Development Of Pancreatic Diseases Research Articles

Application and challenge of pancreatic organoids in therapeutic research

The in-vivo non-human primate animal and in-vitro cell disease models play a crucial part in the study of the mechanisms underlying the occurrence and development of pancreatic diseases, but with increasingly prominent limitations with in-depth research. Organoids derived from human pluripotent and adult stem cells resemble human in-vivo organs in their cellular composition, spatial tissue structure and physiological function, making them as an advantageous research tool. Up until now, numerous human organoids, including pancreas, have been effectively developed, demonstrating significant potential for research in organ development, disease modeling, drug screening, and regenerative medicine. However, different from intestine, liver and other organs, the pancreas is the only special organ in the human body, consisting of an exocrine gland and an endocrine gland. Thus, the development of pancreatic organoid technology faces greater challenges, and how to construct a composite pancreatic organoid with exocrine and endocrine gland is still difficult in current research. By reviewing the fundamental architecture and physiological role of the human pancreas, along with the swiftly developing domain of pancreatic organoids, we summarize the method and characteristics of human pancreatic organoids, and its application in modeling pancreatic diseases, as a platform for individualized drug screening and in regenerative medicine study. As the first comprehensive review that focus on the pharmacological study of human pancreatic organoid, the review hopes to help scholars to have a deeper understanding in the study of pancreatic organoid.

Development of pancreatic diseases during long-term follow-up of patients with acute pancreatitis in a prospective nationwide cohort

Development of pancreatic diseases during long-term follow-up of patients with acute pancreatitis in a prospective nationwide cohort

Piezo1 act as a potential oncogene in pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death. A growing number of studies believe that matrix stiffness plays an important role in the development of pancreatic disease. As one of the famous mechanically activated cation channels, Piezo1 has received more attention recently. Here we tried to describe the role of Piezo1 on PDAC progression. It seemed that Piezo1 was a potential tumor-promoting marker of pancreatic cancer. By using Yoda1, we measured the intracellular calcium flux mediated by Piezo1 which confirmed it did act as an intrinsic cation channel in pancreatic cancer cells. Additionally, we also found the inhibition of Piezo1 could inhibit cancer progression in vitro; however, Piezo1 activation (induced by Yoda1) had an oppositive effect. Moreover, Piezo1 activation may also accelerate pancreatic cancer tumor growth/formation via modulating pancreatic cancer cell-tumor microenvironment interactions in vivo. We concluded that Piezo1 acted as an oncogenic gene in pancreatic cancer progression. It might be one of promising targets for pancreatic cancer therapy.

Atypical Mucin Expression Predicts Worse Overall Survival in Resectable Pancreatic Ductal Adenocarcinoma.

Background Pancreatic ductal adenocarcinoma (PDAC) displays a typical mucin expression pattern which is characterized by MUC1 positive, MUC2 negative, and MUC5AC positive. More and more evidences show that mucins are involved in the development of pancreatic diseases. However, the relationship between mucin expression and prognosis of PDAC patients has been controversial in the past decades; therefore, we aim to figure out the association of mucin expression with survival in PDAC patients who underwent radical resection. Methods We performed immunohistochemistry (IHC) to detect the expression of MUC1, MUC2, and MUC5AC in resected PDAC specimens from Shanghai Cancer Center, Fudan University (FUSCC, n = 427) and obtained the corresponding clinical statistical data for retrospective study. Kaplan-Meier methods and Mantel-Cox tests were used to compare the survival curves, and the Cox regression model was employed for multivariate analyses to determine the independent risk factors. Survival analysis was also performed in the Queensland Centre for Medical Genomics (QCMG, n = 70) PDAC cohort to verify the conclusion. Results Both the FUSCC cohort and the QCMG cohort demonstrated that MUC1 absence was significantly correlated with worse overall survival (OS). The presence of MUC2 showed marginal significance in predicting shorter OS of PDAC patients, while MUC5AC had no prognostic value. In the FUSCC cohort, MUC1 absence was associated with increased proportion of stage III PDAC (p = 0.011), and MUC1 absence and MUC2 presence were associated with tumour perineural aggression (p = 0.011 and p = 0.030, respectively). Multivariable adjusted hazard ratios (HRs) for mortality of MUC1 and MUC2 were 0.492 (95% CI: 0.274-0.883, p = 0.017) and 1.596 (95% CI: 1.061-2.401, p = 0.025), respectively. Conclusions MUC1 absence or MUC2 presence is independently associated with poor OS among patients with resectable PDAC. MUC5AC absence tended to be associated with short-term death.

Gut microbiota in pancreatic diseases: possible new therapeutic strategies.

Pancreatic diseases such as pancreatitis, type 1 diabetes and pancreatic cancer impose substantial health-care costs and contribute to marked morbidity and mortality. Recent studies have suggested a link between gut microbiota dysbiosis and pancreatic diseases; however, the potential roles and mechanisms of action of gut microbiota in pancreatic diseases remain to be fully elucidated. In this review, we summarize the evidence that supports relationship between alterations of gut microbiota and development of pancreatic diseases, and discuss the potential molecular mechanisms of gut microbiota dysbiosis in the pathogenesis of pancreatic diseases. We also propose current strategies toward gut microbiota to advance a developing research field that has clinical potential to reduce the cost of pancreatic diseases.

Research updates on recurrent pancreatitis

Recurrent pancreatitis (RP) can be further divided into two items, including recurrent acute pancreatitis (RAP) and recurrent chronic pancreatitis (RCP). In recent years, with the rising incidence of pancreatitis, the incidence of RP has also been increased. During the development of pancreatic diseases, RP may serve as a transitional disease. Thus, this article reviewed the latest research progress on RP in order to discuss its role in the development of the related pancreatic di-seases and the effects on clinical prognosis, and provide a refe-rence for preventing and treating RP and even cancer. Key words: Recurrent pancreatitis; Recurrent acute pancreatitis; Recurrent chronic pancreatitis; Pancreatic cancer

Retinoids in the pancreas.

Retinoids (vitamin A and its natural and synthetic analogs) are required by most tissues for maintaining the normal health of the tissue. This is certainly true for the pancreas. The recent literature is convincing that retinoids are needed by the adult to assure normal pancreatic endocrine functions, especially those of the α- and β-cells. It is also well established that retinoids are required to insure normal pancreas development in utero, including the development of the endocrine pancreas. The actions of retinoids for maintaining normal pancreatic islet functions has drawn considerable research interest from investigators interested in understanding and treating metabolic disease. Pancreatic retinoids are also of interest to investigators studying the origins of pancreatic disease, including the development of pancreatic fibrosis and its sequelae. This research interest is focused on pancreatic stellate cells (PSCs) which store retinoids and possess the metabolic machinery needed to metabolize retinoids. The literature on pancreatic disease and retinoids suggests that there is an association between impairments in pancreatic retinoid storage and metabolism and the development of pancreatic disease. These topics will be considered in this review.

Pancreatic oncogenic signaling cascades converge at Protein Kinase D1

Pancreatic oncogenic signaling cascades converge at Protein Kinase D1

MiR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro

ObjectivesActivated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic diseases, especially chronic pancreatitis and pancreatic cancer. MicroRNAs have become a focal point of interest as post-transcriptional regulators of gene expression via their interaction with the 3′ untranslated region of target mRNAs, which results in gene silencing. We examined the relative expression of microRNAs (miR-15b and miR-16) and their target gene, Bcl-2, during activation of rat PSCs, and determined their effects on apoptosis of rat PSCs in vitro. MethodsmiR-15b and miR-16 expression levels were analyzed in quiescent and activated PSCs by stem-loop RT-PCR. In addition, the effects of miR-15b and miR-16 on apoptosis of activated PSCs were investigated by immunofluorescence microscopy with Hoechst 33342 staining, and flow cytometry with annexin-V/propidium (PI) co-labeling. Bcl-2 and Bcl-xl were also analyzed by real-time RT-PCR and Western blotting. ResultsDuring activation of PSCs, from the quiescent stage to activated stage, miR-15b and miR_16 were downregulated, while Bcl-2 expression was upregulated. Restoring intracellular miRNA levels by miR-15b and miR-16 administration greatly reduced Bcl-2 protein levels, and significantly induced apoptosis in activated PSCs. ConclusionsmiR-15b and miR-16 could induce apoptosis of rat PSCs by targeting Bcl-2.

Pancreatic stellate cell models for transcriptional studies of desmoplasia-associated genes.

Pancreatic stellate cells are emerging as key players in pathophysiopathological processes underlying the development of pancreatic disease, including pancreatitis and cancer. The cells are scarce in the pancreas making their isolation time and resource use consuming. Therefore, with the ultimate goal of facilitating mechanistic studies, here we report the isolation, characterization, and immortalization of stellate cell lines from rat and mouse origin. These cell lines display morphological and molecular markers as well as non-tumorigenic characteristics similar to the frequently used hepatic counterparts. In addition, we have tested their robustness as a model for transcriptional regulatory studies. We find that these cells respond well to TGFβ signaling by triggering a distinct cascade of gene expression, some genes overlap with the TGFβ response of LX2 cells. These cells express several key chromatin proteins and epigenetic regulators involved in the regulation of gene expression, including co-repressors such as Sin3A (short-term repression), HP1 (long-term repression), as well as CBP/p300 (activation). Furthermore, these cells are well suited for Gal4-based transcriptional activation and repression assays. The cell model reported here may therefore help fuel investigations in the field of signaling, transcription, and perhaps other studies on similarly exciting cellular processes. and IAP.

Differentiation Potential of Pancreatic Fibroblastoid Cells/Stellate Cells: Effects of Peroxisome Proliferator-Activated Receptor Gamma Ligands

Pancreatic stellate cells have been investigated mostly for their activation process, supposed to support the development of pancreatic disease. Few studies have been presented on reversal of the activation process in vitro. Thiazolidinediones (TZDs) have been used as antidiabetics and have now been reported to exert antifibrotic activity. We tested effects of natural and synthetic ligands of peroxisome proliferator-activated receptor gamma (PPARγ) on human pancreatic fibroblastoid cells (hPFCs) in search for specificity of action. Ciglitazone, as a prototype of TZDs, was shown to have reversible growth inhibitory effects on human pancreatic fibroblastoid cells/stellate cells. Cells treated with ciglitazone for three days showed enhanced lipid content and induction of proteins involved in lipid metabolism. Collagen synthesis was reduced in hPFC. Interaction of PPARγ with DNA binding sites upon ligand binding was shown by gel shift analysis. These findings point toward a potential for adipocyte differentiation in human pancreatic fibroblastoid cells.

Pathophysiological effects of nicotine on the pancreas: an update.

Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic diseases. It is well recognized that nicotine, a major component in cigarette smoke, is an addictive agent and, therefore, reinforces smoking behavior. The current review update focuses on the genetics of nicotine dependence and its role on the development of pancreatic diseases. The role of smoking and nicotine in pancreatitis and pancreatic cancer development is also discussed. Exposure of laboratory animals to nicotine clearly supports the notion that nicotine can induce pancreatic injury. The mechanism by which nicotine induces such effects is perhaps mediated via signal transduction pathways in the pancreatic acinar cell, leading to enhanced levels of intracellular calcium release, resulting in cytotoxicity and eventual cell death. The induction of pancreatic injury by nicotine may also involve activation and expression of protooncogene, H-ras, which can increase cytosolic calcium via second messenger pathways. Development of pancreatic carcinoma in cigarette smokers as observed in human populations may be the result of activation and mutation of the H-ras gene. A possible pathogenetic mechanism of nicotine in the pancreas activating multiple signal transduction pathways is schematically summarized in Figure 1.

TGFβ1 autocrine growth control in isolated pancreatic fibroblastoid cells/stellate cells in vitro

TGFβ1 is a multifunctional factor, controlling cellular growth and extracellular matrix production. Deletion of the TGFβ1 gene in mice results in multiple inflammatory reactions. Targeted overexpression of TGFβ1 in pancreatic islet cells leads to fibrosis of the exocrine pancreas in transgenic mice. In pancreatic fibrosis interstitial fibroblasts are primary candidates for production and deposition of extracellular matrix. Still, little is known about regulation of these cells during development of pancreatic disease. We established primary cell lines of pancreatic fibroblastoid/stellate cells (PFC) from rat pancreas. Investigation of rPFCs in vitro shows TGFβ1 expression by RT-PCR analysis. Mature TGFβ1 was detected in culture supernatants by immunoassay. Rat PFCs in culture possess both receptors TGFβ receptor type I, and type II, necessary for TGFβ1 signal transduction. Inhibition of TGFβ1 activity by means of neutralizing antibodies interferes with an autocrine loop and results in a 2-fold stimulation of cell growth. So far, pancreatic fibroblastoid/stellate cells in vitro were known as a target of TGFβ1 action, but not as a source of TGFβ1. Our data indicate TGFβ1 activity in rat pancreas extends beyond regulation of matrix production, but appears to be important in growth control of pancreatic fibroblastoid cells.