Da ChaiHu decoction (DCHD) is used in Chinese medicine to treat pancreatic cancer (PC), but its exact mechanism is not known. The aim of this study was to investigate the main active ingredients and specific mechanisms of DCHD against PC. Firstly, the active ingredients and targets of DCHD and PC-related targets were searched from the TCMSP, DrugBank, NCBI and GeneCards databases, respectively. The intersected targets of both were then taken to construct a PPI network using STRING, and this network was visualized by Cytoscape 3.8.2. GO and KEGG enrichment analyses of the intersected targets were performed using R 4.2.1 "clusterProfiler", "enrichplot", and "ggplot2" packages. Molecular docking was performed utilizing MOE software to detect the binding capacity between compounds and targets. Cell proliferation, apoptosis, invasion and migration were examined through a CCK8 kit, Muse® Cell Analyzer, transwell and wound healing experiment, respectively. The expression levels of five core targets were assessed by RT-qPCR in PANC-1 cells treated with stigmasterol. Molecular dynamic simulations analysis was conducted to analyze the binding affinities and modes of interaction between molecules and stigmasterol using the GROMACS 5.1.4 program package. In this study, 141 common targets of DCHD and PC were obtained. GO-MF items indicated that DCHD exerts its effects on PC primarily by influencing the binding activity of DNA-binding transcription factors. The KEGG analysis revealed that these genes were implicated in various signaling pathways, including the IL-17 signaling pathway and the PI3K/Akt signaling pathway. Stigmasterol was chosen as the final ingredient for subsequent investigation due to its derivation from herb (Da ChaiHu), its encompassment of more common targets, and the scarcity of existing research on its role in PC. The results of molecular docking and Molecular dynamic simulations analysis showed that stigmasterol had good binding activity with BCL2, and ICAM1. In vitro experiments suggested that stigmasterol could effectively inhibit the proliferation, invasion and migration of PANC-1 cells, and promote cell apoptosis. Moreover, stigmasterol treatment led to the reduced expression of AKT1, HIF1A, BCL2, IL1B, and ICAM1. This study is the first to reveal the main active components and potential mechanisms of DCHD against PC, which provides a theoretical basis for studying the role of DCHD in the treatment of PC. Especially, the anti-PC mechanism of active compound stigmasterol might be associated with inhibiting proliferation, invasion and migration and accelerating apoptosis. Furthermore, five targets (AKT1, HIF1A, BCL2, IL1B, and ICAM1) were identified as key targets of stigmasterol, and the mRNA expressions of these genes were down-regulated by stigmasterol through in vitro experiments.

Acute pancreatitis (AP), induced by tetracycline, a widely used antibiotic, poses significant clinical and toxicological challenges, yet its molecular mechanisms remain unclear. This study aims to promote drug toxicology strategies for the effective investigation of the putative toxicity and potential molecular mechanisms of antibiotic drugs through the study of tetracycline in AP. Using the SwissTargetPrediction, SEA Search, Super-PRED, GeneCards, Drugbank, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD), we identified 259 potential targets associated with tetracycline exposure and AP. Further refinement via the STRING database and Cytoscape (version 3.10.1) software highlighted 22 core targets, including TP53, TNF, and AKT1. Functional enrichment via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) identified pathways through Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, highlighting PI3K-Akt, MAPK, HIF-1, and AGE-RAGE as critical mediators in tetracycline-induced AP. Molecular docking confirmed the strong binding between tetracycline and the core targets. Overall, these findings suggest that tetracycline may affect the occurrence and progression of pancreas-related inflammation by regulating pancreatic cell apoptosis and proliferation, activating inflammatory signaling pathways, and regulating lipid metabolic pathways. This study provides a theoretical basis for understanding the molecular mechanism of tetracycline-induced AP and lays the foundation for the prevention and treatment of digestive system diseases associated with excessive exposure to tetracycline antibiotics and certain tetracyclines. In addition, our network toxicology approach has accelerated the elucidation of toxic pathways in antibiotic drugs that lack specific characteristics.

To compare the therapeutic potential of rat bone marrow-derived mesenchymal stem cells (BM-MSCs) preconditioned ex-vivo with resveratrol (MCR) and BM-MSCs isolated from resveratrol-pre-treated rats (MTR) in type-1 diabetic rats.

Type-1 diabetes was induced by a single streptozotocin injection (50 mg/kg; ip) in 24 rats. Following the confirmation of T1DM, diabetic rats were randomly divided into four groups: diabetic control (DC), diabetic rats treated with insulin subcutaneous (7.5 IU/kg/day), diabetic rats treated with MCR cells (3 × 106cells/rat, intravenous) and diabetic rats treated with MTR cells (3 × 106cells/rat, intravenous). Rats were sacrificed 4 weeks following cellular transplantation.

Untreated diabetic rats suffered from pancreatic cell damage, had high blood glucose levels, increased apoptotic, fibrosis, and oxidative stress markers and decreased survival and pancreatic regeneration parameters. Both MSCs preconditioned ex-vivo with RES and MSCs isolated from rats pre-treated with RES homed successfully in injured pancreas and showed therapeutic potential in the treatment of STZ-induced T1DM. MCR cells showed better efficiency than MTR cells.

The pre-conditioning of BM-MSCs with resveratrol may be a promising therapeutic possibility in T1DM. Resveratrol-preconditioned BM-MSCs encouraged effects almost comparable to that of exogenous insulin with the advantages of cured pancreas and restored islets not attained by insulin.

Pancreatic fibrosis is caused by excessive deposition of extracellular matrixes of collagen and fibronectin in the pancreatic tissue as a result of repeated injury often seen in patients with chronic pancreatic diseases. The most common causative conditions include inborn errors of metabolism, chemical toxicity and autoimmune disorders. Its pathophysiology is highly complex, including acinar cell injury, acinar stress response, duct dysfunction, pancreatic stellate cell activation, and persistent inflammatory response. However, the specific mechanism remains to be fully clarified. Although the current therapeutic strategies targeting pancreatic stellate cells show good efficacy in cell culture and animal models, they are not satisfactory in the clinic. Without effective intervention, pancreatic fibrosis can promote the transformation from pancreatitis to pancreatic cancer, one of the most lethal malignancies. In the normal pancreas, the acinar component accounts for 82% of the exocrine tissue. Abnormal acinar cells may activate pancreatic stellate cells directly as cellular source of fibrosis or indirectly via releasing various substances and initiate pancreatic fibrosis. A comprehensive understanding of the role of acinar cells in pancreatic fibrosis is critical for designing effective intervention strategies. In this review, we focus on the role of and mechanisms underlying pancreatic acinar injury in pancreatic fibrosis and their potential clinical significance.

Obesity-related acute pancreatitis (AP) is characterized by increasing prevalence worldwide and worse clinical outcomes compared to AP of other etiologies. Chaiqin chengqi decoction (CQCQD), a Chinese herbal formula, has long been used for the clinical management of AP but its therapeutic actions and the underlying mechanisms have not been fully elucidated. This study has investigated the pharmacological mechanisms of CQCQD in a novel mouse model of obesity-related alcohol-induced AP (OA-AP). The mouse OA-AP model was induced by a high-fat diet for 12 weeks and subsequently two intraperitoneal injections of ethanol, CQCQD was administered 2 h after the first injection of ethanol. The severity of OA-AP was assessed and correlated with changes in transcriptomic profiles and network pharmacology in the pancreatic and adipose tissues, and further docking analysis modeled the interactions between compounds of CQCQD and their key targets. The results showed that CQCQD significantly reduced pancreatic necrosis, alleviated systemic inflammation, and decreased the parameters associated with multi-organ dysfunction. Transcriptomics and network pharmacology analysis, as well as further experimental validation, have shown that CQCQD induced Nrf2/HO-1 antioxidant protein response and decreased Akt phosphorylation in the pancreatic and adipose tissues. In vitro, CQCQD protected freshly isolated pancreatic acinar cells from H₂O₂-elicited oxidative stress and necrotic cell death. The docking results of AKT1 and the active compounds related to AKT1 in CQCQD showed high binding affinity. In conclusion, CQCQD ameliorates the severity of OA-AP by activating of the antioxidant protein response and down-regulating of the PI3K/Akt signaling pathway in the pancreas and visceral adipose tissue.

Pancreatic ductal metaplasia (PDM) is the stepwise replacement of differentiated somatic cells with ductal or ductal-like cells in the pancreas. PDM is usually triggered by cellular and environmental insults. PDM development may involve all cell lineages of the pancreas, and acinar cells with the highest plasticity are the major source of PDM. Pancreatic progenitor cells are also involved as cells of origin or transitional intermediates. PDM is heterogeneous at the histological, cellular, and molecular levels and only certain subsets of PDM develop further into pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDAC). The formation and evolution of PDM is regulated at the cellular and molecular levels through a complex network of signaling pathways. The key molecular mechanisms that drive PDM formation and its progression into PanIN/PDAC remain unclear, but represent key targets for reversing or inhibiting PDM. Alternatively, PDM could be a source of pancreas regeneration, including both exocrine and endocrine components. Cellular aging and apoptosis are obstacles to PDM-to-PanIN progression or pancreas regeneration. Functional identification of the cellular and molecular events driving senescence and apoptosis in PDM and its progression would help not only to restrict the development of PDM into PanIN/PDAC, but may also facilitate pancreatic regeneration. This review systematically assesses recent advances in the understanding of PDM physiology and pathology, with a focus on its implications for enhancing regeneration and prevention of cancer. © 2022 The Pathological Society of Great Britain and Ireland.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant lethal disease due to its asymptomatic at its early lesion of the disease and drug resistance. Target therapy associated with molecular pathways so far seems not to produce reasonable outcomes. Understanding of the molecular mechanisms underlying inflammation-initiated tumorigenesis may be helpful for development of an effective therapy of the disease. A line of studies showed that pancreatic tumorigenesis was resulted from pancreatitis, which was caused synergistically by various pancreatic cells. This review focuses on those players and their possible clinic implications, such as exocrine acinar cells, ductal cells, and various stromal cells, including pancreatic stellate cells (PSCs), macrophages, lymphocytes, neutrophils, mast cells, adipocytes and endothelial cells, working together with each other in an inflammation-mediated microenvironment governed by a myriad of cellular signaling networks towards PDAC.

The most common pancreas-related disorders are diabetes, pancreatitis and different types of pancreatic cancers. Diabetes is a chronic condition which results from insufficient functional β-cell mass, either as a result of an autoimmune destruction of insulin producing β-cells, or as their death or de-differentiation following years of hyperactivity to compensate for insulin resistance. Chronic pancreatitis leads to cell death and can develop into diabetes or pancreatic cancer. To stimulate regeneration in such pathologies, it is of high importance to evaluate the endogenous regeneration capacity of the pancreas, to understand the conditions needed to trigger it, and to investigate the cellular and molecular regenerative responses. This short review focuses on observations made in the last 2 years on the mechanisms enhancing pancreatic cell proliferation, notably new combinations of pharmacological agents, as well as those triggering cellular conversion.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas that causes significant morbidity and mortality worldwide. Unfortunately, there is no specific treatment available to date. Several studies have previously shown that inhibitors of the PI3K/Akt axis downregulate the degree of inflammation in animal models of AP. However, studies on in vivo side-effects of such inhibitors are still lacking. In a recent issue of The Journal of Pathology, Chen, Malagola et al investigated if inhibition of Akt signaling plays a negative role in the regenerative phase of AP. They showed that treating AP mice with an Akt inhibitor (MK2206) impaired acinar regeneration and increased the development of acinar-to-ductal metaplasia. This is the first study to highlight the negative impact of an Akt inhibitor on cellular regeneration while simultaneously inhibiting inflammation in AP. The authors also suggested combining Akt activators to recover pancreatic regeneration. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.