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Heliyon Apr 2024The symptom of hyposalivation associated with hypofunction of the salivary glands is a common feature of diabetes. Inadequate saliva production can cause tissue damage...
The symptom of hyposalivation associated with hypofunction of the salivary glands is a common feature of diabetes. Inadequate saliva production can cause tissue damage in the mouth, making it susceptible to infections and leading to oral health diseases. Previous studies have highlighted the harmful effects of methylglyoxal (MGO) and MGO-derived advanced glycation end products (AGEs) in diabetes. In this study, we investigated the protective effects of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, against MGO-induced salivary gland dysfunction. MGO treatment of immortalized human salivary gland acinar cells induced apoptosis via reactive oxygen species (ROS)-mediated pathways, but this effect was mitigated by gemigliptin. In vivo experiments involved the simultaneous administration of MGO (17.25 mg/kg) with aminoguanidine (100 mg/kg) and gemigliptin (10 and 100 mg/kg) daily to rats for two weeks. Gemigliptin increased the saliva volume and amylase levels in MGO-injected rats. Gemigliptin reduced the DPP-4 activity in both the salivary glands and serum of MGO-injected rats. Furthermore, gemigliptin exerted anti-glycation effects by reducing the accumulation of AGEs in the saliva, salivary glands, and serum and suppressing the expression of the receptor for AGEs. These actions protected the salivary gland cells from ROS-mediated apoptosis. Overall, gemigliptin protected the salivary gland cells from ROS-mediated cell death, reduced the accumulation of amylase and mucins in the salivary glands, and enhanced the salivary function by upregulating aquaporin 5 expression, and it exerted protective effects against MGO-induced salivary gland dysfunction by enhancing the anti-glycation, antioxidant, and salivary secretion activities. Our findings suggest gemigliptin as a potential therapeutic for patients with salivary gland dysfunction caused by the complications of diabetes.
PubMed: 38628768
DOI: 10.1016/j.heliyon.2024.e29362 -
Frontiers in Cellular and Infection... 2024To determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism.
PURPOSE
To determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism.
METHODS
AG6 mice aged two to three weeks were randomly divided into control and EV-A71 infected groups. Slit-lamp observation, fluorescein staining, and phenol red thread test were used to assess symptoms of ocular surface at 4 dpi (days post infection). The pathological changes of cornea and lacrimal gland were observed by H&E staining, PAS staining, TUNEL assay, IHC staining and qRT-PCR. Corneas and lacrimal glands from mice were obtained and processed for RNA sequencing analysis. Newly diagnosed HFMD patients caused by EV-A71 were recruited and ensured they met the inclusion criteria. Ocular surface parameters (TMH and NIKBUT) were measured using the OCULUS Keratograph 5M. Tear samples were taken to examine Cxcl1 and IL-6 levels through the ELISA method.
RESULTS
Mice studies revealed that EV-A71 infection caused tear film instability, decreased tear secretions, decreased in lacrimal gland size, and distinct goblet cell loss. It also resulted in increased large vacuoles within acinar cells and structural damage in lacrimal gland. Apart from minor damage to the epidermis, there was no obvious inflammatory changes or apoptosis in the cornea. However, there were significant inflammatory injury and apoptosis in the lacrimal gland. RNA-seq analysis showed IL-17 and NF-κB signaling pathways were activated in the lacrimal glands of mice infected with EV-A71. In HFMD patients, the THM was in a low range and NITBUT was significantly shorter than the control group by Oculus Keratograph 5M. ELISA assay showed a higher tear Cxcl1 and IL-6 level in them.
CONCLUSION
EV-A71 infection affected lacrimal gland structure and function and induced dry eye-like symptoms.
Topics: Humans; Animals; Mice; Enterovirus; Lacrimal Apparatus; Interleukin-6; Enterovirus Infections; Dry Eye Syndromes; Enterovirus A, Human
PubMed: 38628549
DOI: 10.3389/fcimb.2024.1340075 -
Surgical Case Reports Apr 2024A 61-year-old female was referred to our hospital with a neoplastic lesion in the duodenum. Computed tomography with contrast enhancement revealed a 10-mm tumor in the...
CASE PRESENTATION
A 61-year-old female was referred to our hospital with a neoplastic lesion in the duodenum. Computed tomography with contrast enhancement revealed a 10-mm tumor in the duodenum. Upper gastrointestinal endoscopy revealed a submucosal tumor-like lesion in the descending part of the duodenum. Endoscopic ultrasound revealed a well-defined hypoechoic tumor. Biopsy and immunohistochemical findings including negative Synaptophysin and Chromogranin A staining and positive Trypsin and BCL10 staining suggested a carcinoma with acinar cell differentiation. Pancreatoduodenectomy was performed, and the resected specimen had a 15-mm solid nodule in the submucosal layer of the duodenum. Pancreatogram of the resected specimen revealed a tumor localized in the accessory papilla region. In histopathological examination, the tumor was found in the submucosa of the duodenum with pancreatic tissue present nearby, and these were separated from the pancreatic parenchyma by the duodenal muscle layer. These findings led to a diagnosis of acinar cell carcinoma originating from the accessory papilla of the duodenum.
CONCLUSION
Acinar cell carcinoma originating from the accessory papilla of the duodenum is exceptionally rare, with no reported cases to date. The origin was considered to be pancreatic tissue located in the accessory papilla region.
PubMed: 38625458
DOI: 10.1186/s40792-024-01872-3 -
World Journal of Gastroenterology Mar 2024Increasing evidence has demonstrated that N6-methyladenosine (mA) RNA modification plays an essential role in a wide range of pathological conditions. Impaired autophagy...
BACKGROUND
Increasing evidence has demonstrated that N6-methyladenosine (mA) RNA modification plays an essential role in a wide range of pathological conditions. Impaired autophagy is a critical hallmark of acute pancreatitis (AP).
AIM
To explore the role of the mA modification of in the regulation of autophagy in AP.
METHODS
The AP mouse cell model was established by cerulein-treated mouse pancreatic acinar cells (MPC-83), and the results were confirmed by the levels of amylase and inflammatory factors. Autophagy activity was evaluated by specific identification of the autophagy-related microstructure and the expression of autophagy-related genes. and were knocked down to study the function in AP. A mA RNA binding protein immunoprecipitation assay was used to study how the m6A modification of mRNA is regulated by .
RESULTS
The increased expression of amylase and inflammatory factors in the supernatant and the accumulation of autophagic vacuoles verified that the AP mouse cell model was established. The downregulation of and upregulation of and demonstrated that autophagy was impaired in AP. The expression of was upregulated in AP. Inhibition of increased the expression of and decreased the expression of the inflammatory factors, and . Furthermore, was upregulated in AP. Knockdown of downregulated expression and restored decreased autophagic flux in AP. Notably, the bioinformatic analysis revealed 23 potential mA modification sites on mRNA. The mA modification of mRNA was significantly decreased in AP. Knockdown of increased the modification of mRNA, which confirmed that upregulated expression in a mA-dependent manner.
CONCLUSION
inhibits autophagic flux through mA demethylation of mRNA in AP, thereby aggravating the severity of the disease.
Topics: Animals; Mice; Acute Disease; Adenosine; Amylases; Autophagy; Demethylation; Disease Models, Animal; Pancreatitis; RNA, Messenger; Sequestosome-1 Protein; Transcription Factors
PubMed: 38617741
DOI: 10.3748/wjg.v30.i12.1764 -
International Journal of Molecular... Mar 2024Severe acute pancreatitis (SAP), a widespread inflammatory condition impacting the abdomen with a high mortality rate, poses challenges due to its unclear pathogenesis...
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.
Topics: Animals; Mice; Pancreatitis; Acute Disease; Molecular Docking Simulation; Mitochondria; Signal Transduction; Mitochondrial Diseases; Quercetin
PubMed: 38612598
DOI: 10.3390/ijms25073784 -
Journal of Translational Medicine Apr 2024Acute pancreatitis (AP) is a clinically common acute abdominal disease, whose pathogenesis remains unclear. The severe patients usually have multiple complications and...
BACKGROUND
Acute pancreatitis (AP) is a clinically common acute abdominal disease, whose pathogenesis remains unclear. The severe patients usually have multiple complications and lack specific drugs, leading to a high mortality and poor outcome. Acinar cells are recognized as the initial site of AP. However, there are no precise single-cell transcriptomic profiles to decipher the landscape of acinar cells during AP, which are the missing pieces of jigsaw we aimed to complete in this study.
METHODS
A single-cell sequencing dataset was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in acinar cells. The pathways' activities were evaluated by gene sets enrichment analysis (GSEA) and single-cell gene sets variation analysis (GSVA). Pseudotime analysis was performed to describe the development trajectories of acinar cells. We also constructed the protein-protein interaction (PPI) network and identified the hub genes. Another independent single-cell sequencing dataset of pancreas samples from AP mice and a bulk RNA sequencing dataset of peripheral blood samples from AP patients were also analyzed.
RESULTS
In this study, we identified genetic markers of each cell type in the pancreas of AP mice based on single-cell sequencing datasets and analyzed the transcription changes in acinar cells. We found that acinar cells featured acinar-ductal metaplasia (ADM), as well as increased endocytosis and vesicle transport activity during AP. Notably, the endoplasmic reticulum stress (ERS) and ER-associated degradation (ERAD) pathways activated by accumulation of unfolded/misfolded proteins in acinar cells could be pivotal for the development of AP.
CONCLUSION
We deciphered the distinct roadmap of acinar cells in the early stage of AP at single-cell level. ERS and ERAD pathways are crucially important for acinar homeostasis and the pathogenesis of AP.
Topics: Humans; Mice; Animals; Pancreatitis; Acinar Cells; RNA-Seq; Acute Disease; Endoplasmic Reticulum Stress
PubMed: 38605381
DOI: 10.1186/s12967-024-05156-0 -
World Journal of Clinical Cases Mar 2024Postoperative pancreatic fistula (POPF) contributes significantly to morbidity and mortality after pancreaticoduodenectomy (PD). However, the underlying mechanisms...
BACKGROUND
Postoperative pancreatic fistula (POPF) contributes significantly to morbidity and mortality after pancreaticoduodenectomy (PD). However, the underlying mechanisms remain unclear. This study explored this pathology in the pancreatic stumps and elucidated the mechanisms of POPF following PD.
CASE SUMMARY
Pathological analysis and 16S rRNA gene sequencing were performed on specimens obtained from two patients who underwent complete pancreatectomy for grade C POPF after PD. Gradient inflammation is present in the pancreatic stump. The apoptosis was lower than that in the normal pancreas. Moreover, neutrophil-dominated inflammatory cells are concentrated in the ductal system. Notably, neutrophils migrated through the ductal wall in acinar duct metaplasia-formed ducts. Additionally, evidence indicates that gut microbes migrate from the digestive tract. Gradient inflammation occurs in pancreatic stumps after PD.
CONCLUSION
The mechanisms underlying POPF include high biochemical activity in the pancreas, mechanical injury, and digestive reflux. To prevent POPF and address pancreatic inflammation and reflux, breaking the link with anastomotic dehiscence is practical.
PubMed: 38576729
DOI: 10.12998/wjcc.v12.i9.1649 -
Frontiers in Immunology 2024Pancreatic inflammation is a risk factor for the development of pancreatic cancer. Increased presence of inflammatory macrophages can be found in response to a KRAS... (Review)
Review
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 dedifferentiation 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.
Topics: Humans; Reactive Oxygen Species; Signal Transduction; Pancreatic Neoplasms; Pancreatitis; Macrophages
PubMed: 38576613
DOI: 10.3389/fimmu.2024.1278807 -
Developmental Cell May 2024UBE2F, a neddylation E2, neddylates CUL5 to activate cullin-RING ligase-5, upon coupling with neddylation E3 RBX2/SAG. Whether and how UBE2F controls pancreatic...
UBE2F, a neddylation E2, neddylates CUL5 to activate cullin-RING ligase-5, upon coupling with neddylation E3 RBX2/SAG. Whether and how UBE2F controls pancreatic tumorigenesis is previously unknown. Here, we showed that UBE2F is essential for the growth of human pancreatic cancer cells with KRAS mutation. In the mouse Kras pancreatic ductal adenocarcinoma (PDAC) model, Ube2f deletion suppresses cerulein-induced pancreatitis, and progression of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Mechanistically, Ube2f deletion inactivates the Mapk-c-Myc signals via blocking ubiquitylation of Diras2, a substrate of CRL5 E3 ligase. Biologically, DIRAS2 suppresses growth and survival of human pancreatic cancer cells harboring mutant KRAS, and Diras2 deletion largely rescues the phenotypes induced by Ube2f deletion. Collectively, Ube2f or Diras2 plays a tumor-promoting or tumor-suppressive role in the mouse Kras PDAC model, respectively. The UBE2F-CRL5 axis could serve as a valid target for pancreatic cancer, whereas the levels of UBE2F or DIRAS2 may serve as prognostic biomarkers for PDAC patients.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Genes, Tumor Suppressor; Oncogenes; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 38574733
DOI: 10.1016/j.devcel.2024.03.018 -
Cureus Mar 2024Acute pancreatitis, marked by sudden inflammation of the pancreas, presents a complex spectrum of causative factors including gallstone obstruction, alcohol abuse, and... (Review)
Review
Acute pancreatitis, marked by sudden inflammation of the pancreas, presents a complex spectrum of causative factors including gallstone obstruction, alcohol abuse, and viral infections. Recent studies have illuminated the emergence of vaccine-induced acute pancreatitis, notably associated with COVID-19 vaccinations, presenting diverse mechanisms ranging from direct viral-mediated injury to autoimmune reactions. Understanding this link is pivotal for public health, yet challenges persist in identifying and managing cases post-vaccination. Comprehensive literature reviews employing the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement outline the potential pathways and mechanisms leading to vaccine-induced pancreatitis, emphasizing the need for deeper investigations into underlying health conditions and modifications to vaccine components. Notably, the rare occurrences of vaccine-induced pancreatitis extend beyond COVID-19 vaccines, with reports also documenting associations with measles, mumps, and rubella (MMR), human papillomavirus (HPV), and other viral vaccinations. Mechanistically, hypotheses such as molecular mimicry and immunologic injury have been proposed, necessitating ongoing vigilance and exploration. Regulatory agencies play a crucial role in monitoring and communicating vaccine safety concerns, emphasizing transparency to address potential risks and maintain public trust. Understanding and communicating these rare adverse events with transparency remain integral for informed vaccination policies and to allay concerns surrounding vaccine safety.
PubMed: 38571842
DOI: 10.7759/cureus.55426