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Sphingosine-1-phosphate (S1P) is a sphingolipid metabolic product produced via the phosphorylation of sphingosine by sphingosine kinases (SPHKs), serving as a powerful modulator of various cellular processes through its interaction with S1P receptors (S1PRs). Currently, this incompletely understood mechanism in pancreatic diseases including pancreatitis and pancreatic cancer, largely limits therapeutic options for these disorders. Recent evidence indicates that S1P significantly contributes to pancreatic diseases by modulating inflammation, promoting pyroptosis in pancreatic acinar cells, regulating the activation of pancreatic stellate cells, and affecting organelle functions in pancreatic cancer cells. Nevertheless, no review has encapsulated these advancements. Thus, this review compiles information about the involvement of S1P signaling in exocrine pancreatic disorders, including acute pancreatitis, chronic pancreatitis, and pancreatic cancer, as well as prospective treatment strategies to target S1P signaling for these conditions. The insights presented here possess the potential to offer valuable guidance for the implementation of therapies targeting S1P signaling in various pancreatic diseases. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial autoantigenic glycoprotein 2 (GP2) is an important component of the innate immune system which originates from the exocrine pancreas as well as from the small intestines. The relationship of GP2 with the intestinal microbiome as well as the systemic implications of increased fecal GP2 levels are, however, still unclear. Therefore, fecal samples from 2,812 individuals of the Study of Health in Pomerania (SHIP) were collected to determine GP2 levels (enzyme-linked immunosorbent assay) and gut microbiota profiles (16 S rRNA gene sequencing). These data were correlated and associated with highly standardised and comprehensive phenotypic data of the study participants. Results: Fecal GP2 levels were increased in individuals with higher body mass index and smokers, whereas lower levels were found in case of preserved exocrine pancreatic function, female sex or a healthier diet. Moreover, higher GP2 levels were associated with increased serum levels of high-sensitivity C-reactive protein, loss of gut microbial diversity and an increase of potentially detrimental bacteria (Streptococcus, Haemophilus, Clostridium XIVa, or Collinsella). At the same time, predicted microbial pathways for the biosynthesis of beneficial short-chain fatty acids or lactic acid were depleted in individuals with high fecal GP2. Of note, GP2 exhibited a stronger association to overall microbiome variation than calprotectin. Conclusion: Fecal GP2 is a biomarker of gut microbiota dysbiosis and associated with increased systemic inflammation. The intestines may be more important as origin for GP2 than pancreatic acinar cells. Future studies need to investigate the potential clinical value in disease specific patient cohorts. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acute pancreatitis (AP) is associated with acinar cell death and inflammatory responses. Ferroptosis is characterized by an overwhelming lipid peroxidation downstream of metabolic dysfunction, in which NADPH‐related redox systems have been recognized as the mainstay in ferroptosis control. Nevertheless, it remains unknown how ferroptosis is regulated in AP and whether we can target it to restrict AP development. Experimental Approach: Metabolomics were applied to explore changes in metabolic pathways in pancreatic acinar cells (PACs) in AP. Using wild‐type and Ptf1aCreERT2/+IDH2fl/fl mice, AP was induced by caerulein and sodium taurocholate (NaT). IDH2 overexpressing adenovirus was constructed for infection of PACs. Mice or PACs were pretreated with inhibitors of FSP1 or glutathione reductase. Pancreatitis severity, acinar cell injury, mitochondrial morphological changes and pancreatic lipid peroxidation were analysed. Key Results: Unsaturated fatty acid biosynthesis and the tricarboxylic acid cycle pathways were significantly altered in PACs during AP. Inhibition of ferroptosis reduced mitochondrial damage, lipid peroxidation and the severity of AP. During AP, the NADPH abundance and IDH2 expression were decreased. Acinar cell‐specific deletion of IDH2 exacerbated acinar cell ferroptosis and pancreatic injury. Pharmacological inhibition of NADPH‐dependent GSH/GPX4 and FSP1/CoQ10 pathways abolished the protective effect of IDH2 overexpression on ferroptosis in acinar cells. CoQ10 supplementation attenuated experimental pancreatitis via inhibiting acinar cell ferroptosis. Conclusion and Implications: We identified the IDH2‐NADPH pathway as a novel regulator in protecting against AP via restricting acinar cell ferroptosis. Targeting the pathway and its downstream may shed light on AP treatment. [ABSTRACT FROM AUTHOR]

This document contains three research reports. The first report examines the relationship between El Niño events and rainfall patterns in the eastern Bay of Bengal. The second report focuses on resolving the Mahadayi water dispute by analyzing rainfall data and estimating water discharge in the river basin. The third report explores the use of nanoparticle-based drug delivery systems to improve the treatment of malaria. The first article discusses the dysregulation of calcium ion signaling in pancreatic acinar cells and its implications for medical conditions. The second article investigates the metabolic reprogramming in immune cells during Mycobacterium tuberculosis infection. The third article explores the use of electric fields to repel mosquitoes and prevent mosquito-borne diseases. [Extracted from the article]

AIM: To investigate the activation of Cl- channels by sodium taurocholate （NaTC） in mouse pancreatic acinar cells. METHODS: The single isolated pancreatic acinar cells from FVB/N mice were prepared using collagenase digestion method. Whole-cell patch clamp technique was performed to record the currents. Intracellular adenosine triphosphate （ATP） dependence of the channels was examined via eliminating ATP from the pipette solution. Anion permeability of the channels was investigated with ion-exchange method. The pharmacological characteristics of the channels was confirmed by two Cl- channel blockers. The volume sensitivity of the channels was detected using 47% hypertonic bathing solution. Extracellular Ca2+ dependence of activating the channels was examined through eliminating Ca2+ from the bathing solution. Intracellular reactive oxygen species （ROS） level was detected by an oxidation-sensitive fluorescent probe, 2', 7'-dichlorofluorescin diacetate. The experiment was repeated 6 times in each group. RESULTS: Extracellular application of 5 mmol/L sodium taurocholate induced a Cl- current, exhibiting the properties of outward-rectification, a selectivity sequence of I- > Br- ≥ Cl- > gluconate- and intracellularATP dependence（ P<0. 01）. The currents were inhibited by chloride channel blocker 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid disodium salt hydrate （DIDS） and tamoxifen and by 47% hypertonicity stimulation （P<0. 01）. When ROS production was scavenged by N-acetyl-L-cysteine, the sodium taurocholate-induced Cl- currents were unaffected. The effect of sodium taurocholate on ROS production did not alter with the treatment with DIDS. Sodium taurocholate failed to induce Cl- currents when Ca2+ was absent in extracellular bathing solution （P>0. 05）. CONCLUSION: Sodium taurocholate activates Cl- channels in mouse pancreatic acinar cells, which is dependent on extracellular Ca2+ but not ROS pathway. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis (CP) is a progressive fibroinflammatory disease characterized by destruction of pancreatic acinar cells, infiltration of inflammatory cells, activation of pancreatic stellate cell (PSC), and pancreatic fibrosis. Autophagy participates in the maintenance of cell homeostasis. Recent studies have shown that autophagy closely related to the occurrence and development of CP. However, several autophagy types in the pancreatic microenvironment play different roles in the progression of CP. The autophagy of acinar cells has a "double-edged sword" effect. PSC autophagy is positively correlated with its activation, while the role of autophagy of inflammatory cells is still unclear. This study focused on some key cells in the CP microenvironment and explored the role and mechanism of autophagy in the progression of CP. [ABSTRACT FROM AUTHOR]

Solitary fibrous tumor (SFT) is a spindle cell tumor driven by the NAB2‐STAT6 fusion gene. While it can originate from any soft tissue, primary SFT of the pancreas is rare with limited reports. A 36‐year‐old man came to our department due to abdominal pain. Computed tomography revealed a circular mass with weak peripheral enhancement and an internal cyst in the pancreatic tail. Diagnosis was not confirmed through endoscopic ultrasound‐guided biopsy, and differential diagnoses included acinar cell carcinoma and pancreatic neuroendocrine tumor. A robotic distal pancreatectomy with splenectomy was performed, and the patient was discharged 11 days postoperatively. Histopathological examination showed an irregular arrangement of spindle cells, and immunohistochemical staining was positive for CD34 and STAT6, confirming an SFT diagnosis with low metastatic risk. Robotic surgery effectively managed this tumor. [ABSTRACT FROM AUTHOR]

Acinar cell carcinoma (ACC) and pancreatoblastoma (PBL) are rare pancreatic malignancies with acinar differentiation. Proteogenomic profiling of ACC and PBL revealed distinct protein expression patterns compared to pancreatic ductal adenocarcinoma (PDAC) and benign pancreas. ACC and PBL exhibited similarities, with enrichment in proteins related to RNA processing, chromosome organization, and the mitoribosome, while PDACs overexpressed proteins associated with actin-based processes, extracellular matrix, and immune-active stroma. Pathway activity differences in metabolic adaptation, epithelial-to-mesenchymal transition, and DNA repair were characterized between these diseases. PBL showed upregulation of Wnt-CTNNB1 and IGF2 pathways. Seventeen ACC-specific proteins suggested connections to metabolic diseases with mitochondrial dysfunction, while 34 PBL-specific proteins marked this pediatric cancer with an embryonic stem cell phenotype and alterations in chromosomal proteins and the cell cycle. This study provides novel insights into the proteomic landscapes of ACC and PBL, offering potential targets for diagnostic and therapeutic development. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is the sixth leading cause of cancer-related deaths worldwide, primarily due to late-stage diagnosis and limited treatment options. While novel biomarkers and immunotherapies are promising, further research into specific molecular targets is needed. Glycans, which are carbohydrate structures mainly found on cell surfaces, play crucial roles in health and disease. The Thomsen-Friedenreich-related carbohydrate antigen Sialyl-Tn (STn), a truncated O-glycan structure, is selectively expressed in epithelial tumors, including PC. In this study, we performed a comprehensive analysis of STn expression patterns in normal, premalignant, and malignant pancreatic lesions. Additionally, we analyzed the association between STn expression and various clinicopathological features. STn expression was statistically associated with pathological diagnosis; it was absent in normal pancreatic tissue but prevalent in pancreatic carcinoma lesions, including pancreatic ductal adenocarcinoma (PDAC), pancreatic acinar cell carcinoma, and pancreatic adenosquamous carcinoma. Moreover, we found a significant association between STn expression and tumor stage, with higher STn levels observed in stage II tumors compared to stage I. However, STn expression did not correlate with patient survival or outcomes. Furthermore, STn expression was assessed in PDAC patient-derived xenograft (PDX) models, revealing consistent STn levels throughout engraftment and tumor growth cycles. This finding supports the PDX model as a valuable tool for testing new anti-STn therapeutic strategies for PC in clinical setting. [ABSTRACT FROM AUTHOR]

The WD40 domain (WDD) of ATG16L1 plays a pivotal role in non-canonical autophagy. This study examined the role of recently identified LAP-like non-canonical autophagy (LNCA) in acute pancreatitis. LNCA involves rapid single-membrane LC3 conjugation to endocytic vacuoles in pancreatic acinar cells. The rationale for this study was the previously observed presence of trypsin in the organelles undergoing LNCA; aberrant trypsin formation is an important factor in pancreatitis development. Here we report that the deletion of WDD (attained in ATG16L1[E230] mice) eliminated LNCA, aggravated caerulein-induced acute pancreatitis and suppressed the fast trypsin degradation observed in both a rapid caerulein-induced disease model and in caerulein-treated isolated pancreatic acinar cells. These experiments indicate that LNCA is a WDD-dependent mechanism and suggest that it plays not an activating but a protective role in acute pancreatitis. Furthermore, palmitoleic acid, another inducer of experimental acute pancreatitis, strongly inhibited LNCA, suggesting a novel mechanism of pancreatic lipotoxicity.Abbreviation: AMY: amylase; AP: acute pancreatitis; CASM: conjugation of Atg8 to single membranes; CCK: cholecystokinin; FAEE model: fatty acid and ethanol model; IL6: interleukin 6; LA: linoleic acid; LAP: LC3-associated phagocytosis; LMPO: lung myeloperoxidase; LNCA: LAP-like non-canonical autophagy; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MPO: myeloperoxidase; PMPO: pancreatic myeloperoxidase; POA: palmitoleic acid; WDD: WD40 domain; WT: wild type. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a severe inflammatory disorder for which effective treatments are currently lacking. Cirsilineol (CSL), a flavonoid derived from Artemisia plants, is recognized for its potent anti-inflammation and antioxidant characteristics. The mechanisms underlying AP and potential therapeutic agents remain unknown. This study investigates the effects of CSL on AP and delves into its underlying mechanism. Our results indicate that CSL significantly improved cell viability in AR42J pancreatic acinar cells and influenced the levels of pro-inflammatory cytokines. Furthermore, CSL markedly decreased apoptosis markers and inhibited the Nuclear Factor kappa-B (NF-κB) activation by reducing phosphorylation of p65 and inhibitor of NF-κB alpha (IκBα). These findings underscore the powerful anti-inflammatory and anti-apoptotic properties of CSL, acting through the NF-κB pathway, indicating its promise as a therapeutic option for AP. [ABSTRACT FROM AUTHOR]

Objective: To observe the effect of RND3 intervention on injury of pancreatic acinar cells AR42J induced by caerulein in rats, and explore regulatory mechanism of RND3 in acute pancreatitis (AP) . Methods: Lentiviral AP models with RND3 gene silencing and overexpression, and AR42J cell AP models induced by caerulein were constructed in 6 groups (NC control group, caerulein treatment group, si-con negative control group, pcDNA negative control group, si-RND3 silencing group, and pcDNA-RND3 overexpression group) . After the administration of caerulein, mRNA and protein expression level of RND3 in AR42J cells were quantified at time points of 0 h, 4 h, 8 h, 12 h and 24 h by qRT-PCR and Western blot, respectively. Cell survival and LDH leakage were detected by CCK-8 method. Apoptosis rate of AR42J cells was detected by flow cytometry. mRNA expression levels of related inflammatory factors (TNF-α, IL-6, IL-1β and IL-18) were detected by qRT-PCR. Western blot was used to detect expressions of apoptosisrelated proteins (GSDMD, NLRP3, Cleaved caspase-1 and caspase-1) in AR42J cells. Results: Expression of RND3 mRNA and protein in AR42J cells induced by caerulein was inhibited, and expression of RND3 was inhibited more significantly with the increase of caerulein treatment time. Compared with NC control group, expressions of TNF-α, IL-6, IL-1β and IL-18 in AR42J cells of rats in si- RND3 group and caerulein treatment group were up-regulated (P<0.05), at the same time, expressions of apoptosis-related proteins GSDMD, NLRP3, Cleaved caspase-1 and caspase-1 were increased. On the contrary, levels of cell inflammation and apoptosis were significantly reduced in pcDNA-RND3 overexpression group (P<0.05) . Conclusion: RND3 can reduce the inflammatory reaction and apoptosis of rats pancreatic acinar cells AR42J, which mechanism is related to the activity of NLRP3/caspase-1/GSDMD pathway. [ABSTRACT FROM AUTHOR]

• CFRD is characterised by exocrine pancreatic, islet loss, and insulin insufficiency. • Mechanistic gaps and conflicting data present in current understanding of CFRD. • Oxidative and endoplasmic reticulum stress may play a key role in CF pancreatic damage. • Exosomal microRNA could amplify exocrine-endocrine cross-talk and damage in CFRD. CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor discussing the use of octreotide as a prophylactic treatment for asparaginase-associated pancreatitis (AAP) in patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). The study presented in the letter aimed to assess the effectiveness of octreotide in preventing AAP recurrence in patients who received asparaginase re-administration after AAP development. The results showed that prophylactic octreotide administration reduced the incidence of AAP recurrence and allowed most patients to complete the prescribed number of asparaginase administrations without severe complications. The study suggests that octreotide may be effective in preventing AAP relapses and further research is needed to assess its effectiveness. [Extracted from the article]

Exocrine-to-endocrine cross talk in the pancreas is crucial to maintain β-cell function. However, the molecular mechanisms underlying this cross talk are largely undefined. Trefoil factor 2 (Tff2) is a secreted factor known to promote the proliferation of β-cells in vitro, but its physiological role in vivo in the pancreas is unknown. Also, it remains unclear which pancreatic cell type expresses Tff2 protein. We therefore created a mouse model with a conditional knockout of Tff2 in the murine pancreas. We find that the Tff2 protein is preferentially expressed in acinar but not ductal or endocrine cells. Tff2 deficiency in the pancreas reduces β-cell mass on embryonic day 16.5. However, homozygous mutant mice are born without a reduction of β-cells and with acinar Tff3 compensation by day 7. When mice are aged to 1 year, both male and female homozygous and male heterozygous mutants develop impaired glucose tolerance without affected insulin sensitivity. Perifusion analysis reveals that the second phase of glucose-stimulated insulin secretion from islets is reduced in aged homozygous mutant compared with controls. Collectively, these results demonstrate a previously unknown role of Tff2 as an exocrine acinar cell-derived protein required for maintaining functional endocrine β-cells in mice. Article Highlights: Exocrine-to-endocrine cross talk is important in maintaining pancreatic cell homeostasis, but the molecular mechanisms remain largely undefined. In the pancreas, the physiological role of the secreted factor Tff2 and the cell type that expresses Tff2 has been unclear. Pancreatic acinar cells are the major cell type expressing Tff2 protein, and specific loss of Tff2 in the pancreas reduces β-cells during development and attenuates glucose-stimulated insulin secretion during aging in conditional Tff2 knockout mice. Tff2 is a positive exocrine-produced factor required for the development and function of endocrine β-cells, which has implications in diabetes disease progression and therapy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic ductal adenocarcinoma, is the most prevalent type of pancreatic tumor, predominantly impacting the exocrine portion of the pancreas. Individuals diagnosed with PDAC face a grim prognosis due to its highly malignant nature. By the year 2030, it is projected to emerge as the second leading cause of cancer-related fatalities. PDAC is known for its high degree of genomic instability. This review offers a summary of the frequently mutated genes in PDAC, as well as the morphological features, molecular profiles, available treatment options, and ongoing research in the field of PDAC. [ABSTRACT FROM AUTHOR]

The article "Do nonglycaemic effects such as weight loss account for HbA1c lowering with efpeglenatide?: Insights from the AMPLITUDE‐O trial" published in Diabetes, Obesity & Metabolism explores the impact of the GLP‐1 RA efpeglenatide on HbA1c levels in individuals with type 2 diabetes. The study found that efpeglenatide significantly reduced HbA1c levels by 1.46% within 3 months, along with other positive effects on weight, blood pressure, cholesterol levels, and other health markers. However, the analysis revealed that less than 12% of efpeglenatide's effect on HbA1c could be explained by its impact on weight loss and other nonglycaemic factors. The study suggests that the glycaemic effect of efpeglenatide is primarily due to its incretin-related effects, with weight loss playing a modest role. [Extracted from the article]

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points. Moreover, we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1 α)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of 13C 6 -glucose to 13C 3 -lactate. Lastly, we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels, while pancreatic XO and urate were also increased in severe AP patients. These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1 α -mediated LDHA and NLRP3 signaling pathways. XO was enormously increased in necrotic murine models and severe patients of acute pancreatitis, pharmacological and genetic intervention of XO significantly affected disease severity via HIF-1 α -regulated LDHA and NLRP3 pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC‐derived cell lines. We further demonstrated that TRIP12 was required for PDAC‐derived cell growth and for the expression of E2F‐targeted genes. Acinar‐to‐ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of KrasG12D‐induced preneoplastic lesions and impaired metastasis formation in the presence of mutated KrasG12D and Trp53R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors. [ABSTRACT FROM AUTHOR]

Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high‐fat diet and retrograde administration of sodium taurocholate were employed to establish the HP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator‐activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism‐related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin‐8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α‐amylase, total cholesterol, low‐density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high‐density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP‐1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP. [ABSTRACT FROM AUTHOR]

Fluid and enzyme secretion from exocrine glands is initiated by Ca2+ signalling in acinar cells and is activated by external neural or hormonal signals. A wealth of information has been derived from studies in acutely isolated exocrine cells but Ca2+ signalling has until recently not been studied in undisrupted intact tissue in live mice. Our in vivo observations using animals expressing genetically encoded Ca2+ indicators in specific cell types in exocrine glands revealed both similarities to and differences from the spatiotemporal characteristics previously reported in isolated cells. These in vivo studies facilitate further understanding of how both neuronal and hormonal input shapes Ca2+ signalling events in a physiological setting and how these signals are translated into the stimulation of fluid secretion and exocytosis. [ABSTRACT FROM AUTHOR]

Objective: Acute pancreatitis (AP) stands as a frequent cause for clinical emergency hospital admissions. The X‐box binding protein 1 (XBP1) was found to be implicated in pancreatic acinar cell apoptosis. The objective is to unveil the potential mechanisms governed by XBP1 and SIRT6 in the context of AP. Methods: Caerulein‐treated human pancreatic duct epithelial (HPDE) cells to establish an in vitro research model. The levels and regulatory role of SIRT6 in the treated cells were evaluated, including its effects on inflammatory responses, oxidative stress, apoptosis, and endoplasmic reticulum stress. The relationship between XBP1 and SIRT6 was explored by luciferase and ChIP experiments. Furthermore, the effect of XBP1 overexpression on the regulatory function of SIRT6 on cells was evaluated. Results: Caerulein promoted the decrease of SIRT6 and the increase of XBP1 in HPDE cells. Overexpression of SIRT6 slowed down the secretion of inflammatory factors, oxidative stress, apoptosis level, and endoplasmic reticulum stress in HPDE cells. However, XBP1 negatively regulated SIRT6, and XBP1 overexpression partially reversed the regulation of SIRT6 on the above aspects. Conclusion: Our study illuminates the role of XBP1 in downregulating SIRT6 in HPDE cells, thereby promoting cellular injury. Inhibiting XBP1 or augmenting SIRT6 levels holds promise in preserving cell function and represents a potential therapeutic avenue in the management of AP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Danshen Chuanxiong Injection (DCI) has demonstrated significant clinical efficacy in the treatment of acute pancreatitis (AP); however, the precise molecular mechanisms underlying its therapeutic effects remain incompletely understood. OBJECTIVE: In this study, we employed network pharmacology analysis to comprehensively investigate the active components, potential targets, and signaling pathways involved in DCI-mediated treatment of AP. METHODS: We utilized the mouse pancreatic acinar cell line 266-6 to establish an cholecystokinin (CCK)-induced AP cell injury model and evaluated cell viability using the Cell counting kit-8 assay. Western blotting and quantitative PCR were employed to determine the expression levels of key target proteins and genes. RESULTS: Network pharmacology analysis identified a total of 144 active components and 430 potential targets within DCI. By integrating data from public databases, we identified 762 AP-related genes. Among these, we identified 93 potential targets that may be involved in the therapeutic effects of DCI for AP. These targets were significantly enriched in biological processes such as oxidative stress, regulation of cytokine production, leukocyte migration, and the TNF signaling pathway. Molecular docking studies revealed a high binding affinity between the active components and the key targets AKT1 and NFKBA, indicative of potential interaction. Additionally, CCK-induced acinar cell injury led to upregulation of AKT1, NFKBA, and P53 proteins, as well as TNF, IL6, and MMP9 genes. Conversely, treatment with DCI dose-dependently attenuated CCK-induced acinar cell injury and restored the expression levels of the aforementioned proteins and genes. CONCLUSION: Overall, this study provides a comprehensive understanding of the molecular mechanisms underlying the therapeutic effects of DCI in the treatment of AP. Our findings confirm the protective effect of DCI against CCK-induced acinar cell injury and its regulation of key targets. [ABSTRACT FROM AUTHOR]

Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that β-, α-, and ductal cells have the greatest transcriptional response. We utilize stem cell-derived islets to study islet health through the candidate gene CIB1, which was upregulated under stress in primary human islets. Our findings provide insights into cell type-specific responses to diabetes-associated stress and establish a resource to identify targets for diabetes therapeutics. Endoplasmic reticulum and inflammatory stress are associated with diabetes. Maestas et al. use single-cell sequencing to profile primary human islets under stress and identified tissue and cell-type responses. [ABSTRACT FROM AUTHOR]

Acute pancreatitis represents an inflammatory disease featuring pancreatic necrosis and inflammation. Inflammatory injury of pancreatic acinar cells (PACs) is critically involved in the initiation and progression of acute pancreatitis. Pyroptosis, a new kind of programmed cell death concomitant with a low‐grade inflammatory reaction, plays a function in acute pancreatitis pathology. It is unclear whether saikosaponin d (SSd), a pharmacologically active natural product, could protect PACs by regulating pyroptosis. Here, we established a PAC injury model in vitro using cerulein to treat AR42J cells. SSd restored viability and proliferation and lowered the release of pancreatic enzymes and inflammatory interleukins in cerulein‐treated AR42J cells. Cerulein‐induced pyroptosis was evidenced by typical ultrastructural changes and NLRP3/caspase‐1 activation in AR42J cells, but SSd attenuated cerulein‐induced pyroptosis and inhibited NLRP3/caspase‐1 pathway. Mechanically, SSd reduced mitochondrial damage and mtDNA release, and blocked cGAS‐STING signaling in AR42J cells treated with cerulein, contributing to the inhibition of NLRP3‐mediated pyroptosis. Furthermore, SSd abolished cerulein‐elevated oxidative stress in AR42J cells, leading to the mitigation of mitochondrial damage and inhibition of cGAS‐STING signaling and pyroptosis. In conclusion, SSd protected PACs against cerulein‐induced pyroptosis by alleviating mitochondrial damage and inhibiting the cGAS‐STING pathway, and it could be a therapeutic candidate for acute pancreatitis. Acute pancreatitis is a non‐infectious inflammatory disease and these are no effective drugs for this disease. Here, we found that Saikosaponin d (SSd) alleviated NLRP3‐mediated pyroptosis and inflammatory injury by blocking cGAS‐STNG signaling pathway in pancreatic acinar cells (PACs) treated with cerulein. These actions were attributed to SSd suppression of oxidative stress and mitigation of mitochondrial damage. Regulating pyroptosis of PACs could be a promising strategy for combating acute pancreatitis, and SSd could be a potent candidate for further development. [ABSTRACT FROM AUTHOR]

Introduction: The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that Ehmt2 inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Methods: Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from Ehmt2 conditional knockout animals (Ehmt2fl/fl) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48Cre/+), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the Ehmt2fl/fl pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. Results and discussion: The Ehmt2fl/fl pancreas displays an enhanced injuryinflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional Ehmt2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific Ehmt2- regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases. [ABSTRACT FROM AUTHOR]

This study aimed to investigate Ganoderic acid A’s (GAA) possible effects on inflammation and oxidative stress of caerulein-stimulated pancreatic acinar cells and uncover its effects on acute pancreatitis (AP). A cell model of AP was constructed by treating pancreatic acinar AR42J cells with caerulein. Cell counting kit-8 (CCK-8) assay was used to measure cell viability, while Enzyme-Linked Immunosorbent Assay (ELISA) and 2′,7′ -Dichlorofluorescein (DCF) fluorescence assays were used to measure inflammation and oxidative stress. Western blot analysis was used to investigate Nuclear Factor-kappa B (NF-κB) signaling pathway inhibition, focusing on p65 and NF-kappa-B inhibitor alpha (IκBα) phosphorylation states. GAA significantly enhanced cell viability in caerulein-stimulated pancreatic acinar AR42J cells. It also significantly reduced AR42J cells’ inflammatory response. Furthermore, GAA treatment mitigated oxidative stress by decreasing Reactive oxygen species (ROS) production. Lastly, GAA inhibited the NF-κB pathway, as evidenced by decreased p65 and IκBα phosphorylation. By inhibiting NF-B-mediated inflammation, GAA attenuated caerulein-induced AP. [ABSTRACT FROM AUTHOR]

Background: Severe acute pancreatitis (SAP) is a serious gastrointestinal disease that is facilitated by pancreatic acinar cell death. The protective role of human placental mesenchymal stem cells (hP-MSCs) in SAP has been demonstrated in our previous studies. However, the underlying mechanisms of this therapy remain unclear. Herein, we investigated the regularity of acinar cell pyroptosis during SAP and investigated whether the protective effect of hP-MSCs was associated with the inhibition of acinar cell pyroptosis. Methods: A mouse model of SAP was established by the retrograde injection of sodium taurocholate (NaTC) solution in the pancreatic duct. For the hP-MSCs group, hP-MSCs were injected via the tail vein and were monitored in vivo. Transmission electron microscopy (TEM) was used to observe the pyroptosis-associated ultramorphology of acinar cells. Immunofluorescence and Western blotting were subsequently used to assess the localization and expression of pyroptosis-associated proteins in acinar cells. Systemic inflammation and local injury-associated parameters were evaluated. Results: Acinar cell pyroptosis was observed during SAP, and the expression of pyroptosis-associated proteins initially increased, peaked at 24 h, and subsequently showed a decreasing trend. hP-MSCs effectively attenuated systemic inflammation and local injury in the SAP model mice. Importantly, hP-MSCs decreased the expression of pyroptosis-associated proteins and the activity of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in acinar cells. Conclusions: Our study demonstrates the regularity and important role of acinar cell pyroptosis during SAP. hP-MSCs attenuate inflammation and inhibit acinar cell pyroptosis via suppressing NLRP3 inflammasome activation, thereby exerting a protective effect against SAP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mechanism of long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) in acute pancreatitis (AP). Methods: The mouse pancreatic acinar cell line (MPC-83) was cultured in vitro, and treated with lipopoly- saccharide (LPS, 10 µg/ml) and cerulein (Caerulein, 100 nmol/L) for 3 h to establish the AP model. The experiment was divided into control group, AP group, AP+sh-NC group, AP+sh-TUG1 group, AP+sh-TUG1+inhibitor-NC group, and AP+sh-TUG1+miR-31-5p inhibitor group. Quantitative real-time PCR (qRT-PCR) was performed to measure the expression levels of lncRNA TUG1 and miR-31-5p in cells; CCK-8 method was performed to measure cell viability; flow cytometry was performed to measure apoptosis; ELISA was performed to measure the levels of IL-lp and tumor necrosis factor a (TNF-a) in the cell supernatant; and dual-luciferase reporter gene experiments was performed to verify the targeting relationship between lncRNA TUG1 and miR-31-5p. The AP mouse model was constructed, and after corresponding intervention, qRT-PCR was performed to determine the lncRNA TUG1 and miR-31-5p expression levels in pancreatic tissue; the serum inflammatory factors IL-1β, TNF-α contents and amylase (AMY) and lipase (Lipase) activities were determined by kits; HE staining was performed to observe histopathological changes of pancreas; TUNEL was performed to detect apoptosis in pancreatic tissue. Results: In MPC-83 cells co-treated with Caerulein and LPS, the lncRNA TUG1 level, apoptosis rate, IL-1β and TNF-α levels were increased, while miR-31-5p level and cell viability were decreased (all P<0.05) ; knockdown of lncRNA TUG1 up-regulated miR-31-5p, increased cell viability, decreased IL-1β and TNF-α levels, and inhibited cell apoptosis (all P<0.05) ; down-regulation of miR-31-5p expression attenuated the inhibitory effect of lncRNA TUG1 knockdown on cellular inflammatory responses. miR-31-5p was a direct target of lncRNA TUGl. Knockdown of lncRNA TUGl expression in vivo was able to up-regulate the expression of miR-31-5p in pancreatic tissue of AP mice, reduce the levels of IL-1β and TNF-α, reduce cell apoptosis, and improve pancreatic tissue damage. Conclusion: Knockdown of lncRNA TUGl may improve AP by up-regulating the expression level of miR-3l-5p and inhibiting the inflammatory response. [ABSTRACT FROM AUTHOR]

Objective: Pancreatic cancer (PC) originates and progresses with genetic mutations in various oncogenes and suppressor genes, notably KRAS, CDKN2A, TP53, and SMAD4, prevalent across diverse PC cells. In addition to genetic mutations/deletions, persistent exposure to high-risk factors, including obesity, induces whole-genome scale epigenetic alterations contributing to malignancy. However, the impact of obesity on DNA methylation in the presymptomatic stage, particularly in genes prone to PC mutation, remains uncharacterized. Results: We analyzed the methylation levels of 197 loci in six genes (KRAS, CDKN2A, TP53, SMAD4, GNAS and RNF43) using Illumina Mouse Methylation BeadChip array (280 K) data from pancreatic exocrine cells obtained from high-fat-diet (HFD) induced obese mice. Results revealed no significant differences in methylation levels in loci between HFD- and normal-fat-diet (NFD)-fed mice, except for RNF43, a negative regulator of Wnt signaling, which showed hypermethylation in three loci. These findings indicate that, in mouse pancreatic exocrine cells, high-fat dietary obesity induced aberrant DNA methylation in RNF43 but not in other frequently mutated PC-related genes. [ABSTRACT FROM AUTHOR]

Fluorescence-guided surgery (FGS) is a technique that uses fluorescent contrast agents to accurately detect tumors during oncologic surgery. A folic acid analog called OTL-38 became the first clinically approved FGS agent in 2021. This study focuses on the development of a second-generation FGS agent, MMC(FNIR-Tag)-TOC, for pancreatic neuroendocrine tumors (pNETs). The agent targets somatostatin receptor subtype-2 (SSTR2), which is overexpressed in pNETs. The study demonstrates the binding of MMC(FNIR-Tag)-TOC to human tumors and its potential use for intraoperative tumor localization and assessment of surgical margins. Further research is planned to investigate the feasibility of using MMC(FNIR-Tag)-TOC for FGS in patients with pNETs. [Extracted from the article]

Severe acute pancreatitis (SAP), a widespread inflammatory condition impacting the abdomen with a high mortality rate, poses challenges due to its unclear pathogenesis and the absence of effective treatment options. Isorhamnetin (ISO), a naturally occurring flavonoid, demonstrates robust antioxidant and anti-inflammatory properties intricately linked to the modulation of mitochondrial function. However, the specific protective impact of ISO on SAP remains to be fully elucidated. In this study, we demonstrated that ISO treatment significantly alleviated pancreatic damage and reduced serum lipase and amylase levels in the mouse model of SAP induced by sodium taurocholate (STC) or L-arginine. Utilizing an in vitro SAP cell model, we found that ISO co-administration markedly prevented STC-induced pancreatic acinar cell necrosis, primarily by inhibiting mitochondrial ROS generation, preserving ATP production, maintaining mitochondrial membrane potential, and preventing the oxidative damage and release of mitochondrial DNA. Mechanistically, our investigation identified that high-temperature requirement A2 (HtrA2) may play a central regulatory role in mediating the protective effect of ISO on mitochondrial dysfunction in STC-injured acinar cells. Furthermore, through an integrated approach involving bioinformatics analysis, molecular docking analysis, and experimental validation, we uncovered that ISO may directly impede the histone demethylation activity of KDM5B, leading to the restoration of pancreatic HtrA2 expression and thereby preserving mitochondrial function in pancreatic acinar cells following STC treatment. In conclusion, this study not only sheds new light on the intricate molecular complexities associated with mitochondrial dysfunction during the progression of SAP but also underscores the promising value of ISO as a natural therapeutic option for SAP. [ABSTRACT FROM AUTHOR]

Pancreatic inflammation is a risk factor for the development of pancreatic cancer. Increased presence of inflammatory macrophages can be found in response to a KRAS mutation in acinar cells or in response to experimentally-induced pancreatitis. Inflammatory macrophages induce pancreatic acinar cells to undergo dedifferentiate to a duct-like progenitor stage, a process called acinar-to-ductal metaplasia (ADM). Occurrence of ADM lesions are believed to be the initiating event in tumorigenesis. Here we will discuss how macrophage-induced oxidative stress contributes to ADM and how ADM cells shape the fibrotic stroma needed for further progression. [ABSTRACT FROM AUTHOR]

Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC. [ABSTRACT FROM AUTHOR]

Mouse models of diet-induced type 2 diabetes mellitus provide powerful tools for studying the structural and physiological changes that are related to the disease progression. In this study, diabetic-like glucose dysregulation was induced in mice by feeding them a western diet, and light and transmission electron microscopy were used to study the ultrastructural changes in the pancreatic acinar cells. Acinar necrosis and vacuolization of the cytoplasm were the most prominent features. Furthermore, we observed intracellular and extracellular accumulation of lipid compounds in the form of lipid droplets, structural enlargement of the cisternae of the rough endoplasmic reticulum (RER), and altered mitochondrial morphology, with mitochondria lacking the typical organization of the inner membrane. Last, autophagic structures, i.e., autophagosomes, autolysosomes, and residual bodies, were abundant within the acinar cells of western diet-fed mice, and the autolysosomes contained lipids and material of varying electron density. While diets inducing obesity and type 2 diabetes are clearly associated with structural changes and dysfunction of the endocrine pancreas, we here demonstrate the strong effect of dietary intervention on the structure of acinar cells in the exocrine part of the organ before detectable changes in plasma amylase activity, which may help us better understand the development of non-alcoholic fatty pancreas disease and its association with endo- and exocrine dysfunction. [ABSTRACT FROM AUTHOR]

The immunoregulatory role of mesenchymal stem cells (MSCs) in inflammation is heterogeneous and can exhibit anti-inflammatory or proinflammatory properties depending on the microenvironment. We herein observed that the activation of Toll-like receptor 3 (TLR3) by polyinosinic : polycytidylic acid (poly(I : C)) stimulation facilitated the transformation of adipose-derived stem cells (ADSCs) into an anti-inflammatory phenotype. The enhanced anti-inflammatory properties were assessed in a taurocholate-induced pancreatitis model. The results demonstrated that poly(I : C) pretreated ADSCs exhibited enhanced anti-inflammatory properties than untreated ADSCs in taurocholate-induced pancreatitis. Mechanistically, poly(I : C)-treated ADSCs showed increased production and secretion of interleukin-10 (IL-10), which demonstrates a potent ability to alleviate inflammatory signaling cascades in acinar cells. Simultaneously, the heightened anti-inflammatory effects of poly(I : C)-treated ADSCs in pancreatitis were associated with the regulation of macrophage classical/alternative transformation, thereby mitigating inflammatory factor-mediated damage to the pancreatic acinar cell. We propose that TLR3 activation by poly(I : C) is an effective strategy to enhance the anti-inflammatory properties of MSCs, which offers a valuable consideration for improving the therapeutic efficacy of MSCs in inflammatory diseases. [ABSTRACT FROM AUTHOR]

This case report details a patient with Pancreatic Acinar Cell Carcinoma (PACC), a rare malignancy with distinctive biological and imaging features. In the absence of standardized treatment protocols for PACC, we embarked on a diagnostic journey that led to the adoption of an innovative therapeutic regimen in our institution. A 45-year-old female patient presented with a pancreatic mass, which was histologically confirmed as PACC following a biopsy. Subsequent genomic profiling revealed a high tumor mutational burden (21.4/Mb), prompting the initiation of combined immunotherapy and targeted therapy. Notably, the patient experienced a unique adverse reaction to the immunotherapy—recurrent subcutaneous soft tissue nodules, particularly in the gluteal and lower limb regions, accompanied by pain, yet resolving spontaneously. Following six cycles of the dual therapy, radiological evaluations indicated a decrease in tumor size, leading to a successful surgical excision. Over a 20-month postsurgical follow-up, the patient showed no signs of disease recurrence. This narrative adds to the existing knowledge on PACC and highlights the potential efficacy of immunotherapy in managing this challenging condition, emphasizing the importance of close monitoring for any adverse reactions. [ABSTRACT FROM AUTHOR]

Objective(s): Investigating the ameliorative effects of melatonin on cytokine levels, apoptosis, and NF-κB immunoreactivity in rats with cerulein-induced acute pancreatitis. Materials and Methods: Thirthy-two Wistar Albino rats were divided into four groups: Control group which didn't undergo acute pancreatitis induction and was left without treatment, pancreatitis group in which the acute pancreatitis was induced by 2 successive intraperitoneal doses of cerulein at a 2-hour interval (50 µg/kg and then 25 µg/kg), melatonin-treated pancreatitis group which was intraperitoneally administrated with 50 mg/kg of melatonin, 30 min before each cerulein injection, and melatonin group which was intraperitoneally administrated with 2 successive doses of melatonin (50 mg/kg each) at a 2-hour interval. Pancreatic tissue and blood samples were taken from animals of all groups. IL-1ß, TNF-a, and IL-10 levels were determined in blood samples. Apoptosis was determined by the TUNEL assay and the NF-κB was detected immunohistochemically in acinar cells of the exocrine pancreatic portion. Results: IL-1ß, TNF-a, and IL-10 levels in the acute pancreatitis group were significantly increased when compared to the control negative group. IL-1ß and TNF-a levels in the melatonin-treated pancreatitis group were significantly lower than those of the acute pancreatitis group. While number of apoptotic cells and percentage of NF-κB immunopositive cells in the acute pancreatitis group were significantly increased compared to other groups and it was observed that these parameters were significantly reduced in the melatonin-treated pancreatitis group compared to the acute pancreatitis group. Conclusion: These findings suggest that melatonin administration can significantly reduce the severity of acute pancreatitis in rats. [ABSTRACT FROM AUTHOR]

Pedigree analysis, clinical, gross, microscopic, ultrastructural, and lipidomic findings in 4 female superb bird-of-paradise (SBOP, Lophorina superba) siblings led to the diagnosis of a primary inherited glycerolipid storage disease. These birds were the offspring of a related breeding pair (inbreeding coefficient = 0.1797) and are the only known SBOPs to display this constellation of lesions. The birds ranged from 0.75 to 4.3 years of age at the time of death. Two birds were euthanized and 1 died naturally due to the disease, and 1 died of head trauma with no prior clinical signs. Macroscopic findings included hepatomegaly and pallor (4/4), cardiac and renal pallor (2/4), and coelomic effusion (1/4). Microscopic examination found marked tissue distortion due to cytoplasmic lipid vacuoles in hepatocytes (4/4), cardiomyocytes (4/4), renal tubular epithelial cells (4/4), parathyroid gland principal cells (2/2), exocrine pancreatic cells (3/3), and the glandular cells of the ventriculus and proventriculus (3/3). Ultrastructurally, the lipids were deposited in single to coalescing or fused droplets lined by an inconspicuous or discontinuous monolayer membrane. Lipidomic profiling found that the cytoplasmic lipid deposits were primarily composed of triacylglycerols. Future work, including sequencing of the SBOP genome and genotyping, will be required to definitively determine the underlying genetic mechanism of this disease. [ABSTRACT FROM AUTHOR]

Background & aimsMitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production.MethodsTwo models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts.ResultsBlocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis.ConclusionsCollectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Background: Malignant neoplasms arising from Meckel's diverticulum are rare and an adenocarcinoma in Meckel's diverticulum originating from ectopic pancreatic tissue is even rarer. Herein, we report a patient with an ectopic pancreatic adenocarcinoma in Meckel's diverticulum who was successfully treated with surgery and chemotherapy. Case presentation: A woman in her sixties presented to another hospital with abdominal pain. Plain computed tomography suggested an abdominal tumor and she was referred to our hospital. Enhanced computed tomography revealed a 23-mm low-density tumor in the abdominal cavity. Surgery was performed with a tentative diagnosis of a mesenteric tumor, such as a gastrointestinal stromal tumor, schwannoma, or lymphoma. First, we inspected the peritoneal cavity with a laparoscope. This revealed numerous nodules in the small bowel mesentery, suggesting peritoneal dissemination. A 20-mm-diameter white tumor was found in the small intestine and diagnosed as a small intestinal cancer. The small intestine was partially resected laparoscopically through a small skin incision. The patient's postoperative course was uneventful, and she was discharged on postoperative day 9. Pathological examination revealed well-differentiated adenocarcinoma in the small intestine. The tumor had developed from a sac-like portion protruding toward the serosal side and had a glandular structure lined with flattened atypical cells. Neither pancreatic acinar cells nor islets of Langerhans were evident, suggesting a Heinrich type 3 ectopic pancreas. The final diagnosis was an adenocarcinoma originating from an ectopic pancreas in Meckel's diverticulum. After a smooth recovery, the patient commenced chemotherapy for pancreatic cancer. Conclusions: We present a very rare case of ectopic pancreatic carcinoma in Meckel's diverticulum. [ABSTRACT FROM AUTHOR]

Our previous study confirmed that umbilical cord mesenchymal stem cells‐exosomes (ucMSC‐Ex) inhibit apoptosis of pancreatic acinar cells to exert protective effects. However, the relationship between apoptosis and autophagy in traumatic pancreatitis (TP) has rarely been reported. We dissected the transcriptomics after pancreatic trauma and ucMSC‐Ex therapy by high‐throughput sequencing. Additionally, we used rapamycin and MHY1485 to regulate mTOR. HE, inflammatory factors and pancreatic enzymatic assays were used to comprehensively determine the local versus systemic injury level, fluorescence staining and electron microscopy were used to detect the effect of autophagy, and observe the expression levels of autophagy‐related markers at the gene and protein levels. High‐throughput sequencing identified that autophagy played a crucial role in the pathophysiological process of TP and ucMSC‐Ex therapy. The results of electron microscopy, immunofluorescence staining, polymerase chain reaction and western blot suggested that therapeutic effect of ucMSC‐Ex was mediated by activation of autophagy in pancreatic acinar cells through inhibition of mTOR. ucMSC‐Ex can attenuate pancreas injury by inhibiting mTOR to regulate acinar cell autophagy after TP. Future studies will build on the comprehensive sequencing of RNA carried by ucMSC‐Ex to predict and verify specific non‐coding RNA. [ABSTRACT FROM AUTHOR]

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers. The cellular origin of human pancreatic ductal adenocarcinoma (PDAC) is still unclear. Here the authors used human primary acinar and ductal cells to successfully reconstitute PDAC tumorigenesis from both lineages and revealed transcriptional changes during early PDAC progression. [ABSTRACT FROM AUTHOR]

Alcohol is believed to harm acinar cells, pancreatic ductal epithelium, and pancreatic stellate cells. After giving ethanol and/or β-carotene to C57BL/6 mice, our goal was to evaluate their biochemistry, histology, and morpho-quantitative features. There were six groups of C57BL/6 mice: 1. Group C (control), 2. Group LA (low-dose alcohol), 3. Group MA (moderate-dose alcohol), 4. Group B (β-carotene), 5. Group LA + B (low-dose alcohol combined with β-carotene), and 6. Group MA + B (moderate-dose alcohol combined with β-carotene). After the animals were euthanized on day 28, each specimen's pancreatic tissue was taken. Lipase, uric acid, and amylase were assessed using biochemical assessment. Furthermore, the examination of the pancreatic structure was conducted using Ammann's fibrosis scoring system. Finally, the morpho-quantitative characteristics of the pancreatic islets and acinar cells were determined. In the serum of the MA + B group, there were higher amounts of total amylase (825.953 ± 193.412 U/L) and lower amounts of lipase (47.139 ± 6.099 U/L) (p < 0.05). Furthermore, Ammann's fibrosis punctuation in the pancreas revealed significant variations between the groups (p < 0.001). Finally, the stereological analysis of pancreatic islets showed that the groups were different (p < 0.001). These findings suggest that antioxidant treatments might help decrease the negative effects of ethanol exposure in animal models. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar cells. Secondary infection and sepsis are independent prognosticators for AP progression and increased mortality. Accumulating anatomical and epidemiological evidence suggests that the dysbiosis of gut microbiota affects the etiology and severity of AP through intestinal barrier disruption, local or systemic inflammatory response, bacterial translocation, and the regulatory role of microbial metabolites in AP patients and animal models. Recent studies discussing the interactions between gut microbiota and the pancreas have opened new scopes for AP, and new therapeutic interventions that target the bacteria community have received substantial attention. This review concentrates on the alterations of gut microbiota and its roles in modulating gut–pancreas axis in AP. The potential therapies of targeting microbes as well as the major challenges of applying those interventions are explored. We expect to understand the roles of microbes in AP diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Acute pancreatitis is initiated within pancreatic exocrine cells and sustained by dysregulated systemic inflammatory responses mediated by neutrophils. Store-operated Ca2+ entry (SOCE) through ORAI1 channels in pancreatic acinar cells triggers acute pancreatitis, and ORAI1 inhibitors ameliorate experimental acute pancreatitis, but the role of ORAI1 in pancreatitis-associated acute lung injury has not been determined. Here, we showed mice with pancreas-specific deletion of Orai1 (Orai1ΔPdx1, ∼70% reduction in the expression of Orai1) are protected against pancreatic tissue damage and immune cell infiltration, but not pancreatitis-associated acute lung injury, suggesting the involvement of unknown cells that may cause such injury through SOCE via ORAI1. Genetic (Orai1ΔMRP8) or pharmacological inhibition of ORAI1 in murine and human neutrophils decreased Ca2+ influx and impaired chemotaxis, reactive oxygen species production, and neutrophil extracellular trap formation. Unlike pancreas-specific Orai1 deletion, mice with neutrophil-specific deletion of Orai1 (Orai1ΔMRP8) were protected against pancreatitis- and sepsis-associated lung cytokine release and injury, but not pancreatic injury in experimental acute pancreatitis. These results define critical differences between contributions from different cell types to either pancreatic or systemic organ injury in acute pancreatitis. Our findings suggest that any therapy for acute pancreatitis that targets multiple rather than single cell types is more likely to be effective. Graphical Abstract [ABSTRACT FROM AUTHOR]