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BioRxiv : the Preprint Server For... May 2024SARS-CoV-2 targets salivary glands potentially impacting oral health. We show that presence of replicating viruses in the acinar cells of salivary glands compromises...
SARS-CoV-2 targets salivary glands potentially impacting oral health. We show that presence of replicating viruses in the acinar cells of salivary glands compromises production and secretion of histatin-5, a key host-produced antifungal peptide. The salivary levels of histatin-5 were significantly reduced in SARS-CoV-2 infected subjects, concomitant with enhanced prevalence of the fungal opportunistic pathogen Candida albicans. These findings provide direct evidence associating SARS-CoV-2 infection with predisposition to oral candidiasis.
PubMed: 38798323
DOI: 10.1101/2024.05.13.593942 -
Cancers May 2024We conducted a pilot study to analyze the differential methylation status of 20 primary acinar adenocarcinomas of the lungs. These adenocarcinomas had to be wild type in...
We conducted a pilot study to analyze the differential methylation status of 20 primary acinar adenocarcinomas of the lungs. These adenocarcinomas had to be wild type in mutation analysis and had either high (TPS > 50%; = 10) or negative (TPS < 1%; = 10) PD-L1 status to be integrated into our study. To examine the methylation of 866,895 specific sites, we utilized the Illumina Infinium EPIC bead chip array. Both hypermethylation and hypomethylation play significant roles in tumor development, progression, and metastasis. They also impact the formation of the tumor microenvironment, which plays a decisive role in tumor differentiation, epigenetics, dissemination, and immune evasion. The gained methylation patterns were correlated with PD-L1 expression. Our analysis has identified distinct methylation patterns in lung adenocarcinomas with high and negative PD-L1 expression. After analyzing the correlation between the methylation results of genes and promoters with their pathobiology, we found that tumors with high expression of PD-L1 tend to exhibit oncogenic effects through hypermethylation. On the other hand, tumors with negative PD-L1 expression show loss of their suppressor functions through hypomethylation. The suppressor functions of hypermethylated genes and promoters are ineffective compared to simultaneously activated dominant oncogenic mechanisms. The tumor microenvironment supports tumor growth in both groups.
PubMed: 38791918
DOI: 10.3390/cancers16101841 -
Current Issues in Molecular Biology May 2024Acute pancreatitis (AP) is characterized by elevated intracellular Ca concentrations, mitochondrial dysfunction, and oxidative stress in pancreatic acinar cells. Algal...
Acute pancreatitis (AP) is characterized by elevated intracellular Ca concentrations, mitochondrial dysfunction, and oxidative stress in pancreatic acinar cells. Algal oil (AO) has demonstrated antioxidant and anti-inflammatory properties. This study aims to explore the effects of algal oil on the microenvironment of AP. Rat pancreatic acinar AR42J cells were pretreated with AO containing 0, 50, 100, or 150 μM of docosahexaenoic acid (DHA) 2 h prior to AP induction using sodium taurocholate (STC). After 1 h of STC treatment, AR42J cells exhibited a significant increase in intracellular Ca concentration and the production of amylase, lipase, reactive oxygen species, and pro-inflammatory mediators, including tumor necrosis factor-α and interleukin-6. These STC-induced increases were markedly reduced in cells pretreated with AO. In comparison to cells without AO, those treated with a high dose of AO before STC exposure demonstrated a significant increase in mitochondrial membrane potential and a decrease in lipid peroxidation. Furthermore, STC-activated nuclear factor kappa-B (NF-κB) was attenuated in AO-pretreated cells, as evidenced by a significant decrease in activated NF-κB. In conclusion, AO may prevent damage to pancreatic acinar cells by alleviating intracellular Ca overload, mitigating mitochondrial dysfunction, reducing oxidative stress, and attenuating NF-κB-targeted inflammation.
PubMed: 38785535
DOI: 10.3390/cimb46050267 -
JCI Insight May 2024Acute Pancreatitis (AP) is among the most common hospital gastrointestinal diagnosis; understanding the mechanisms underlying the severity of AP are critical for...
Acute Pancreatitis (AP) is among the most common hospital gastrointestinal diagnosis; understanding the mechanisms underlying the severity of AP are critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in two independent genetically engineered mouse models of AP. PFKFB3 is elevated in AP and severe AP (SAP) and knockout of Pfkfb3 abrogates the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies we define the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this dismal condition.
PubMed: 38781030
DOI: 10.1172/jci.insight.169481 -
Modern Pathology : An Official Journal... May 2024The new grading system for lung adenocarcinoma (ADC) proposed by the International Association for the Study of Lung Cancer (IASLC) defines prognostic subgroups based on...
The new grading system for lung adenocarcinoma (ADC) proposed by the International Association for the Study of Lung Cancer (IASLC) defines prognostic subgroups based on histologic patterns observed on surgical specimens. This study seeks to provide novel insights into the IASLC grading system, with a particular focus on recurrence-specific survival (RSS) and lung cancer-specific survival (LCSS) among patients with stage I ADC. Under the IASLC grading system, tumors were classified as grade 1 (lepidic predominant with <20% high-grade patterns [micropapillary, solid, complex glandular]), grade 2 (acinar or papillary predominant with <20% high-grade patterns), or grade 3 (≥20% high-grade patterns). Kaplan-Meier survival estimates, pathologic features, and genomic profiles were investigated for patients whose disease was reclassified to a higher grade under the IASLC grading system on the basis of the hypothesis that they would strongly resemble patients with predominant high-grade tumors. Overall, 423 of 1443 patients (29%) with grade 1 or 2 tumors by the predominant pattern-based grading system had their tumors upgraded to grade 3 by the IASLC grading system. The RSS curves for patients with upgraded tumors were significantly different from those for patients with grade 1 or 2 tumors (log-rank p<0.001) but not from those for patients with predominant high-grade patterns (p=0.3). Patients with upgraded tumors had a similar incidence of visceral pleural invasion and spread of tumor through air spaces as patients with predominant high-grade patterns. In multivariable models, the IASLC grading system remained significantly associated with RSS and LCSS after adjustment for aggressive pathologic features such as visceral pleural invasion and spread of tumor through air spaces. The IASLC grading system outperforms the predominant pattern-based grading system and appropriately reclassifies tumors into higher grades with worse prognosis, even after other pathologic features of aggressiveness are considered.
PubMed: 38777035
DOI: 10.1016/j.modpat.2024.100520 -
Investigative Ophthalmology & Visual... May 2024Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4...
PURPOSE
Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4 mRNA levels have been observed in experimental dry eye and during pregnancy, the impact of AQP4 in LG ductal fluid production remains unclear. In our recent work, the role of AQP4 in LG ductal fluid secretion was investigated utilizing wild type (WT) and AQP4 knock out (KO) mice.
METHODS
Tear production was assessed in both WT and KO animals. Immunostaining was used to identify AQP4 protein. Duct segments were harvested from LGs of WT and KO mice. Fluid secretion and filtration permeability (Pf) were quantified using video-microscopy. Ductal tear production, elicited by a cell-permeable cAMP analogue (8-bromo cAMP), carbachol, vasoactive intestinal peptide (VIP), and phenylephrine (PHE), were assessed in both WT and KO ducts.
RESULTS
A higher expression of AQP4 protein was noted in the duct cells from WT mice when compared to acinar cells. Pf did not show notable alterations between WT and AQP4 KO ducts. Carbachol elicited comparable secretory responses in ducts from both WT and KO animals. However, 8-bromo cAMP, VIP, and PHE stimulation resulted in decreased secretion in ducts from AQP4 KO LGs.
CONCLUSIONS
Our findings underscore the functional relevance of AQP4 in the fluid production of mouse LG ducts. AQP4 seems to play different roles in fluid secretions elicited by different secretagogues. Specifically, cAMP-mediated, and adrenergic agonist-related secretions were reduced in AQP4 KO ducts.
Topics: Animals; Mice; Lacrimal Apparatus; Tears; Mice, Knockout; Aquaporin 4; Mice, Inbred C57BL; Female
PubMed: 38771571
DOI: 10.1167/iovs.65.5.30 -
EGastroenterology Apr 2024Acute pancreatitis is a common inflammatory gastrointestinal disease without any successful treatment. Pancreatic exocrine acinar cells have high rates of protein...
Acute pancreatitis is a common inflammatory gastrointestinal disease without any successful treatment. Pancreatic exocrine acinar cells have high rates of protein synthesis to produce and secrete large amounts of digestive enzymes. When the regulation of organelle and protein homeostasis is disrupted, it can lead to endoplasmic reticulum (ER) stress, damage to the mitochondria and improper intracellular trypsinogen activation, ultimately resulting in acinar cell damage and the onset of pancreatitis. To balance the homeostasis of organelles and adapt to protect themselves from organelle stress, cells use protective mechanisms such as autophagy. In the mouse pancreas, defective basal autophagy disrupts ER homoeostasis, leading to ER stress and trypsinogen activation, resulting in spontaneous pancreatitis. In this review, we discuss the regulation of autophagy and its physiological role in maintaining acinar cell homeostasis and function. We also summarise the current understanding of the mechanisms and the role of defective autophagy at multiple stages in experimental pancreatitis induced by cerulein or alcohol.
PubMed: 38770349
DOI: 10.1136/egastro-2023-100057 -
Frontiers in Immunology 2024This study aimed to analyze active compounds and signaling pathways of CH applying network pharmacology methods, and to additionally verify the molecular mechanism of CH...
Material basis and molecular mechanisms of Chaihuang Qingyi Huoxue Granule in the treatment of acute pancreatitis based on network pharmacology and molecular docking-based strategy.
OBJECTIVES
This study aimed to analyze active compounds and signaling pathways of CH applying network pharmacology methods, and to additionally verify the molecular mechanism of CH in treating AP.
MATERIALS AND METHODS
Network pharmacology and molecular docking were firstly used to identify the active components of CH and its potential targets in the treatment of AP. The pancreaticobiliary duct was retrogradely injected with sodium taurocholate (3.5%) to create an acute pancreatitis (AP) model in rats. Histological examination, enzyme-linked immunosorbent assay, Western blot and TUNEL staining were used to determine the pathway and mechanism of action of CH in AP.
RESULTS
Network pharmacological analysis identified 168 active compounds and 276 target proteins. In addition, there were 2060 targets associated with AP, and CH had 177 targets in common with AP. These shared targets, including STAT3, IL6, MYC, CDKN1A, AKT1, MAPK1, MAPK3, MAPK14, HSP90AA1, HIF1A, ESR1, TP53, FOS, and RELA, were recognized as core targets. Furthermore, we filtered out 5252 entries from the Gene Ontology(GO) and 186 signaling pathways from the Kyoto Encyclopedia of Genes and Genomes(KEGG). Enrichment and network analyses of protein-protein interactions predicted that CH significantly affected the PI3K/AKT signaling pathway, which played a critical role in programmed cell death. The core components and key targets showed strong binding activity based on molecular docking results. Subsequently, experimental validation demonstrated that CH inhibited the phosphorylation of PI3K and AKT in pancreatic tissues, promoted the apoptosis of pancreatic acinar cells, and further alleviated inflammation and histopathological damage to the pancreas in AP rats.
CONCLUSION
Apoptosis of pancreatic acinar cells can be enhanced and the inflammatory response can be reduced through the modulation of the PI3K/AKT signaling pathway, resulting in the amelioration of pancreatic disease.
Topics: Animals; Molecular Docking Simulation; Pancreatitis; Drugs, Chinese Herbal; Rats; Network Pharmacology; Signal Transduction; Male; Disease Models, Animal; Apoptosis; Rats, Sprague-Dawley; Protein Interaction Maps
PubMed: 38765004
DOI: 10.3389/fimmu.2024.1353695 -
International Journal of Molecular... Apr 2024Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic mutations are transdifferentiated to...
Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic mutations are transdifferentiated to a duct-like phenotype that further progresses to become pancreatic intraepithelial neoplasia (PanIN) lesions, giving rise to PDAC. Although ADM formation is frequently observed in Kras transgenic mouse models of PDAC, the exact mechanisms of how oncogenic Kras regulates this process remain an enigma. Herein, we revealed a new downstream target of oncogenic Kras, cytokine CCL9, during ADM formation. Higher levels of CCL9 and its receptors, CCR1 and CCR3, were detected in ADM regions of the pancreas in p48:Kras mice and human PDAC patients. Knockdown of CCL9 in Kras-expressed pancreatic acini reduced Kras-induced ADM in a 3D organoid culture system. Moreover, exogenously added recombinant CCL9 and overexpression of CCL9 in primary pancreatic acini induced pancreatic ADM. We also showed that, functioning as a downstream target of Kras, CCL9 promoted pancreatic ADM through upregulation of the intracellular levels of reactive oxygen species (ROS) and metalloproteinases (MMPs), including MMP14, MMP3 and MMP2. Blockade of MMPs via its generic inhibitor GM6001 or knockdown of specific MMP such as MMP14 and MMP3 decreased CCL9-induced pancreatic ADM. In p48:Kras transgenic mice, blockade of CCL9 through its specific neutralizing antibody attenuated pancreatic ADM structures and PanIN lesion formation. Furthermore, it also diminished infiltrating macrophages and expression of MMP14, MMP3 and MMP2 in the ADM areas. Altogether, our results provide novel mechanistic insight into how oncogenic Kras enhances pancreatic ADM through its new downstream target molecule, CCL9, to initiate PDAC.
Topics: Animals; Proto-Oncogene Proteins p21(ras); Mice; Reactive Oxygen Species; Humans; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Metaplasia; Acinar Cells; Mice, Transgenic; Chemokines, CC; Macrophage Inflammatory Proteins; Pancreas
PubMed: 38731942
DOI: 10.3390/ijms25094726 -
Gastroenterology May 2024Acinar to ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the induction and resolution of...
BACKGROUND AND AIMS
Acinar to ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human.
METHODS
We identified Sox4 among the top upregulated genes. We validated the analysis by RNA in situ hybridization (ISH). We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26; Sox4 ) with and without an activating mutation in Kras (Kras). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization and single cell RNA sequencing.
RESULTS
We demonstrated that Sox4 is reactivated in ADM and PanINs. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression.
CONCLUSIONS
Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of PDAC.
PubMed: 38729450
DOI: 10.1053/j.gastro.2024.04.031