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Gut Jun 2024Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in (encoding trypsin inhibitor) are common in patients with CP and are...
OBJECTIVE
Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human () for pancreatitis therapy in mice.
DESIGN
A capsid-optimised AAV8-mediated expression vector (AAV8-) to target the pancreas was constructed. Mice were treated with AAV8- by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8- were dynamically evaluated in infected mice. The effectiveness of AAV8- on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and c.194+2T>C mouse models).
RESULTS
The constructed AAV8- vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×10 vg/animal). The expression and efficacy of peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process.
CONCLUSION
One-time injection of AAV8 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.
Topics: Animals; Mice; Genetic Therapy; Dependovirus; Genetic Vectors; Disease Models, Animal; Trypsin Inhibitor, Kazal Pancreatic; Pancreas; Humans; Pancreatitis, Chronic; Male; Pancreatitis
PubMed: 38553043
DOI: 10.1136/gutjnl-2023-330788 -
JCI Insight Aug 2021Evidence suggests an association between severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) infection and the occurrence of new-onset diabetes. We examined...
Evidence suggests an association between severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) infection and the occurrence of new-onset diabetes. We examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), the cell entry factors for SARS-CoV-2, using publicly available single-cell RNA sequencing data sets, and pancreatic tissue from control male and female nonhuman primates (NHPs) and humans. We also examined SARS-CoV-2 immunolocalization in pancreatic cells of SARS-CoV-2-infected NHPs and patients who had died from coronavirus disease 2019 (COVID-19). We report expression of ACE2 in pancreatic islet, ductal, and endothelial cells in NHPs and humans. In pancreata from SARS-CoV-2-infected NHPs and COVID-19 patients, SARS-CoV-2 infected ductal, endothelial, and islet cells. These pancreata also exhibited generalized fibrosis associated with multiple vascular thrombi. Two out of 8 NHPs developed new-onset diabetes following SARS-CoV-2 infection. Two out of 5 COVID-19 patients exhibited new-onset diabetes at admission. These results suggest that SARS-CoV-2 infection of the pancreas may promote acute and especially chronic pancreatic dysfunction that could potentially lead to new-onset diabetes.
Topics: Angiotensin-Converting Enzyme 2; Animals; COVID-19; Chlorocebus aethiops; Diabetes Mellitus; Female; Fibrosis; Humans; Macaca mulatta; Male; Pancreas; SARS-CoV-2; Serine Endopeptidases; Thrombosis
PubMed: 34241597
DOI: 10.1172/jci.insight.151551 -
The Korean Journal of Gastroenterology... May 2020The gut microbiota is part of the human body that is involved in body metabolism and the occurrence of various diseases. Detecting and analyzing their genetic... (Review)
Review
The gut microbiota is part of the human body that is involved in body metabolism and the occurrence of various diseases. Detecting and analyzing their genetic information (microbiome) is as important as analyzing human genes. The core microbiome, the key functional genes shared by all humans, helps better understand the physiology of the human body. Information on the gut microbiome of a diseased person can help diagnose and treat disease. The pancreatobiliary system releases functional antimicrobial substances, such as bile acids and antimicrobial peptides, which affect the gut microbiota directly. In response, the gut microbiota influences pancreatobiliary secretion by controlling the generation and emission of substances through indirect signaling. This crosstalk maintains homeostasis of the pancreatobiliary system secretion and microbiota. Dysbiosis and disease can occur if this fails to work properly. Bile acid therapy has been used widely and may affect the microbial environment in the intestine. An association of the gut microbiota has been reported in many cases of pancreatobiliary diseases, including malignant tumors. Traditionally, most pancreatobiliary diseases are accompanied by infections from the gut microbiota, which is an important target for treatment. The pancreatobiliary system can control its function through physical and drug therapy. This may be a new pioneering field in the study or treatment of the gut microbiota.
Topics: Animals; Bile Acids and Salts; Biliary Tract; Gastrointestinal Microbiome; Humans; Hydrogen-Ion Concentration; Intestines; Pancreas
PubMed: 32448854
DOI: 10.4166/kjg.2020.75.5.231 -
Function (Oxford, England) 2021
Topics: Humans; Bradykinin; COVID-19; Pancreatitis; Pancreas
PubMed: 34642664
DOI: 10.1093/function/zqab046 -
The Journal of Infectious Diseases Nov 2022Isolated reports of new-onset diabetes in patients with coronavirus disease 2019 (COVID-19) have led researchers to hypothesize that severe acute respiratory syndrome...
Isolated reports of new-onset diabetes in patients with coronavirus disease 2019 (COVID-19) have led researchers to hypothesize that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human exocrine and endocrine pancreatic cells ex vivo and in vivo. However, existing research lacks experimental evidence indicating that SARS-CoV-2 can infect pancreatic tissue. Here, we found that cats infected with a high dose of SARS-CoV-2 exhibited hyperglycemia. We also detected SARS-CoV-2 RNA in pancreatic tissues of these cats, and immunohistochemical staining revealed the presence of SARS-CoV-2 nucleocapsid protein (NP) in islet cells. SARS-CoV-2 NP and spike proteins were primarily detected in glucagon-positive cells, and most glucagon-positive cells expressed ACE2. Additionally, immune protection experiments conducted on cats showed that blood glucose levels of immunized cats did not increase postchallenge. Our data indicate cat pancreas as a SARS-CoV-2 target and suggest that the infection of glucagon-positive cells could contribute to the metabolic dysregulation observed in SARS-CoV-2-infected cats.
Topics: Animals; Cats; Humans; COVID-19; Glucagon; Hyperglycemia; RNA, Viral; SARS-CoV-2
PubMed: 35639863
DOI: 10.1093/infdis/jiac143 -
Reviews in Medical Virology Mar 2023Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying... (Review)
Review
Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there remains a paucity of data characterising infectious agents at the molecular level. This gap in the literature precludes the identification of the specific infectious agents driving the association between RTI and T1D. Furthermore, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on the development of IA/T1D remains undeciphered. Here, we provide a comprehensive overview of the evidence to date, implicating RTIs (viral and non-viral) as potential risk factors for IA/T1D.
Topics: Humans; Diabetes Mellitus, Type 1; Islets of Langerhans; COVID-19; SARS-CoV-2; Respiratory Tract Infections
PubMed: 36790804
DOI: 10.1002/rmv.2429 -
Canadian Journal of Diabetes Jun 2022The coronavirus-2019 (COVID-19) pandemic has had significant impact on research directions and productivity in the past 2 years. Despite these challenges, since 2020,... (Review)
Review
The coronavirus-2019 (COVID-19) pandemic has had significant impact on research directions and productivity in the past 2 years. Despite these challenges, since 2020, more than 2,500 peer-reviewed articles have been published on pancreatic islet biology. These include updates on the roles of isocitrate dehydrogenase, pyruvate kinase and incretin hormones in insulin secretion, as well as the discovery of inceptor and signalling by circulating RNAs. The year 2020 also brought advancements in in vivo and in vitro models, including a new transgenic mouse for assessing beta-cell proliferation, a "pancreas-on-a-chip" to study glucose-stimulated insulin secretion and successful genetic editing of primary human islet cells. Islet biologists evaluated the functionality of stem-cell-derived islet-like cells coated with semipermeable biomaterials to prevent autoimmune attack, revealing the importance of cell maturation after transplantation. Prompted by observations that COVID-19 symptoms can worsen for people with obesity or diabetes, researchers examined how islets are directly affected by severe acute respiratory syndrome coronavirus 2. Herein, we highlight novel functional insights, technologies and therapeutic approaches that emerged between March 2020 and July 2021, written for both scientific and lay audiences. We also include a response to these advancements from patient stakeholders, to help lend a broader perspective to developments and challenges in islet research.
Topics: Animals; Biology; COVID-19; Diabetes Mellitus, Type 1; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Mice
PubMed: 35589534
DOI: 10.1016/j.jcjd.2021.11.002 -
Protein & Cell Apr 2022Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved... (Review)
Review
Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved in the development, structure, and function of human pancreatic islets under pathological conditions. Stem cell-based islet organoids faithfully recapitulate islet development in vitro and provide large amounts of three-dimensional functional islet biomimetic materials with a morphological structure and cellular composition similar to those of native islets. Thus, islet organoids hold great promise for modeling islet development and function, deciphering the mechanisms underlying the onset of diabetes, providing an in vitro human organ model for infection of viruses such as SARS-CoV-2, and contributing to drug screening and autologous islet transplantation. However, the currently established islet organoids are generally immature compared with native islets, and further efforts should be made to improve the heterogeneity and functionality of islet organoids, making it an authentic and informative disease model for diabetes. Here, we review the advances and challenges in the generation of islet organoids, focusing on human pluripotent stem cell-derived islet organoids, and the potential applications of islet organoids as disease models and regenerative therapies for diabetes.
Topics: COVID-19; Diabetes Mellitus; Humans; Islets of Langerhans; Organoids; SARS-CoV-2
PubMed: 33751396
DOI: 10.1007/s13238-021-00831-0 -
Cellular and Molecular Gastroenterology... 2021Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated... (Review)
Review
Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated with pancreatic surgery in women. Although diagnostic criteria for pancreatitis are the same in men and women, major sex differences in etiology are reported. Alcohol and tobacco predominate in men, whereas idiopathic and obstructive etiologies predominate in women. Circulating levels of estrogens, progesterone, and androgens contribute significantly to overall health outcomes; premenopausal women have lower prevalence of cardiovascular and pancreatic diseases suggesting protective effects of estrogens, whereas androgens promote growth of normal and cancerous cells. Sex chromosomes and gonadal and nongonadal hormones together determine an individual's sex, which is distinct from gender or gender identity. Human pancreatic disease etiology, outcomes, and sex-specific mechanisms are largely unknown. In rodents of both sexes, glucocorticoids and estrogens from the adrenal glands influence pancreatic secretion and acinar cell zymogen granule numbers. Lack of corticotropin-releasing factor receptor 2 function, a G protein-coupled receptor whose expression is regulated by both estrogens and glucocorticoids, causes sex-specific changes in pancreatic histopathology, zymogen granule numbers, and endoplasmic reticulum ultrastructure changes in acute pancreatitis model. Here, we review existing literature on sex differences in the normal exocrine pancreas and mechanisms that operate at homeostasis and diseased states in both sexes. Finally, we review pregnancy-related pancreatic diseases and discuss the effects of sex differences on proposed treatments in pancreatic disease.
Topics: COVID-19; Female; Hormones; Humans; Male; Pancreas, Exocrine; Pancreatic Diseases; Pregnancy; Sex Characteristics
PubMed: 33895424
DOI: 10.1016/j.jcmgh.2021.04.005 -
American Journal of Transplantation :... Feb 2023The number of pancreas transplants in the United States was largely unchanged in 2021 at 963 transplants compared with 962 in 2020, showing that recovery from the...
The number of pancreas transplants in the United States was largely unchanged in 2021 at 963 transplants compared with 962 in 2020, showing that recovery from the COVID-19 pandemic was not as pronounced in pancreas transplantation as in other organs. The number of simultaneous pancreas-kidney transplants (SPKs) decreased from 827 to 820, whereas the number of pancreas-after-kidney transplants and pancreas transplants alone increased marginally to compensate. The proportion of patients with type 2 diabetes on the waiting list increased to 22.9% in 2021, compared with 20.1% in 2020. Consequently, the proportion of transplants in patients with type 2 diabetes increased from 21.3% in 2020 to 25.9% in 2021. The proportion of transplants in older recipients (aged 55 years or older) also increased to 13.5% in 2021 from 11.7% in 2020. Outcomes after SPK continue to be the best of the three categories of pancreas transplants: 1-year graft failure for kidney at 5.7% and pancreas at 10.5% for transplants performed in 2020. The proportion of pancreas transplants performed by medium-volume centers (11-24 transplants per year) increased sharply to 48.3% in 2021 from 35.1% in 2020, with a corresponding decrease in transplants in large-volume centers (25 or more transplants per year) to 15.9% in 2021 from 25.7% in 2020.
Topics: Humans; United States; Aged; Tissue and Organ Procurement; Diabetes Mellitus, Type 2; Graft Survival; COVID-19; Pancreas Transplantation; Pancreas
PubMed: 37132349
DOI: 10.1016/j.ajt.2023.02.005