to obtain such scaffolds are harsh because they are largely detergent based. Thus, we propose a new, detergent-free method that creates less ECM damage and can preserve critical components of pancreatic ECM. The results show that the newly developed decellularization protocol allowed the achievement of complete DNA clearance while the ECM components were retained. The ECM obtained was tested for cytotoxicity and encapsulated with human pancreatic islets which showed a positive cellular behavior with insulin secretion when stimulated with glucose challenge. Collectively, we propose a new method for the decellularization of the human pancreas without the use of conventional ionic and non-ionic chemical detergents. This protocol and the ECM obtained with it could be of use for both in vitro and in vivo applications.

High-speed imaging of living specimen was performed using two-photon microscopy equipped with a spinning-disk scanning unit. Typically, a high-peak-power laser light source is needed to simultaneously induce two-photon excitation processes at several hundred focal points, generating the limitations of excitable fluorophores. Therefore, a high-peak-power neodymium-based 918-nm laser light source was used for intravital imaging of the most popular fluorophores, green fluorescent proteins. As a result, the proposed system obtained approximately 30 times brighter fluorescent signal than that obtained using a conventional mode-locked titanium:sapphire laser light source. Furthermore, the system visualized four-dimensional (xyz-t) calcium responses of pancreatic acinar cells agonist stimulations in the living G-CaMP7-expressing mouse with 60 million μm 3 volume., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this research work was to study the histological structure of the pancreatic acini by transmission electron microscope in two avian species, duck and pigeon. The specimens were collected and processed for electron microscopic study. The results showed that the acini of the two avian species were two types; the first one was an electron dense and the second one an electron lucent. The light acinar cells were larger in size than the dark cells. These cells contained centrally located ovoid nuclei with prominent nucleoli and abundant euchromatin. The cytoplasm was electron lucent, with many rough endoplasmic reticulum, polymorphic mitochondria. Numerous zymogen granules were distributed in the basal part and around the nucleus, so these cells considered active cells. The dark acinar cells were characterized by an electron dense cytoplasm. The most prominent cell organelle in these cells were the zymogen granules that appeared in different sizes while other organelles as mitochondria, and rough endoplasmic reticulum were inconspicuous or few, so these cells were considered as inactive cells. The nucleus with indented nuclear membrane located centrally with prominent nucleoli and abundant heterochromatin. Prominent intercellular spaces between the individual acinar cells, as well as well-developed basement membrane separating the electron dense cells and the lumen contained the secretion between acinar cells. It could be concluded that the acinar cells in ducks and pigeons were divided into two types, that is, light and dark acinar cells which mainly attributed to the activity of these cells., (© 2020 Blackwell Verlag GmbH.)

The existence of telocytes (TCs) has not yet been established in the pancreases of aquatic reptiles. Here, we report TCs in the exocrine pancreas of Pelodiscus sinensis using transmission electron microscope (TEM), immunohistochemistry (IHC), and immunofluorescence (IF) techniques. TCs surrounded the acini and ducts of the connective tissue of the exocrine pancreas and between lobules and gland cells. The cells were located preferably close to the blood vessels, interlobular ducts, and nerve fibers. Ultrastructurally, TCs exhibited small and large bodies with thick and thin portions, podoms, and podomers, and prolongations that form dichotomous branching with hetero-cellular and homo-cellular junctions. The podom (thick) portions showed caveolae, mitochondria, rough endoplasmic reticulum, and vesicles. The nucleus carries heterochromatin and is irregular in shape. The shape of TCs depends on the number of telopodes (Tps) bearing long, short, spindle, triangular, and "beads on a string" shapes with twisted, tortuous prolongations and ramifications. Shed extracellular vesicles and exosomes were found frequently released from projections and Tps within connective tissue in the vicinity of the acini and collagen fibers. IHC and IF results showed CD34+, α-SMA+, and vimentin + , long and triangle-shaped TCs, consistent with the TEM findings. The presence of shaded vesicles from TCs might implicate their possible role in immune surveillance, tissue regeneration as well as regulatory functions in the reptilian pancreas.

Acute pancreatitis (AP) is one of the leading causes of hospital admission for gastrointestinal disorders. Although lipid peroxides are produced in AP, it is unknown if targeting lipid peroxides prevents AP. This study aimed to investigate the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for lipid peroxide degradation, in AP and the possible underlying mechanisms. Cerulein was used to induce AP in C57BL/6 J male mice and pancreatic acinar cells were used to elucidate underlying mechanisms in vitro. Pancreatic enzymes in the serum, lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and Bcl-2, Bax and cleaved caspase-3 were measured. ALDH2 activation with a small-molecule activator, Alda-1, reduced the levels of the pancreatic enzymes in the serum and the lipid peroxidation products MDA and 4-HNE. In addition, Alda-1 decreased Bax and cleaved caspase-3 expression and increased Bcl-2 expression in vivo and in vitro. In conclusion, ALDH2 activation by Alda-1 has a protective effect in cerulein-induced AP by mitigating apoptosis in pancreatic acinar cells by alleviating lipid peroxidation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

An adequate experimental model is important to understand pathophysiological processes ongoing in the pancreas with diabetes mellitus. Our study was aimed to describe early ultra- and microstructural changes in the rat pancreas in 12-48 h after alloxan administration in a dose of 180 mg/kg. A histopathological examination of the endocrine pancreas revealed the loss of borders between endocrine cells, granular dystrophy and degranulation, sings of necrosis in central cells of the Langerhans islets and apoptosis of their peripheral ones manifested as DNA fragmentation and an increased expression of apoptosis markers. There was a gradual increase of a Langerhans islet area, a decreased percentage of insulin+ cells and an increased one of glucagon+ cells, as well as the presence of proliferating islet cells were found. Structural changes of the exocrine pancreas included fatty degeneration, signs of exocrine cell mitochondrial damage, increased acini, which are located mainly around the Langerhans islets, as well as perivascular edema and leukocytic infiltration. Described ultra- and microstructural alterations suggest a significant contribution of apoptosis to death of endocrine cells exposed to alloxan. Coexisting damage of the exocrine pancreas with its stroma involvement is for the first time described.

Pancreatic β cell damage is one of the crucial factors responsible for the development of type 2 diabetes mellitus (T2DM). Previous studies have suggested that puerarin (PR) could regulate the activities of the mitochondrial respiratory chain complex in diabetic nephropathy (DN); however, whether PR can inhibit pancreatic β-cell apoptosis in T2DM remains to be elucidated. In the present study, T2DM mice induced by high-fat diet and streptozotocin (STZ) injection were used as a working model to investigate the mechanism of PR on pancreatic β cell apoptosis. The results showed that PR decreased the serum fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) levels but significantly increased the fasting blood insulin (FINS) and high-density lipoprotein (HDL) levels. Furthermore, decreased caspase-3, 8, 9 and apoptosis-inducing factor (AIF) proteins in the pancreas were detected by Western blot analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining demonstrated that the pancreatic β cell apoptosis was inhibited by PR. Furthermore, PR improved the histopathological changes in pancreatic tissue in T2DM mice. Collectively, the data show that PR can protect the β cells from apoptotic death in a mouse model of T2DM through regulating the expression of apoptosis-related protein-AIF and caspase family proteins.

Decellularized (DC) organs/tissues offer a promising scaffold for regenerative bioengineering. However, it is not clear whether the diabetic mellitus (DM) pancreas can be used in decellularized and recellularized bioengineering. For assessment of these questions, murine pancreatic scaffolds of normal, type 1DM (T1DM) and type 2 DM (T2DM) pancreas were generated using a perfusion decellularization technique and assessed by histology, scanning electron microscopy, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). The capacity of DC pancreatic scaffolds to support attachment and proliferation of human umbilical vein endothelial cells (HUVECs) and MIN-6 β cells was also assessed. Our results showed that DC pancreatic scaffolds were successfully produced from T1DM and T2DM pancreas and maintained their extracellular matrix (ECM) composition, 3D ultrastructure, and various cytokines. All of the pancreatic scaffolds were sufficiently cytocompatible and were able to support proliferation and adhesion of HUVECs and MIN-6 β cells. The preliminary results support the biological utility of diabetes mellitus pancreatic scaffolds and pave the way for further investigations to assess the potential ability of using diabetes mellitus pancreas as scaffolds for recellularization and eventual medical applications., (© 2018 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Objective: We aim to investigate whether C21, a selective angiotensin type 2 receptor agonist, can exert protective effects on pancreatic β-cells through activation of antiapoptosis and autophagy., Methods: The high-fat diet-induced obese rats (HFDs) were under C21 treatment for 4 weeks., Results: C21 treatment decreased the fasting glucose levels and improved β-cell insulin secretory function in the HFD group. Hematoxylin and eosin staining and electron microscopy indicated that the islet morphology was improved in the C21-treated obese rats, which was associated with increased levels of the key transcription factor PDX1, glucose sensing, and uptaking protein GCK and GLUT2, respectively. C21 treatment exerted antiapoptotic effects through decreasing the levels of apoptotic marker Caspase-3 while increasing the levels of antiapoptotic markers AKT, p-AKT, and BCL2. C21 treatment also induced autophagosome formation in the mitochondria of the β-cells in the HFD group accompanied by increased levels of autophagy markers, LC-3B and Beclin-1., Conclusions: The results suggested C21 treatment decreased the fasting glucose level and protected β-cell function in the HFD-induced obese rat model, which in part through activation of antiapoptotic and autophagy processes. This study provided preclinical evidence for the utilization of C21 in the treatment of type 2 diabetes.

Increasing evidence shows that the endoplasmic reticulum (ER) stress is an early event that injures pancreatic acinar cells and contributes to the pathogenesis of acute pancreatitis. In the present work we sought to establish whether atrial natriuretic peptide (ANP) alleviated ER stress in rats with cerulein-induced pancreatitis. The major components of the unfolded protein response (UPR) and their downstream effectors were assessed by immunoblotting or fluorimetry and the ultrastructure of ER evaluated by electron transmission microscopy. Cross-talk with autophagy was evaluated by beclin-1 expression. ANP reduced binding immunoglobulin protein (Bip) expression (UPR major controller) which under non-stress conditions keeps inactive the stress sensor proteins: protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6). Although ANP did not change PERK expression it decreased p-eIF2α and enhanced downstream effector CHOP, suggesting that ANP stimulates ER-dependent apoptosis. In accordance, ANP also decreased Bcl2 expression and enhanced proapoptotic proteins Bax and Bak. The atrial peptide enhanced ATF6 expression and although it did not affect IRE1/sXBP1 signaling, it increased caspase-2 activity, also involved in ER-dependent apoptosis. Furthermore, ANP decreased beclin-1 expression. The ultrastructure of the RE revealed decreased swelling and conserved ribosomes in the presence of ANP. Present findings support that ANP alleviates ER stress in acute pancreatitis by modulating the three branches of the UPR and stimulates ER-dependent apoptosis. Gaining insights into the modulation of ER stress may help to develop specific therapeutic strategies for acute pancreatitis and/or medical interventions at risk of its developing like endoscopic retrograde cholangiopancreatography., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a subset expressing autoantibodies associated with the early stages of T1D., Research Design and Methods: MRI was performed in individuals with recent-onset stage 3 T1D ( n = 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants ( n = 57) and in autoantibody-positive individuals without diabetes ( n = 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition., Results: Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL; P < 0.001), including when normalized by individual weight ( P < 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis ( P < 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort ( P = 0.017) but smaller than that of the control cohort ( P = 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient ( P = 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution., Conclusions: These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes., (© 2018 by the American Diabetes Association.)

The observation of two precursor groups of the early stem cells (Groups I and II) leads to the realization that a first amount of fetal stem cells (Group I) migrate from the AMG (Aortal-Mesonephric-Gonadal)-region into the aorta and its branching vessels. A second group (Group II) gains quite a new significance during human development. This group presents a specific developmental step which is found only in the human. This continuation of the early development along a different way indicates a general alteration of the stem cell biology. This changed process in the stem cell scene dominates the further development of the human stem cells. It remains unclear where this phylogenetic step first appears. By far not all advanced mammals show this second group of stem cells and their axonal migration. Essentially only primates seem to be involved in this special development.

Background: Hyperlipidaemia is a risk factor for the development and progression of atherosclerosis and is linked to various diseases. This study was done to evaluate the possible protective effects of virgin olive oil and Nigella sativa seeds on the biochemical and histopathological changes which occurred in the pancreas of the rats. The study lasted 8 weeks and included 24 albino rats that were divided into four groups (6 rats each); Group I - control group, fed with normal standard diet, Group II - fed with high fat diet (HFD), Group III - fed with HFD and virgin olive oil, Group IV - fed with HFD and Nigella sativa seeds powder., Materials and Methods: After finishing the experiment, blood samples were collected and assessed for the lipid profile, fasting blood glucose, pancreatic amylase and insulin levels. Then, the rats were sacrificed and the pancreata were extracted and slices of them were processed for histological examination using haematoxylin stain and Masson's trichrome stain. Small fragments from the tail of the pancreata were extracted and processed for electron microscopic examination. The statistical analysis of the data using the appropriate statistical tests was also conducted., Results: In the present study, the serum lipid profile in hyperlipidaemic rats was ameliorated in rats fed on high fat diet with virgin olive oil or Nigella sativa seed powder, which was reflected by a significant decrease in total cholesterol, low-density lipoprotein-cholesterol and triglycerides. Moreover, Nigella sativa decreased high-density lipoprotein (HDL), while virgin olive oil significantly increased HDL. Also a significant decrease in the serum levels of blood glucose and amylase and a significant increase in insulin levels were present in these groups. The histological and ultrastructural results revealed regeneration of the exocrine and endocrine parts of the pancreatic tissues from the hyperlipidaemic rats fed with virgin olive oil or Nigella sativa seeds., Conclusions: In this study, the biochemical results were paralleled to the histological and ultrastructural results; therefore, it could be concluded that virgin olive oil and Nigella sativa seeds had antihyperlipidaemic and hypoglycaemic effects and they could protect the pancreas from hyperlipidaemia-induced injury. Daily consumption of virgin olive oil and Nigella sativa seeds in the diet is highly recommended.

Notch is activated globally in pancreatic progenitors; however, for progenitors to differentiate into endocrine cells, they must escape Notch activation to express Neurogenin-3. Here, we find that the transcription factor nuclear factor I/A (NFIA) promotes endocrine development by regulating Notch ligand Dll1 trafficking. Pancreatic deletion of NFIA leads to cell fate defects, with increased duct and decreased endocrine formation, while ectopic expression promotes endocrine formation in mice and human pancreatic progenitors. NFIA-deficient mice exhibit dysregulation of trafficking-related genes including increased expression of Mib1, which acts to target Dll1 for endocytosis. We find that NFIA binds to the Mib1 promoter, with loss of NFIA leading to an increase in Dll1 internalization and enhanced Notch activation with rescue of the cell fate defects after Mib1 knockdown. This study reveals NFIA as a pro-endocrine factor in the pancreas, acting to repress Mib1, inhibit Dll1 endocytosis and thus promote escape from Notch activation., (Copyright © 2018. Published by Elsevier Inc.)

Nociceptin (NC), also known as Orphanin FQ, is a brain peptide involved in the regulation of pain, but its role in the endocrine pancreas is poorly understood. The present study examines the pattern of distribution of NC and its effect on insulin and glucagon secretion after the onset of diabetes mellitus (DM). Male Wistar rats weighing 150-200 g were made diabetic with streptozotocin (60 mg/kg body weight, intraperitoneally). Four weeks after the induction of DM, pancreatic tissues were retrieved and processed for immunofluorescence, immunoelectron microscopy, and insulin and glucagon secretion. Isolated islets from non-diabetic and diabetic rats were used to determine the effect of NC on insulin release. NC was discerned in islet cells of non-diabetic control and diabetic rat pancreata. NC co-localized only with insulin in pancreatic beta cells. NC did not co-localize with either glucagon or somatostatin or pancreatic polypeptide. The number of NC-positive cells was markedly (p < 0.001) reduced after the onset of DM. Electron microscopy study showed that NC is located with insulin in the same secretory granules of the beta cells of both non-diabetic and diabetic rat pancreas. NC inhibits insulin release markedly (p < 0.05) from pancreatic tissue fragments of non-diabetic and diabetic rats. In contrast, NC at 10 -12  M stimulates insulin release in isolated islets of DM rats. In conclusion, NC co-localizes with insulin only in the islet of Langerhans. The co-localization of NC with insulin suggests a role for NC in the regulation of pancreatic beta cell function.

Obesity, diabetes and related metabolic disorders are among the top prevalent metabolism-related diseases with increasing threat to human health throughout the world. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins possessing anti-diabetic, antioxidant, hypolipidemic and anti-inflammatory activities. A nano-formulation of OA was recently developed to evaluate the efficiency of nano-OA in the treatment of insulin-resistance and metabolic disorders in high fat and fructose (HFF) diet-fed rats. This study further identified that nano-OA could reduce the increase of body weights, serum insulin, insulin sensitivity index, serum triglycerides, and cholesterol in HFF-fed rats. In consistence, nano-OA was able to attenuate HFF diet-induced lipid accumulation in the liver and improve the structural integrity of mitochondria and endoplasmic reticulum in liver and pancreas in animals fed with HFF diet. In addition, nan-OA can efficaciously mitigate the increase of levels of malondialdehyde (MDA) and nitric oxide (NO), and serum superoxide dismutase (SOD) and catalase (CAT) activities in blood samples. The beneficial effects of nano-OA was further evidenced to be superior to OA formulated in arabic gum and rosiglitazone treatment. Together, this study provides the evidence that nano-OA can effectively improve HFF diet-induced metabolic dysfunctions in rats by improving its bioavailability and pharmacodynamic properties and thus nano-OA may be a potentially efficient agent to treat obesity-related diabetes and metabolic disorders., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objectives: The purpose of this study was to evaluate the diagnostic performance of magnetization transfer (MT) imaging and multigradient echo magnetic resonance imaging (MRI) to quantify pancreatic fibrosis and lipomatosis in patients before pancreatoduodenectomy for postoperative risk stratification with histopathology as the reference standard., Materials and Methods: Twenty-four patients (age, 68 ± 8 years, 16 males) prospectively underwent quantitative MT imaging using a 2-dimensional gradient echo sequence with and without MT prepulse and multigradient echo imaging on a 3 T MRI 1 day before pancreatoduodenectomy due to adenocarcinoma of the pancreatic head region (n = 20), neuroendocrine tumor (n = 3), or intraductal papillary mucinous neoplasm (n = 1). Magnetization transfer ratio (MTR) and proton density fat fraction (PDFF) were measured in pancreatic tail (PT) and at the resection margin (RM). Histopathologically, pancreatic fibrosis was graded as mild, moderate, or severe (F1-F3), lipomatosis was graded as 0% to 10%, 11% to 30%, and greater than 30% fat deposition (L1-L3). In addition, MTR and histopathologic fibrosis was assessed in pancreatic adenocarcinoma. Mann-Whitney U test and Spearman correlation were used., Results: Patients with advanced pancreatic fibrosis (F3) showed a significantly higher MTR compared with the F1 group at the RM and PT (38 ± 4 vs 32.3 ± 1.6, P = 0.018 and 39.7 ± 5.5 vs 31.2 ± 1.7, P = 0.001). Spearman correlation coefficient of MTR and fibrosis grade was r = 0.532 (P = 0.011) and 0.554 (P = 0.008), respectively. Pancreatic parenchyma with advanced fat deposition (L2-L3) showed significantly higher PDFF compared with lipomatosis grade L1 (RM: P = 0.002 and PT: P = 0.001). Proton density fat fraction of pancreatic parenchyma exhibited a moderate and significant correlation with histopathologic lipomatosis grade (RM: r = 0.668 and PT: r = 0.707, P < 0.001). Magnetization transfer ratio was significantly higher in pancreatic adenocarcinoma compared with pancreatic parenchyma (44 ± 5.5 vs 36.0 ± 4.4 and 37.4 ± 5.4, P = 0.004)., Conclusions: Multiparametric MRI of the pancreas including MTR and PDFF maps may provide quantitative and noninvasive information on pancreatic fibrosis and lipomatosis before surgery.

The animal experiment was preformed to investigate the roles of PPAR-γ/PI3K/Akt pathway in apoptosis triggered by cadmium (Cd) and in the antagonistic effects of selenium (Se) on Cd in the pancreas of chicken. The current study showed that Cd treatment obviously increased the accumulation of Cd and directly led to lower activities of amylase, trypsin and lipase in chicken pancreas. The expression of PPAR-γ, PI3K, and Akt was declined, whereas the level of Bax, Cyt C and caspase-3 were increased in Cd group. In the result of TUNEL assay and the histological examination, typical apoptosis characteristics in the pancreas of Cd group were confirmed. Cd group also showed high levels of inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) content in pancreas. However, those Cd-induced changes were obviously alleviated in Cd + Se group. Our study revealed that Cd could impact the pancreas function and induce the activation of Bax and the overproduction of NO via PPAR-γ/PI3K/Akt pathway to promote apoptosis in chicken pancreas. However, Se could reduce Cd accumulation and antagonize Cd-triggered apoptosis in chicken pancreas., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Endoplasmic reticulum (ER), a dynamic organelle, plays an essential role in organizing the signaling pathways involved in cellular adaptation, resilience, and survival. Impairment in the functions of ER occurs in a variety of nutritive disorders including obesity and type 2 diabetes. Here, we hypothesize that (scopoletin) SPL, a coumarin, has the potential to alleviate ER stress induced in vitro and in vivo models by lipotoxicity. To test this hypothesis, the ability of SPL to restore the levels of proteins of ER stress was analyzed. Rat insulinoma 5f (RIN5f) cells and Sprague Dawley rats were the models used for this study. Groups of control and high-fat, high-fructose diet (HFFD)-fed rats were treated with either SPL or 4-phenylbutyric acid. Status of ER stress was enumerated by quantitative RT-PCR, Western blot, electron microscopic, and immunohistochemical studies. Proximal proteins of ER stress inositol requiring enzyme 1 (IRE1), protein kinase like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) were reduced in the β-cells by SPL. The subsequent signaling proteins X-box binding protein 1, eukaryotic initiation factor2α, activating transcription factor 4, and C/EBP homologous protein were also suppressed in their expression levels when treated with SPL. IRE1, PERK signaling leads to c-Jun-N-terminal kinases phosphorylation, a kinase that interrupts insulin signaling, which was also reverted upon scopoletin treatment. Finally, we confirm that SPL has the ability to suppress the stress proteins and limit pancreatic ER stress which might help in delaying the progression of insulin resistance.

Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate-globotriaosylceramide (Gb3Cer)-B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease-FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Herein, we provide a comprehensive overview of the biochemical and structural abnormalities in pancreatic tissue from two male FD patients with blood group B. In both patients, we found major accumulation of a variety of complex B-GSLs carrying predominantly hexa- and hepta-saccharide structures. The subcellular pathology was dominated by deposits containing B-glycoconjugates and autofluorescent ceroid. The contribution of Gb3Cer to the storage was minor. This abnormal storage pattern was specific for the pancreatic acinar epithelial cells. Other pancreatic cell types including those of islets of Langerhans were affected much less or not at all.Altogether, we provide evidence for a key role of B-antigens in the biochemical and morphological pathology of the exocrine pancreas in FD patients with blood group B. We believe that our findings will trigger further studies aimed at assessing the potential pancreatic dysfunction in this disease.

Combination antiretroviral therapy (cART) has shown to cause inflammation, cellular injury and oxidative stress, whereas melatonin has been successful in reducing these effects. The aim of the study was to determine potential morphometric changes caused by cART in combination with melatonin supplementation in human immunodeficiency virus (HIV)-free rats. Tissue samples (N = 40) of the pancreas, liver and kidney from a control (C/ART-/M-), cART group (C/ART + ), melatonin (C/M + ) and experimental group (ART+/M + ) were collected and stained with haematoxylin and eosin (H&E) and evaluated for histopathology. The pancreata were labelled with anti-insulin and anti-glucagon to determine α- and β-cell regions. Kidneys were stained with periodic acid Schiff (PAS) to measure the area, perimeter, diameter and radius of renal corpuscles, glomeruli and proximal convoluted tubules (PCTs). Blood tests were conducted to determine hepatotoxicity. No significant changes in histopathology were seen. Melatonin stimulated pancreatic islet abundance, as the number of islets per mm 2 was significantly higher in the C/M+ than in the C/ART-/M- and ART+/M+. Parameters of the renal corpuscle, glomeruli, renal space and PCTs were significantly lower in the C/ART+ compared to the other groups, thus cART may have caused tubular dysfunction or cellular damage. A significant increase in serum haemoglobin was observed in the C/ART+ compared to the C/ART-, which showed cART increases serum haemoglobin in the absence of immune deficiency. Serum lipids were significantly decreased in the C/M+ compared to the C/ART-, possibly due to the effect of melatonin on the decrease of lipolysis, decreasing effect on cholesterol absorption and stimulation of lipoprotein lipase (LPL) activity. In conclusion, we have demonstrated that melatonin stimulated α-cell production, increased the number of pancreatic islets and caused a decrease in total lipids, whereas cART increased serum haemoglobin and decreased various parameters of the nephron in an HIV-free rat model, suggestive of tubular dysfunction., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Hexokinase domain component 1 (HKDC1) is a recently discovered novel protein, which is being promoted as a putative fifth hexokinase. Although the exact role HKDC1 plays in physiology is still unclear, it has been shown to be important during pregnancy in the regulation of glucose homeostasis. In this study, we have comprehensively studied the expression pattern of HKDC1 in the human body. Using human tissue sample, immunohistochemistry imaging was performed. Our studies indicate that the tissues with highest HKDC1 expression were the brush border epithelium of the intestines, parts of the pancreas, and lung alveolar macrophages. Future directions will be to understand the role of this fifth hexokinase in these tissues, with a focus on its relative function as compared with other endogenously expressed hexokinases.

Technological advances in mass spectrometry imaging (MSI) have contributed to growing interest in 3D MSI. However, the large size of 3D MSI data sets has made their efficient analysis and visualization and the identification of informative molecular patterns computationally challenging. Hierarchical stochastic neighbor embedding (HSNE), a nonlinear dimensionality reduction technique that aims at finding hierarchical and multiscale representations of large data sets, is a recent development that enables the analysis of millions of data points, with manageable time and memory complexities. We demonstrate that HSNE can be used to analyze large 3D MSI data sets at full mass spectral and spatial resolution. To benchmark the technique as well as demonstrate its broad applicability, we have analyzed a number of publicly available 3D MSI data sets, recorded from various biological systems and spanning different mass-spectrometry ionization techniques. We demonstrate that HSNE is able to rapidly identify regions of interest within these large high-dimensionality data sets as well as aid the identification of molecular ions that characterize these regions of interest; furthermore, through clearly separating measurement artifacts, the HSNE analysis exhibits a degree of robustness to measurement batch effects, spatially correlated noise, and mass spectral misalignment.

We used transmission electron microscopy to study the pancreatic main endocrine cell types in the embryos of the grass snake Natrix natrix L. with focus on the morphology of their secretory granules. The embryonic endocrine part of the pancreas in the grass snake contains four main types of cells (A, B, D, and PP), which is similar to other vertebrates. The B granules contained a moderately electron-dense crystalline-like core that was polygonal in shape and an electron-dense outer zone. The A granules had a spherical electron-dense eccentrically located core and a moderately electron-dense outer zone. The D granules were filled with a moderately electron-dense non-homogeneous content. The PP granules had a spherical electron-dense core with an electron translucent outer zone. Within the main types of granules (A, B, D, PP), different morphological subtypes were recognized that indicated their maturity, which may be related to the different content of these granules during the process of maturation. The sequence of pancreatic endocrine cell differentiation in grass snake embryos differs from that in many vertebrates. In the grass snake embryos, the B and D cells differentiated earlier than A and PP cells. The different sequence of endocrine cell differentiation in snakes and other vertebrates has been related to phylogenetic position and nutrition during early developmental stages., (© 2017 Wiley Periodicals, Inc.)

Dimethoate is a widely used organophosphate insecticide known to be toxic to the pancreas. The aim of this study is to detect the possible protective effects of the fenugreek seed ethanolic extract on the biochemical, histological, and ultra-structural abnormalities induced by dimethoate chronic exposure in the pancreas of adult male rats. The study was conducted on 50 adult male albino rats that were divided equally into 5 groups: (group I) negative control, (group II) vehicle control group, (group III) fenugreek-treated group that was given 400 mg/kg ethanolic fenugreek seed extract once daily, (group IV) dimethoate group received 20 mg/kg/day dimethoate, and (group V) dimethoate- + fenugreek-treated group received a combination of dimethoate and fenugreek in the same previous doses. Dimethoate treatment caused a significant increase in serum glucose, amylase, and lipase levels and a significant decrease in serum insulin. A significant increase in lipid peroxidation and pro-fibrotic cytokine (TGF-β1) together with a significant reduction of the antioxidant {reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD)} activities and the anti-inflammatory (IL-4) in pancreatic tissues was also recorded. There was a histological and ultra-structural evidence of pancreatic acinar and islet cell injury. The recorded abnormalities were reversed in dimethoate+fenugreek treated group indicating that fenugreek ethanolic extract can serve as an antidote for dimethoate-induced pancreatic insult.

Mechanisms of selective autophagy of the ER, known as ER-phagy, require molecular delineation, particularly in vivo. It is unclear how these events control ER proteostasis and cellular health. Here, we identify cell-cycle progression gene 1 (CCPG1), an ER-resident protein with no known physiological role, as a non-canonical cargo receptor that directly binds to core autophagy proteins via an LIR motif to mammalian ATG8 proteins and, independently and via a discrete motif, to FIP200. These interactions facilitate ER-phagy. The CCPG1 gene is inducible by the unfolded protein response and thus directly links ER stress to ER-phagy. In vivo, CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas. Thus, via identification of this autophagy protein, we describe an unexpected molecular mechanism of ER-phagy and provide evidence that this may be physiologically relevant in ER luminal proteostasis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The formation of amyloid fibrils by human islet amyloid polypeptide protein (hIAPP) has been implicated in pancreas dysfunction and diabetes. However, efficient treatment options to reduce amyloid fibrils in vivo are still lacking. Therefore, we tested the effect of epigallocatechin gallate (EGCG) on fibril formation in vitro and in vivo. To determine the binding of hIAPP and EGCG, in vitro interaction studies were performed. To inhibit amyloid plaque formation in vivo, homozygous (tg/tg), hemizygous (wt/tg), and control mice (wt/wt) were treated with EGCG. EGCG bound to hIAPP in vitro and induced formation of amorphous aggregates instead of amyloid fibrils. Amyloid fibrils were detected in the pancreatic islets of tg/tg mice, which was associated with disrupted islet structure and diabetes. Although pancreatic amyloid fibrils could be detected in wt/tg mice, these animals were non-diabetic. EGCG application decreased amyloid fibril intensity in wt/tg mice, however it was ineffective in tg/tg animals. Our data indicate that EGCG inhibits amyloid fibril formation in vitro and reduces fibril intensity in non-diabetic wt/tg mice. These results demonstrate a possible in vivo effectiveness of EGCG on amyloid formation and suggest an early therapeutical application.

The salivary glands and pancreas have comparable anatomic and antigenic properties and can share common pathogenetic mechanisms involving toxic or autoimmune processes. The aim of this study is to assess the correlation in size between the normal submandibular glands and the pancreas. The study was based on human autopsy specimens of the pancreas, neck and oral base from 22 adults, both sexes (mean age, 57.9 years). The pancreatic and submandibular ducts were injected with a contrast medium, and the area of the salivary and pancreatic glandular ductograms was measured with the aid of software for quantification of visual information. Samples of tissue from the salivary glands and the pancreas were studied by means of light microscopy. A high correlation was found between the planimetric size of the pancreas and the submandibular glands (correlation coefficient 0.497 and 0.699 for the right and the left gland, respectively). This ratio was close to 5:1. There were no significant differences in size for the left vs. right submandibular gland (p = 0.39). The ductograms were significantly larger in size in males than in females (p < 0.001). This study has proven a positive correlation in planimetric size between the normal submandibular glands and pancreas, a result that is expected to have possible clinical implications in the long-term follow-up of patients with chronic pancreatitis.

Previously, high-resolution three-dimensional imaging of a whole and intact pancreas was not possible, since light is scattered when it passes through cell compartments with different refractive indices. CLARITY is one of the tissue clearing techniques that has yielded success with the central nervous system. To preserve tissue integrity after delipidation, conventional protocols embed tissue in an acrylamide-based hydrogel, which involves the use of specialized equipment. Recently, we determined that the hydrogel-embedding step could be simplified and replaced by passive tissue fixation in 4% paraformaldehyde (PFA). The whole procedure is less time-consuming and less error-prone, and can be completed within a week, compared to conventional CLARITY protocols that may take weeks to complete. Here, the detailed stepwise procedures involved in the simplified CLARITY workflow are applied to the pancreas of wild-type and gene-knockout 6-week old mice expressing green fluorescent protein (GFP) under the mouse insulin 1 promoter (MIP-GFP). This technique could facilitate high-resolution, three-dimensional imaging of pancreatic islets and comparison between different mouse genotypes under different disease and treatment conditions. © 2017 by John Wiley & Sons, Inc., (Copyright © 2017 John Wiley & Sons, Inc.)

Proper lumen morphogenesis during pancreas development is critical to endocrine and exocrine cell fate. Recent studies showed that a central network of lumens (termed core), but not the surrounding terminal branches (termed periphery), produces most islet endocrine cells. To date, it remains unclear how pancreatic lumens form and remodel and which aspects of lumen morphogenesis influence cell fate. Importantly, models testing the function of the central lumen network as an endocrine niche are lacking. Here, we identify mechanisms underlying lumen formation and remodeling and show that central lumen network morphogenesis impacts pancreatic endocrine mass. We show that loss of the scaffolding protein Afadin disrupts de novo lumenogenesis and lumen continuity in the tip epithelium. Codepletion of the actomyosin regulator RhoA and Afadin results in defects in the central lumens and arrests lumen remodeling. This arrest leads to prolonged perdurance of the central lumen network over developmental time and expansion of the endocrine progenitor population and, eventually, endocrine mass. Our study uncovers essential roles of Afadin and RhoA in pancreatic central lumen morphogenesis, which subsequently determines endocrine cell mass., (© 2018 Azizoglu et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Emodin, a traditional Chinese medicine, has a therapeutic effect on severe acute pancreatitis (SAP), whereas the underlying mechanism is still unclear. Studies showed that the intestinal mucosa impairment, and subsequent release of endotoxin and proinflammatory cytokines such as IL-1β, which further leads to the dysfunction of multiple organs, is the potentially lethal mechanism of SAP. Caspase-1, an IL-1β-converting enzyme, plays an important role in this cytokine cascade process. Investigation of the effect of emodin on regulating the caspase-1 expression and the release proinflammatory cytokines will help to reveal mechanism of emodin in treating SAP., Methods: Eighty Sprague-Dawley rats were randomly divided into four groups (n=20 each group): SAP, sham-operated (SO), emodin-treated (EM) and caspase-1 inhibitor-treated (ICE-I) groups. SAP was induced by retrograde infusion of 3.5% sodium taurocholate into the pancreatic duct. Emodin and caspase-1 inhibitor were given 30 minutes before and 12 hours after SAP induction. Serum levels of IL-1β, IL-18 and endotoxin, histopathological alteration of pancreas tissues, intestinal mucosa, and the intestinal caspase-1 mRNA and protein expressions were assessed 24 hours after SAP induction., Results: Rats in the SAP group had higher serum levels of IL-1β and IL-18 (P<0.05), pancreatic and gut pathological scores (P<0.05), and caspase-1 mRNA and protein expressions (P<0.05) compared with the SO group. Compared with the SAP group, rats in the EM and ICE-I groups had lower IL-1β and IL-18 levels (P<0.05), lower pancreatic and gut pathological scores (P<0.05), and decreased expression of intestine caspase-1 mRNA (P<0.05). Ultrastructural analysis by transmission electron microscopy found that rats in the SAP group had vaguer epithelial junctions, more disappeared intercellular joints, and more damaged intracellular organelles compared with those in the SO group or the EM and ICE-I groups., Conclusions: Emodin alleviated pancreatic and intestinal mucosa injury in experimental SAP. Its mechanism may partly be mediated by the inhibition of caspase-1 and its downstream inflammatory cytokines, including IL-1β and IL-18. Our animal data may be applicable in clinical practice., (Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.)

Considering the physiological importance of the pancreas as an endocrine and exocrine organ, this study described the characteristics of the gross and microscopic morphology of this organ using 16 Myrmecophaga tridactyla individuals. The pancreas was located in the left antimere of the body, was pale in colour and exhibited an elongated shape with a central body and lobulated surface. It was positioned in the abdomen, following the curvatura ventriculi major of the stomach, and was attached to the initial portion of the duodenum. The corpus pancreatis was elongated and showed a caudal curvature of 45°. The pancreas exhibited a facies dorsalis (related to the spleen and stomach) and a facies ventralis (related to the renal capsule and intestine). Macroscopically, a craniodorsal, medial, and caudoventral regions were identified, in addition to the left lobe. Structurally, the organ exhibited two distinct parts: the first had exocrine characteristics, consisting of acini and ducts; the second, which was the endocrine portion, consisted of the pancreatic islets, which were located in the medial, caudoventral and left lobe regions. Ultrastructural analysis identified secretory vesicles containing zymogen granules, mitochondria, Golgi apparatus and rough endoplasmic reticulum in pancreatic centroacinar cells. Morphological data on the anatomy of members of the Xenarthra have revealed important peculiarities of several organs and systems, adding great biological value to the representatives of this group. In addition, these studies significantly contribute not only to knowledge of the biology, taxonomy and, consequently, preservation of these animals but also to the discovery of new experimental models. Anat Rec, 300:1104-1113, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Normothermic machine perfusion has enormous potential to improve organ preservation and expand the organ donor pool. It is well established in other organs but not the pancreas, which has especially strict organ acceptance criteria. We established a model of normothermic hemoperfusion of the porcine pancreas with and without addition of the kidney as a dialysis organ. Four pancreases were harvested and perfused for 120 min with autologous whole blood at body temperature, two with parallel perfusion of the kidney and two without. The organs and perfusion circuit were evaluated for gross appearance, pH, histology and perfusion parameters. The organs maintained steadily increasing flow rate and perfusion pressure. Gross appearance of the organs was stable but appeared grossly ischemic toward the end of the perfusion period. Histology demonstrated necrosis centered in acinar tissue but islet cells were preserved. pH was significantly alkalotic toward the end of the perfusion, likely due to pancreatic tissue damage. Addition of the kidney did not result in significant improvement of the acid-base environment in this small series. In conclusion, normothermic perfusion of the pancreas is still in the experimental stages but holds great potential. Further studies to optimize perfusion parameters will significantly improve results. Parallel perfusion of the kidney may facilitate improvement in the acid-base environment., (© 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Acute pancreatitis (AP) is one of the most common diseases in gastroenterology. However, neither the etiology nor the pathophysiology of the disease is fully understood and no specific or effective treatment has been developed. Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains of HS sulfate proteoglycans into shorter oligosaccharides, activity that is highly implicated in cellular invasion associated with cancer metastasis and inflammation. Given that AP involves a strong inflammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are significantly increased following cerulein treatment. Moreover, pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a significant role in AP. Notably, all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in AP. Heparanase, therefore, emerges as a potential new target in AP, and heparanase inhibitors, now in phase I/II clinical trials in cancer patients, are hoped to prove beneficial also in AP.

The device for cell encapsulation makes it possible to fabricate microcapsules of a preset size with even smooth surface, without defects or adhesion to each other, with viable cells inside the capsule. The cells were derived from newborn piglet pancreases.

The aim of this study was to investigate the effectiveness of alpha-lipoic acid (α-LA) against cyclosporine A (CsA)-induced pancreatic toxicity in rats. Thirty-two male albino rats were divided into four equal groups. Group I treated orally (per os, p.o.) with vehicles and served as control; Group II received α-LA (100 mg/kg b.w. /day, p.o.) for 21 days; Group III received CsA (25 mg/kg b.w./day, p.o.) for 21 days; and Group IV received α-LA 1 hr before oral treatment by CsA for 21 days. Histological examination of the pancreas of CsA-treated rats showed marked changes represented by wide interlobular septae that contained congested blood vessels, cytoplasmic vacuolation of some acinar cells, and distortion of the other cells. Most of the islets of Langerhans showed vacuolation, degenerative changes, and loss of uniform cellular distribution. Some of the islets appeared shrunken with few cells. In the CsA group, the immunohistochemical and morphometric study demonstrated a decrease in the number of insulin-secreting β-cells and also a reduction in islet diameters, with statistically significant difference (p < 0.001 and p = 0.004), respectively, compared with the control group. Ultrastructure of the exocrine and endocrine pancreatic cells of the CsA-treated group confirmed the light microscopic observation and showed dilated rough endoplasmic reticulum, decreased zymogen and secretory granules, damaged mitochondria, and abnormal nuclei. However, α-LA administration simultaneously with CsA resulted in some sort of regression of the previously mentioned effects., Conclusion: α-LA attenuated CsA-induced structural and ultrastructural changes in pancreatic cells, which were nearly reverted to their normal structure.

Sericin has been implicated in lower cholesterolemic effect due to its properties with several mechanisms. Mitochondria are one of the most important targets to be affected in high blood cholesterol and glucose conditions. The protective role of sericin on mitochondria remains doubtful. To examine this role, electron microscopic, histopathologic, immunohistochemical, and biochemical studies were performed in a high-cholesterol diet/streptozotocin rat model. The results demonstrated that sericin reduced blood cholesterol without hypoglycemic effect. Sericin alleviated dysmorphic mitochondria in heart and liver but not in kidney and also decreased peculiar endoplasmic reticulum in the exocrine pancreas. In addition, sericin decreased hepatic steatosis and preserved zymogen granule referable to the decline of reactive oxygen species production in hepatic mitochondrial extraction and down-regulation of malondialdehyde expression in the liver and exocrine pancreas however irrelevant to lipase activity. This study suggests that sericin has antioxidative property to reduce blood cholesterol by means of diminishing fat deposit in hepatocyte and improves mitochondria and endoplasmic reticulum integrities. [Box: see text].

Zhen Qi Hypoglycemic Capsules (ZQHC) is a traditional Chinese herbal medicine containing medical activities by ougi (Astragalus membranaceus) and ousei (Polygonatum rhizome). Although ZQHC has been traditionally utilized as an anti-diabetic medicine in China, there is no evidence. Therefore, this study investigated the beneficial effects of ZQHC against diabetes using streptozotocin (STZ)-induced diabetic rats by biochemical and morphological methods. Eight-week old male Fisher strain rats were intraperitoneally injected with STZ (50 mg/kg of B.W.) to induce diabetes and were fed ad lib feeding with normal diet containing 4% ZQHC for 30 days. Blood and urine samples were collected for biochemical analysis, and liver and pancreas samples were prepared for morphological analysis. Values of blood glucose, AST and ALT of ZQHC oral administrated diabetic rats were lower than those of diabetic rats without administration. Morphological analysis revealed that ZQHC induced sustainment of insulin secreted β cells survival and suppression of hepatocellular fat droplet accumulation. These results suggested that oral administration of ZQHC has anti-diabetic activities those were mainly associated with improvement of liver metabolism.