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Frontiers in Endocrinology 2023To assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and...
OBJECTIVE
To assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and the risk of cardiometabolic diseases.
METHOD
A prospective, multicenter study including NAFLD patients with biopsy and paired Magnetic Resonance Imaging (MRI) was performed. Liver biopsies were evaluated according to NASH Clinical Research Network, hepatic iron storages were scored, and digital pathology quantified the tissue proportionate areas of fat and iron. MRI-biomarkers of fat fraction (PDFF) and iron accumulation (R2*) were obtained from the liver and pancreas. Different metabolic traits were evaluated, cardiovascular disease (CVD) risk was estimated with the atherosclerotic CVD score, and the severity of iron metabolism alteration was determined by grading metabolic hiperferritinemia (MHF). Associations between CVD, histology and MRI were investigated.
RESULTS
In total, 324 patients were included. MRI-determined pancreatic iron overload and moderate-to severe steatosis were present in 45% and 25%, respectively. Liver and pancreatic MRI-biomarkers showed a weak correlation (r=0.32 for PDFF, r=0.17 for R2*). Pancreatic PDFF increased with hepatic histologic steatosis grades and NASH diagnosis (<0.001). Prevalence of pancreatic steatosis and iron overload increased with the number of metabolic traits (<0.001). Liver R2* significantly correlated with MHF (AUC=0.77 [0.72-0.82]). MRI-determined pancreatic steatosis (OR=3.15 [1.63-6.09]), and iron overload (OR=2.39 [1.32-4.37]) were independently associated with high-risk CVD. Histologic diagnosis of NASH and advanced fibrosis were also associated with high-risk CVD.
CONCLUSION
Pancreatic steatosis and iron overload could be of utility in clinical decision-making and prognostication of NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Cardiovascular Diseases; Prospective Studies; Risk Factors; Lipid Metabolism Disorders; Pancreatic Diseases; Iron Overload; Iron; Heart Disease Risk Factors
PubMed: 37600695
DOI: 10.3389/fendo.2023.1213441 -
Molecular Medicine Reports Jul 2024As a pluripotent cell, activated pancreatic stellate cells (PSCs) can differentiate into various pancreatic parenchymal cells and participate in the secretion of... (Review)
Review
As a pluripotent cell, activated pancreatic stellate cells (PSCs) can differentiate into various pancreatic parenchymal cells and participate in the secretion of extracellular matrix and the repair of pancreatic damage. Additionally, PSCs characteristics allow them to contribute to pancreatic inflammation and carcinogenesis. Moreover, a detailed study of the pathogenesis of activated PSCs in pancreatic disease can offer promise for the development of innovative therapeutic strategies and improved patient prognoses. Therefore, the present study review aimed to examine the involvement of activated PSCs in pancreatic diseases and elucidate the underlying mechanisms to provide a viable therapeutic strategy for the management of pancreas‑related diseases.
Topics: Humans; Pancreatic Stellate Cells; Pancreas; Pancreatic Diseases; Animals; Extracellular Matrix; Cell Differentiation; Pancreatic Neoplasms
PubMed: 38695254
DOI: 10.3892/mmr.2024.13233 -
Digestive Endoscopy : Official Journal... Sep 2023Pancreatic fluid collections (PFCs) typically develop as local complications of acute pancreatitis and complicate the clinical course of patients with acute pancreatitis... (Review)
Review
Pancreatic fluid collections (PFCs) typically develop as local complications of acute pancreatitis and complicate the clinical course of patients with acute pancreatitis and potentially fatal clinical outcomes. Interventions are required in cases of symptomatic walled-off necrosis (WON) (matured PFCs with necrosis) and pancreatic pseudocysts (matured PFCs without necrosis). In the management of necrotizing pancreatitis and WON, endoscopic ultrasound-guided transluminal drainage combined with on-demand endoscopic necrosectomy (i.e. the step-up approach) is increasingly used as a less invasive treatment modality compared with a surgical or percutaneous approach. Through the substantial research efforts and development of specific devices and stents (e.g. lumen-apposing metal stents), endoscopic techniques of PFC management have been standardized to some extent. However, there has been no consensus about timing of carrying out each treatment step; for instance, it is uncertain when direct endoscopic necrosectomy should be initiated and finished and when a plastic or metal stent should be removed following clinical treatment success. Despite emerging evidence for the effectiveness of noninterventional supportive treatment (e.g. antibiotics, nutritional support, irrigation of the cavity), there has been only limited data on the timing of starting and stopping the treatment. Large studies are required to optimize the timing of those treatment options and improve clinical outcomes of patients with PFCs. In this review, we summarize the current available evidence on the indications and timing of interventional and supportive treatment modalities for this patient population and discussed clinical unmet needs that should be addressed in future research.
Topics: Humans; Acute Disease; Pancreatitis, Acute Necrotizing; Endoscopy; Treatment Outcome; Drainage; Stents; Necrosis; Retrospective Studies
PubMed: 37209365
DOI: 10.1111/den.14598 -
Phytomedicine : International Journal... Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling exerts a vital effect on the growth and progression of PDAC. While dietary flavonoid phloretin has anti-inflammatory and antioxidant activities, it remains unclear whether phloretin has anti-tumor effects on PDAC.
PURPOSE
The focus of the present study is to elucidate the effects of phloretin on PDAC and investigate its underlying molecular mechanisms.
STUDY DESIGN AND METHODS
Effect of phloretin were assessed in the pancreatic cancer cells (PCCs) by colony formation assay, real-time cell analysis, flow cytometry, Immunofluorescence staining, and cell migration assay. The expressions of mRNA and protein were respectively analyzed by quantitative PCR and Western blotting. A xenograft model was used to appraise the antitumor efficacy of phloretin.
RESULTS
Phloretin treatment significantly restrained cell viability and metastasis, induced DNA injury and ROS accumulation, and triggered mitochondrial-dependent apoptosis in PCCs. Mechanistically, phloretin exhibits anti-tumor potential via inactivating STAT3 signaling and enhancing Nrf2 activity. STAT3 overexpression and Nrf2 silencing partially relieved phloretin-induced inhibition on cell growth and metastasis in PCCs. Phloretin remarkably blocked pancreatic tumor growth and metastasis in vivo.
CONCLUSIONS
Phloretin suppresses pancreatic cancer growth and progression through inhibition of STAT3 mediated by enhancing Nrf2 activity. Phloretin may serve as a promising therapeutic agent for PDAC.
Topics: Humans; NF-E2-Related Factor 2; Phloretin; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cell Proliferation; Gene Expression Regulation, Neoplastic; STAT3 Transcription Factor
PubMed: 37494874
DOI: 10.1016/j.phymed.2023.154990 -
Frontiers in Immunology 2023The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor antagonist (IL-1RA) levels reduce the risk of acute and chronic pancreatitis and pancreatic cancer.
METHODS
Genetic variants associated with blood IL-1RA levels at the genome-wide significance level and located 5MB downstream or upstream of the gene were extracted from a genome-wide meta-analysis of 21,758 participants. After pruning, genetic variants without linkage disequilibrium were used as genetic instrument for IL-1RA. Summary-level data on acute and chronic pancreatitis and pancreatic cancer were obtained from the UK Biobank and FinnGen studies. The associations were meta-analyzed for one outcome from two sources.
RESULTS
Genetically predicted higher levels of IL-1RA were associated with a lower risk of acute and chronic pancreatitis and pancreatic cancer. In the meta-analysis of UK Biobank and FinnGen, the combined odds ratio was 0.87 (95% confidence interval [CI] 0.77-0.97, =0.003) for acute pancreatitis, 0.73 (95% CI 0.65-0.82, =2.93×10) for chronic pancreatitis, and 0.86 (95% CI 0.77-0.96, =0.009) for pancreatic cancer per one standard deviation increment in genetically predicted levels of IL-1RA.
CONCLUSION
This study suggests a protective role of IL-1RA in three major pancreatic diseases, which hints the therapeutic potentials of IL-1RA in pancreatic diseases.
Topics: Humans; Interleukin 1 Receptor Antagonist Protein; Acute Disease; Mendelian Randomization Analysis; Receptors, Interleukin-1; Pancreatitis, Chronic; Pancreatic Neoplasms
PubMed: 37781392
DOI: 10.3389/fimmu.2023.1240754 -
Frontiers in Immunology 2023Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease mainly affecting the rectum and colon and causing diarrhoea and mucopurulent stools. UC can present... (Review)
Review
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease mainly affecting the rectum and colon and causing diarrhoea and mucopurulent stools. UC can present with extraintestinal manifestations in various organs and systems and can be associated with various comorbidities. Autoimmune pancreatitis (AIP) is a specific type of pancreatitis associated with autoimmune abnormalities and is divided into two clinical types: type 1 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic ductocentric pancreatitis). The current study shows an association between type 2 AIP and UC, which may be related to genetic susceptibility, inflammatory factors, and immune response. The most common manifestation of AIP in patients with type 2 AIP-UC is abdominal pain with elevated pancreatic enzymes, whereas the presentation of UC in type 2 AIP-UC is more severe, with an increased risk of UC-related surgery. This review focuses on diagnosis, prevalence, pathogenesis, impact, and treatment to better understand type 2 AIP-UC, explore the molecular mechanisms of this condition, and encourage further research into the management of type 2 AIP-UC.
Topics: Humans; Colitis, Ulcerative; Autoimmune Pancreatitis; Retrospective Studies; Autoimmune Diseases; Pancreatitis
PubMed: 38124742
DOI: 10.3389/fimmu.2023.1288390 -
United European Gastroenterology Journal Nov 2023Chronic Pancreatitis (CP) causes morphological changes in the pancreatic tissue, leading to complications and pain, which may require endoscopic interventions.
BACKGROUND
Chronic Pancreatitis (CP) causes morphological changes in the pancreatic tissue, leading to complications and pain, which may require endoscopic interventions.
OBJECTIVE
Our aim was to determine the frequency of endoscopic procedures (EP) in CP patients and to analyse pain and quality of life (QoL) in these patients after their EP.
METHODS
This study included 1327 CP patients from the Scandinavian Baltic Pancreatic Club (SBPC) database including four countries and eight centres. We analysed patients undergoing EPs and gathered information on the EP, pancreatic function, pain, disease and duration. The EORTC C-30 QoL questionnaire was gathered prospectively and multivariable analysis was conducted on independent parameters between the groups. The reference population had no interventions (n = 870).
RESULTS
260 CP patients (22%) underwent EPs, median one year (range 0-39 years) after CP diagnosis. 68% were males. The median age was 59 (20-90) years. Most common aetiological factors were alcohol in 65% and smoking in 71%. Extracorporeal shock wave lithotripsy (ESWL) was used in 6% of the CP population and in 21% of the EP group. Biliary duct stenting was performed on 37% and pancreatic stenting was performed on 56% of the patients. There was no difference in pain patterns between patients who had pancreatic stenting and the reference population. The EP group had slightly better QoL (p = 0.047), functioning and fewer symptoms than the reference population, in the multivariable analysis there was no interaction effect analysis between the groups. The pancreatic stent group had better QoL and the same amount of pain than the reference group. The patients who needed later surgery (23%) had more pain (p = 0.043) and fatigue (p = 0.021).
CONCLUSIONS
One in five of the CP patients underwent EP. These patients scored higher on QoL responses and had better symptom scores. CP patients who had pancreatic stenting performed had the same pain patterns as the reference population. Randomised prospective trials are needed to determine the effect of endoscopy procedures on CP patients.
Topics: Male; Humans; Middle Aged; Female; Quality of Life; Prospective Studies; Pancreatic Ducts; Pancreatitis, Chronic; Endoscopy; Pain
PubMed: 37812591
DOI: 10.1002/ueg2.12466 -
Clinical Cancer Research : An Official... Dec 2023Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis...
PURPOSE
Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1α (HIF-1α) and its mechanistic roles underlying PDA response to oxygen and glucose restrains.
EXPERIMENTAL DESIGN
Gene expression and its association with clinicopathologic characteristics of patients with PDA and mouse models were analyzed using IHC. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-immunoprecipitation, and dual luciferase reporter.
RESULTS
There was concomitant overexpression of both GRP78 and HIF-1α in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1α, particularly colocalization in nucleus. Induction of HIF-1α expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1α and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1α protein complexes to the promoters of HIF-1α and LDHA genes and transactivation of their transcriptional activity.
CONCLUSIONS
Protein complex of GRP78 and HIF-1α directly binds to HIF-1α own promoter and LDHA promoter, enhances the transcription of both HIF-1α and LDHA, whereas glucose deprivation increases GRP78 expression and further enhances HIF-1α and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Glucose; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Metabolic Reprogramming; Pancreatic Neoplasms
PubMed: 37819952
DOI: 10.1158/1078-0432.CCR-23-1143 -
Birth Defects Research Nov 2023Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy... (Review)
Review
Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes to control gene expression during differentiation to generate all of the distinct pancreatic cell types. Epigenetic changes involving DNA methylation and histone modifications can be controlled by noncoding RNAs (ncRNAs). Indeed, increasing evidence suggests that ncRNAs are indispensable for proper organogenesis. Here, we summarize recent insight into the role of ncRNAs in the epigenetic regulation of pancreatic development. We further discuss how disruptions in ncRNA biogenesis and expression lead to developmental defects and diseases. This review summarizes in vivo data from animal models and in vitro studies using stem cell differentiation as a model for pancreatic development.
Topics: Animals; Epigenesis, Genetic; RNA, Untranslated; Pancreas; Pancreatic Neoplasms; Diabetes Mellitus
PubMed: 37066622
DOI: 10.1002/bdr2.2178 -
BMC Pediatrics Oct 2023Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic...
BACKGROUND
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS.
METHODS
We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included.
RESULTS
The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years.
CONCLUSIONS
Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.
Topics: Female; Humans; Infant; Male; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Mutation; Phenotype; Shwachman-Diamond Syndrome; Signal Recognition Particle
PubMed: 37803383
DOI: 10.1186/s12887-023-04324-3