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Nature Cell Biology Mar 2024Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors....
Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors. Here, we report that N-methyladenosine (mA) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. mA writer methyltransferase 3 (METTL3) levels increase drastically in β-cells at T1D onset but rapidly decline with disease progression. mA sequencing revealed the mA hypermethylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-βH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in β-cells delayed diabetes progression in the non-obese diabetic mouse model of T1D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human β-cells. Collectively, we report that mA regulates the innate immune response at the β-cell level during the onset of T1D in humans.
Topics: Animals; Humans; Mice; Adenosine Deaminase; Diabetes Mellitus, Type 1; Immunity, Innate; Insulin-Secreting Cells; Methyltransferases; Oxidation-Reduction
PubMed: 38409327
DOI: 10.1038/s41556-024-01368-0 -
Respiratory Research Aug 2023Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease...
BACKGROUND
Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear.
METHODS
We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD.
RESULTS
Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality.
CONCLUSIONS
AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD.
TRIAL REGISTRATION
This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).
Topics: Animals; Mice; Apoptosis; Cohort Studies; Emphysema; Immunoglobulin M; Macrophages; Matrix Metalloproteinase 12; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Humans; Apoptosis Regulatory Proteins
PubMed: 37592330
DOI: 10.1186/s12931-023-02508-0 -
Frontiers in Endocrinology 2023Coronavirus disease 2019 (COVID-19) caused a major pandemic affecting human health and economy around the world since the beginning of 2020. The virus responsible for... (Review)
Review
Coronavirus disease 2019 (COVID-19) caused a major pandemic affecting human health and economy around the world since the beginning of 2020. The virus responsible for the disease is "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). It invades the target cells by binding to angiotensin-converting enzyme 2 (ACE2). ACE2 is expressed in several organs including endocrine glands. Multiple endocrine and metabolic systems including the endocrine pancreas have been impacted by COVID-19 infection/pandemic. COVID-19 pandemic can promote obesity through alterations in lifestyle (e.g., unhealthy diet and reduced physical activity due to confinement and isolation) leading to type 2 diabetes and/or can directly impair the function of the endocrine pancreas particularly through a cytokine storm, promoting or aggravating type 1 or type 2 diabetes. The increased ACE2 receptors of high adiposity commonly associated with type 2 diabetes and the chronic hyperglycemia of diabetes with its negative impact on the immune system can increase the risk of COVID-19 infection and its morbidity/mortality. In conclusion, there are bidirectional interactions between COVID-19 pandemic and diabetes (e.g., COVID-19 infection can impact diabetes and diabetes can impact COVID-19 infection). The services offered by healthcare systems for the management of diabetes have been adapted accordingly.
Topics: Humans; COVID-19; SARS-CoV-2; Renin-Angiotensin System; Angiotensin-Converting Enzyme 2; Peptidyl-Dipeptidase A; Diabetes Mellitus, Type 2; Pandemics
PubMed: 38292772
DOI: 10.3389/fendo.2023.1306290 -
Journal of Biochemical and Molecular... Apr 2024The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is... (Review)
Review
The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1β into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.
Topics: Humans; Substance P; Neuralgia; Pancreas; Pancreatic Neoplasms; Fibroblasts; Tumor Microenvironment
PubMed: 38613466
DOI: 10.1002/jbt.23638 -
European Journal of Pharmacology Oct 2023Ferroptosis, a new type of cell death, is associated with pancreatic β cell damage. However, the role of glucolipotoxicity in inducing β cell ferroptosis remains...
Ferroptosis, a new type of cell death, is associated with pancreatic β cell damage. However, the role of glucolipotoxicity in inducing β cell ferroptosis remains unclear. Metformin (Met), exenatide (Exe), and saxagliptin (Sax) are frequently used anti-hyperglycaemic drugs. However, their protective effects on β cells through ferroptosis modulation are not well-established. In this study, we observed significant ferroptosis in NIT-1 cells and primary mouse islets after exposure to high glucose and palmitate (HG/PA). Compared to Exe and Sax, Met significantly alleviated glucolipotoxicity-induced pancreatic β cell ferroptosis. Blocking the activity of glutathione peroxidase 4 (GPX4) with Ras-selective lethal 3 or inhibiting its expression by small interfering RNA transfection significantly attenuated the anti-ferroptosis effects of Met. Mechanistically, Met alleviates HG/PA-induced β cell ferroptosis by regulating the GPX4/ACSL4 axis. Collectively, our findings highlight the significance of ferroptosis in pancreatic β cell glucolipotoxicity-induced injury and provide novel insights into the protective effects of Met on islet β cells.
Topics: Animals; Mice; Cell Death; Ferroptosis; Insulin-Secreting Cells; Islets of Langerhans; Metformin
PubMed: 37549729
DOI: 10.1016/j.ejphar.2023.175967 -
Journal of Visceral Surgery Dec 2023The morbidity and mortality of pancreatic cancer surgery has seen substantial improvement due to the standardization of surgical techniques, the optimization of... (Review)
Review
The morbidity and mortality of pancreatic cancer surgery has seen substantial improvement due to the standardization of surgical techniques, the optimization of perioperative multidisciplinary management and the organization of specialized care systems. The identification and treatment of postoperative functional and nutritional sequelae have thereby become major issues in patients who undergo pancreatic surgery. This review addresses the functional sequelae of pancreatic resection for cancerous and pre-cancerous lesions (excluding chronic pancreatitis). Its aim is to specify the prevalence and severity of sequelae according to the type of pancreatic resection and to document, where appropriate, the therapeutic management. Exocrine pancreatic insufficiency (ExPI) is observed in nearly one out of three patients at one year after surgery, and endocrine pancreatic insufficiency (EnPI) is present in one out of five patients after pancreatoduodenectomy (PD) and one out of three patients after distal pancreatectomy (DP). In addition, digestive functional disorders may appear, such as delayed gastric emptying (DGE), which affects 10 to 45% of patients after PD and nearly 8% after DP. Beyond these functional sequelae, pancreatic surgery can also induce nutritional and vitamin deficiencies secondary to a lack of uptake for certain vitamins or to the loss of absorption site in the duodenum. In addition to the treatment of ExPI with oral pancreatic enzymes, nutritional management is based on a high-calorie, high-protein diet with normal lipid intake in frequent small feedings, combined with vitamin supplementation adapted to monitored deficiencies. Better knowledge of the functional consequences of pancreatic cancer surgery can improve the overall management of patients.
Topics: Humans; Pancreatectomy; Pancreas; Pancreaticoduodenectomy; Pancreatic Neoplasms; Exocrine Pancreatic Insufficiency; Postoperative Complications
PubMed: 37783613
DOI: 10.1016/j.jviscsurg.2023.09.002 -
Cell Metabolism Nov 2023Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered...
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.
Topics: Humans; Diabetes Mellitus, Type 2; Human Embryonic Stem Cells; Genetic Predisposition to Disease; Genome-Wide Association Study; Insulin-Secreting Cells; Polymorphism, Single Nucleotide; Carbonyl Reductase (NADPH)
PubMed: 37858332
DOI: 10.1016/j.cmet.2023.09.013 -
Liver International : Official Journal... Sep 2023PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these...
BACKGROUND & AIMS
PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen.
METHODS
Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non-disruptive tag in native PIEZO1 or endothelial-specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively.
RESULTS
PIEZO1 activation leads to nitric oxide synthase- and endothelium-dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium-dependent but independent of nitric oxide synthase. The TRPV4-mediated contraction is suppressed by inhibitors of phospholipase A and cyclooxygenases and mimicked by prostaglandin E , suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo-osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses.
CONCLUSIONS
The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures.
Topics: Animals; Male; Mice; Endothelium; Nitric Oxide; Nitric Oxide Synthase; Osmotic Pressure; Portal Vein; TRPV Cation Channels; Vasodilation; Ion Channels
PubMed: 37349903
DOI: 10.1111/liv.15646 -
International Immunopharmacology Aug 2023Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology....
BACKGROUND
Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology. Acetyl-11-keto-β-boswellic acid (AKBA) is an active triterpenoid with antioxidant activity. This article seeks to assess the impact of AKBA on AP and investigate its underlying mechanisms.
METHODS
AP was induced in wild-type, Lyz2 Nrf2 mice and Pdx1 Nrf2 mice by caerulein. Serum amylase and lipase levels, along with histological grading, were utilized to evaluate the severity of AP. Murine bone marrow-derived macrophages (BMDMs) were isolated, cultured, and polarized to the M1 subtype. Flow cytometry and ELISA were utilized to identify the macrophage phenotype. Alterations in oxidative stress damage and intracellular ROS were observed. Nrf2/HO-1 signaling pathways were also evaluated.
RESULTS
In a caerulein-induced mouse model of AP, treatment with AKBA reduced blood amylase and lipase activity and ameliorated pancreatic tissue histological and pathological features. Furthermore, AKBA significantly mitigated oxidative stress-induced damage and induced the expression of Nrf2 and HO-1 protein. Additionally, by using conditional knockout mice (Lyz2 Nrf2 and Pdx1 Nrf2 mice), we verified that Nrf2 primarily functions in macrophages rather than acinar cells. In vitro, AKBA inhibits pro-inflammatory M1-subtype macrophage polarization and reduces ROS generation through Nrf2/HO-1 oxidative stress pathway. Moreover, the protective effects of AKBA against AP were abolished in myeloid-specific Nrf2-deficient mice and BMDMs. Molecular docking results revealed interactions between AKBA and Nrf2.
CONCLUSION
Our results confirm that AKBA exerts protective effects against AP in mice by inhibiting oxidative stress in macrophages through the Nrf2/HO-1 Pathway.
Topics: Animals; Mice; Pancreatitis; NF-E2-Related Factor 2; Reactive Oxygen Species; Ceruletide; Acute Disease; Molecular Docking Simulation; Oxidative Stress; Macrophages; Lipase; Amylases
PubMed: 37364326
DOI: 10.1016/j.intimp.2023.110501