-
British Journal of Pharmacology Sep 2021Pyroptosis is a lytic form of pro-inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation....
BACKGROUND AND PURPOSE
Pyroptosis is a lytic form of pro-inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in AP.
EXPERIMENTAL APPROACH
Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo was investigated. Effects of pharmacological (NLRP3 and caspase-1 inhibitors), constitutive (Nlrp3 , Casp1 and Gsdmd ) and acinar cell conditional (Pdx1 Nlrp3 and Pdx1 Gsdmd ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate and l-arginine). Effects of Pdx1 Gsdmd versus myeloid conditional knockout (Lyz2 Gsdmd ) and Gsdmd versus receptor-interacting protein 3 (RIP3) inhibitor were compared in CER-AP.
KEY RESULTS
There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo, which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1 Gsdmd but not Lyz2 Gsdmd mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein-AP. Co-application of RIP3 inhibitor on Gsdmd mice further increased protection on caerulein-AP.
CONCLUSION AND IMPLICATIONS
This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation-mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy.
Topics: Acinar Cells; Acute Disease; Animals; Inflammasomes; Inflammation; Intracellular Signaling Peptides and Proteins; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis; Phosphate-Binding Proteins; Pyroptosis
PubMed: 33871879
DOI: 10.1111/bph.15499 -
Visceral Medicine Feb 2022Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has no effective early detection method or treatment to date. (Review)
Review
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has no effective early detection method or treatment to date.
SUMMARY
The normal cell type that initiates PDAC, or its cellular origin, is still unknown. To investigate the contribution of distinct normal epithelial cell types to PDAC tumorigenesis, genetically engineered mouse models were used to show that both acinar and ductal cells are capable of giving rise to PDAC. These studies indicated that genetic mutations and pancreatic injury interact differently with each cellular origin to affect their predilection and process for forming PDAC. In this review, we summarize recent findings using various genetically engineered mouse models in the identification and characterization of the PDAC cell of origin. We also discuss potential implications for cellular origin on tumor development, PDAC transcriptional subtype, and disease prognosis of patients.
KEY MESSAGE
Although it is clear that both ductal and acinar cells have the potential to form PDAC, whether cellular origin can indeed influence patient prognosis and whether knowledge of cellular origin will aid in the diagnosis or treatment of patients in the future will need further study.
PubMed: 35295896
DOI: 10.1159/000520946 -
Gastroenterology Oct 2022Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the...
BACKGROUND & AIMS
Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized.
METHODS
Tandem mass tag-based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 μg/mL) for the mechanistic studies.
RESULTS
A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P < .001) and attenuated unfolded protein response (P < .04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers.
CONCLUSIONS
The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis.
Topics: Acetaldehyde; Acute Disease; Aldehydes; Animals; Ceruletide; Cyclin-Dependent Kinases; Ethanol; Extracellular Matrix Proteins; Malondialdehyde; Mice; Pancreatitis, Chronic; Proteome; Proteomics; Smoking; Unfolded Protein Response
PubMed: 35788346
DOI: 10.1053/j.gastro.2022.06.071 -
Scientific Reports Apr 2023In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia...
In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia (ADM), and intraepithelial neoplasia (PanIN), a precancerous lesion. The mechanisms underlying these changes remain unclear. The presence of enterovirus (EV) encoded-capsid protein 1 (VP1) and -2A protease (2A) and the innate immune responses of the pancreas were studied using immunohistochemistry and in situ hybridization in 12 SPIDDM and 19 non-diabetic control pancreases. VP1, 2A, and EV-RNA were detected in islets and the exocrine pancreas in all SPIDDM pancreases. Innate immune receptor, melanoma differentiation-associated gene 5 (MDA5), and interferon (IFN)-beta1 were intensified in the islets of SPIDDM patients with short disease duration. However, expressions of MDA5 and IFN-beta1were suppressed in those with longer disease duration. CD3 T cell infiltration was observed in the VP1- and insulin-positive islets (insulitis) and exocrine acinar cells. CD11c dendritic cells (DCs) in islets were scarce in long-term SPIDDM. This study showed the consistent presence of EV, suggesting an association with inflammatory changes in the endocrine and exocrine pancreas in SPIDDM. Suppressed expressions of MDA5 and IFN-beta1, as well as decreased numbers of DCs in the host cells, may contribute to persistent EV infection and induction of ADM/PanIN lesions, which may potentially provide a scaffold for pancreatic neoplasms.
Topics: Humans; Enterovirus; Diabetes Mellitus, Type 1; Pancreas; Enterovirus Infections; Pancreas, Exocrine; Antigens, Viral; Islets of Langerhans
PubMed: 37117225
DOI: 10.1038/s41598-023-33011-7 -
PeerJ 2023With the number of patients with acute pancreatitis (AP) increasing year by year, it is pressing to explore new key genes and markers for the treatment of AP....
OBJECTIVE
With the number of patients with acute pancreatitis (AP) increasing year by year, it is pressing to explore new key genes and markers for the treatment of AP. miR-455-3p/solute carrier family 2 member 1 (Slc2a1) obtained through bioinformatics analysis may participate in the progression of AP.
MATERIALS AND METHODS
The C57BL/6 mouse model of AP was constructed for subsequent studies. Through bioinformatics analysis, the differentially expressed genes related to AP were screened and hub genes were identified. A caerulein-induced AP animal model was constructed to detect the pathological changes of mouse pancreas by HE staining. The concentrations of amylase and lipase were measured. Primary mouse pancreatic acinar cells were isolated and subjected to microscopy to observe their morphology. The enzymatic activities of trypsin and amylase were detected. The secretion of inflammatory cytokines in mouse were measured with the ELISA kits of TNF-, IL-6 and IL-1 to determine pancreatic acinar cell damage. A binding site between the Slc2a1 3' UTR region and the miR-455-3p sequence was verified by dual-luciferase reporter assay. The expression of miR-455-3p was quantified by qRT-PCR, and Slc2a1 were detected by western blot.
RESULTS
A total of five (Fyn, Gadd45a, Sdc1, Slc2a1, and Src) were identified by bioinformatics analysis, and miR-455-3p/Slc2a1 were further studied. HE staining results showed that the AP models were successfully established by caerulein induction. In mice with AP, the expression of miR-455-3p was reduced, while that of Slc2a1 was increased. In the caerulein-induced cell model, the expression of Slc2a1 was significantly reduced after intervention of miR-455-3p mimics, whereas increased after miR-455-3p inhibitor treatment. miR-455-3p decreased the secretion of inflammatory cytokines in the cell supernatant, reduced the activity of trypsin and amylase, and alleviated the cell damage induced by caerulein. In addition, Slc2a1 3'UTR region was bound by miR-455-3p, and its protein expression was also regulated.
CONCLUSION
miR-455-3p alleviated caerulein-induced mouse pancreatic acinar cell damage by regulating the expression of Slc2a1.
Topics: Animals; Mice; Acinar Cells; Acute Disease; Amylases; Ceruletide; Cytokines; Mice, Inbred C57BL; MicroRNAs; Pancreatitis; Trypsin
PubMed: 37404474
DOI: 10.7717/peerj.15612 -
Cancers Feb 2022Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for -mediated lung cancer initiation and progression....
Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for -mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and -mediated pancreatic cancer development. Knockout of pancreatic significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. -ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic promoted -mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.
PubMed: 35159064
DOI: 10.3390/cancers14030796 -
BioRxiv : the Preprint Server For... Nov 2023Activating mutations in extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these...
Activating mutations in extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.
PubMed: 37986898
DOI: 10.1101/2023.11.06.565895 -
Journal of Dental Research Jul 2022Current treatments for xerostomia/dry mouth are palliative and largely ineffective. A permanent clinical resolution is being developed to correct hyposalivation using...
Current treatments for xerostomia/dry mouth are palliative and largely ineffective. A permanent clinical resolution is being developed to correct hyposalivation using implanted hydrogel-encapsulated salivary human stem/progenitor cells (hS/PCs) to restore functional salivary components and increase salivary flow. Pluripotent epithelial cell populations derived from hS/PCs, representing a basal stem cell population in tissue, can differentiate along either secretory acinar or fluid-transporting ductal lineages. To develop tissue-engineered salivary gland replacement tissues, it is critical to reliably identify cells in tissue and as they enter these alternative lineages. The secreted protein α-amylase, the transcription factor MIST1, and aquaporin-5 are typical markers for acinar cells, and K19 is the classical ductal marker in salivary tissue. We found that early ductal progenitors derived from hS/PCs do not express K19, and thus earlier markers were needed to distinguish these cells from acinar progenitors. Salivary ductal cells express distinct polarity complex proteins that we hypothesized could serve as lineage biomarkers to distinguish ductal cells from acinar cells in differentiating hS/PC populations. Based on our studies of primary salivary tissue, both parotid and submandibular glands, and differentiating hS/PCs, we conclude that the apical marker MUC1 along with the polarity markers INADL/PATJ and SCRIB reliably can identify ductal cells in salivary glands and in ductal progenitor populations of hS/PCs being used for salivary tissue engineering. Other markers of epithelial maturation, including E-cadherin, ZO-1, and partition complex component PAR3, are present in both ductal and acinar cells, where they can serve as general markers of differentiation but not lineage markers.
Topics: Acinar Cells; Biomarkers; Cell Differentiation; Cells, Cultured; Epithelial Cells; Humans; Membrane Proteins; Mucin-1; Salivary Glands; Tight Junction Proteins; Tumor Suppressor Proteins; Xerostomia
PubMed: 35259994
DOI: 10.1177/00220345221076122 -
Experimental Biology and Medicine... Dec 2021The pancreatic β cells can synthesize dopamine by taking L-dihydroxyphenylalanine, but whether pancreatic acinar cells synthesize dopamine has not been confirmed. By...
The pancreatic β cells can synthesize dopamine by taking L-dihydroxyphenylalanine, but whether pancreatic acinar cells synthesize dopamine has not been confirmed. By means of immunofluorescence, the tyrosine hydroxylase -immunoreactivity and aromatic amino acid decarboxylase (AADC)- immunoreactivity were respectively observed in pancreatic acinar cells and islet β cells. Treatment with L-dihydroxyphenylalanine, not tyrosine, caused the production of dopamine in the incubation of INS-1 cells (rat islet β cell line) and primary isolated islets, which was blocked by AADC inhibitor NSD-1015. However, only L-dihydroxyphenylalanine, but not dopamine, was detected when AR42J cells (rat pancreatic acinar cell line) were treated with tyrosine, which was blocked by tyrosine hydroxylase inhibitor AMPT. Dopamine was detected in the coculture of INS-1 cells with AR42J cells after treatment with tyrosine. In an study, pancreatic juice contained high levels of L-dihydroxyphenylalanine and dopamine. Both L-dihydroxyphenylalanine and dopamine accompanied with pancreatic enzymes and insulin in the pancreatic juice were all significantly increased after intraperitoneal injection of bethanechol chloride and their increases were all blocked by atropine. Inhibiting TH with AMPT blocked bethanechol chloride-induced increases in L-dihydroxyphenylalanine and dopamine, while inhibiting AADC with NSD-1015 only blocked the dopamine increase. Bilateral subdiaphragmatic vagotomy of rats leads to significant decreases of L-dihydroxyphenylalanine and dopamine in pancreatic juice. These results suggested that pancreatic acinar cells could utilize tyrosine to synthesize L-dihydroxyphenylalanine, not dopamine. Islet β cells only used L-dihydroxyphenylalanine, not tyrosine, to synthesize dopamine. Both L-dihydroxyphenylalanine and dopamine were respectively released into the pancreatic duct, which was regulated by the vagal cholinergic pathway. The present study provides important evidences for the source of L-dihydroxyphenylalanine and dopamine in the pancreas.
Topics: Acinar Cells; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Aromatic-L-Amino-Acid Decarboxylases; Atropine; Bethanechol; Cell Line; Dihydroxyphenylalanine; Dopamine; Hydrazines; Islets of Langerhans; Rats; Rats, Sprague-Dawley; Tyrosine; Tyrosine 3-Monooxygenase
PubMed: 34313482
DOI: 10.1177/15353702211032552 -
Trends in Molecular Medicine Aug 2020The bulk of the pancreas primarily comprises long-lived acinar cells that are not considered a bona fide source for stem cells. However, certain acinar subpopulations... (Review)
Review
The bulk of the pancreas primarily comprises long-lived acinar cells that are not considered a bona fide source for stem cells. However, certain acinar subpopulations have a repopulating capacity during regeneration, raising the hypothesis as to the presence of regenerative progenitor-like populations in the adult pancreas. Here, we describe recent discoveries based on fate-mapping techniques that support the existence of progenitor-like acinar subpopulations, including active progenitor-like cells that maintain tissue homeostasis and facultative progenitor-like cells that drive tissue regeneration. A possible link between progenitor-like acinar cells and cancer initiators is proposed. Further analysis of these cellular components is needed, because it would help uncover possible cellular sources for regeneration and cancer, as well as potential targets for therapy.
Topics: Acinar Cells; Animals; Homeostasis; Humans; Neoplasms; Pancreas, Exocrine; Regeneration; Stem Cells
PubMed: 32362534
DOI: 10.1016/j.molmed.2020.04.003