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Journal of Affective Disorders May 2024The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium...
BACKGROUND
The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLiGen).
METHODS
We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg.
RESULTS
The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLiGen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium.
LIMITATIONS
Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLiGen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies.
CONCLUSIONS
The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption.
PubMed: 38735581
DOI: 10.1016/j.jad.2024.05.050 -
Cellular and Molecular Life Sciences :... May 2024The co-localization of the lysosomal protease cathepsin B (CTSB) and the digestive zymogen trypsinogen is a prerequisite for the initiation of acute pancreatitis....
The co-localization of the lysosomal protease cathepsin B (CTSB) and the digestive zymogen trypsinogen is a prerequisite for the initiation of acute pancreatitis. However, the exact molecular mechanisms of co-localization are not fully understood. In this study, we investigated the role of lysosomes in the onset of acute pancreatitis by using two different experimental approaches. Using an acinar cell-specific genetic deletion of the ras-related protein Rab7, important for intracellular vesicle trafficking and fusion, we analyzed the subcellular distribution of lysosomal enzymes and the severity of pancreatitis in vivo and ex vivo. Lysosomal permeabilization was performed by the lysosomotropic agent Glycyl-L-phenylalanine 2-naphthylamide (GPN). Acinar cell-specific deletion of Rab7 increased endogenous CTSB activity and despite the lack of re-distribution of CTSB from lysosomes to the secretory vesicles, the activation of CTSB localized in the zymogen compartment still took place leading to trypsinogen activation and pancreatic injury. Disease severity was comparable to controls during the early phase but more severe at later time points. Similarly, GPN did not prevent CTSB activation inside the secretory compartment upon caerulein stimulation, while lysosomal CTSB shifted to the cytosol. Intracellular trypsinogen activation was maintained leading to acute pancreatitis similar to controls. Our results indicate that initiation of acute pancreatitis seems to be independent of the presence of lysosomes and that fusion of lysosomes and zymogen granules is dispensable for the disease onset. Intact lysosomes rather appear to have protective effects at later disease stages.
Topics: Animals; Lysosomes; Pancreatitis; Cathepsin B; Mice; Secretory Vesicles; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins; Acute Disease; Acinar Cells; Trypsinogen; Ceruletide; Enzyme Precursors; Mice, Inbred C57BL; Mice, Knockout
PubMed: 38709385
DOI: 10.1007/s00018-024-05247-7 -
BMC Medical Genomics Apr 2024Acute pancreatitis (AP) is a common systemic inflammatory disease resulting from the activation of trypsinogen by various incentives in ICU. The annual incidence rate is...
Acute pancreatitis (AP) is a common systemic inflammatory disease resulting from the activation of trypsinogen by various incentives in ICU. The annual incidence rate is approximately 30 out of 100,000. Some patients may progress to severe acute pancreatitis, with a mortality rate of up to 40%. Therefore, the goal of this article is to explore the key genes for effective diagnosis and treatment of AP. The analysis data for this study were merged from two GEO datasets. 1357 DEGs were used for functional enrichment and cMAP analysis, aiming to reveal the pathogenic genes and potential mechanisms of AP, as well as potential drugs for treating AP. Importantly, the study used LASSO and SVM-RFE machine learning to screen the most likely AP occurrence biomarker for Prdx4 among numerous candidate genes. A receiver operating characteristic of Prdx4 was used to estimate the incidence of AP. The ssGSEA algorithm was employed to investigate immune cell infiltration in AP. The biomarker Prdx4 gene exhibited significant associations with a majority of immune cells and was identified as being expressed in NKT cells, macrophages, granulocytes, and B cells based on single-cell transcriptome data. Finally, we found an increase in Prdx4 expression in the pancreatic tissue of AP mice through immunohistochemistry. After treatment with recombinant Prdx4, the pathological damage to the pancreatic tissue of AP mice was relieved. In conclusion, our study identified Prdx4 as a potential AP hub gene, providing a new target for treatment.
Topics: Animals; Humans; Mice; Acute Disease; Algorithms; Biomarkers; Machine Learning; Pancreatitis
PubMed: 38641608
DOI: 10.1186/s12920-024-01854-2 -
Cellular Signalling Jun 2024Acute pancreatitis (AP) is a pathological condition characterized by the premature release and activation of trypsinogens and other enzyme precursors. In severe cases,...
BACKGROUND
Acute pancreatitis (AP) is a pathological condition characterized by the premature release and activation of trypsinogens and other enzyme precursors. In severe cases, the mortality rates are in the range of 20-30% and may even be as high as 50%. Though various prophylaxes are available for AP, the mechanism of its progression is unclear. Marginal zone B and B-1 cell-specific protein 1 (MZB1) is found in the endoplasmic reticulum (ER) where it is expressed exclusively in the B cells there. MZB1 promotes proliferation, inhibits apoptosis, invasion, and inflammation, and mitigates mitochondrial damage in cells. However, the importance of MZB1 in AP has not yet been determined.
METHODS
Differentially expressed genes (DEGs) between healthy pancreatic cells and those affected by AP were identified using datasets from Gene Expression Omnibus (GEO) datasets. Relative differences in MZB1 expression between normal and diseased tissues and cells were validated in vivo using a rat AP model induced with 4% (w/v) sodium taurocholate and in vitro using the AR42J rat pancreatic cell line exposed to caerulein (CAE). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2`-deoxyuridine (EdU) assays were performed to detect and compare normal and pathological cell proliferation. Flow cytometry was employed to assess and compare cellular apoptosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB) were applied to evaluate the apoptotic factors Bax and Bcl. The inflammatory factors interleukin (IL)-6 and IL-1β were quantified using Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR techniques. Mitochondrial function was evaluated using assays for reactive oxygen species (ROS) and tetramethylrhodamine methyl ester (TMRM). WB and qRT-PCR were utilized to measure the expression levels of the PI3K-Akt signaling pathway, followed by a rescue experiment involving the inhibitor of wortmannin.
RESULTS
MZB1 was upregulated in the AP cases screened from the GEO datasets, the rat AP model, and the AR42J cells exposed to CAE. Overexpression of MZB1 enhanced the growth and supressed the cell death of AR42J cells while also activating the PI3K-Akt signaling pathway. MZB1 knockdown led to mitochondrial dysfunction and exacerbated inflammation. The rescue experiment demonstrated that MZB1 enhanced proliferation and inhibited apoptosis, mitochondrial dysfunction, and inflammation in pancreatic cells through the PI3K-Akt pathway.
CONCLUSIONS
AP cells and tissues exhibited markedly elevated levels of MZB1 expression compared to their healthy counterparts. MZB1 overexpression promoted proliferation and supressed apoptosis, mitochondrial dysfunction, and inflammation in pancreatic cells through the positive regulation of the PI3K-Akt signaling pathway.
Topics: Animals; Rats; Acute Disease; Apoptosis; Cell Proliferation; Inflammation; Interleukin-6; Mitochondrial Diseases; Pancreatitis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 38508349
DOI: 10.1016/j.cellsig.2024.111143 -
Frontiers in Immunology 2024Intrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable... (Review)
Review
INTRODUCTION
Intrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable events in the development of acute pancreatitis. In addition to this trypsin-centered paradigm, recent studies provide evidence that innate immune responses triggered by translocation of intestinal bacteria to the pancreas due to intestinal barrier dysfunction underlie the immunopathogenesis of acute pancreatitis. Although severe acute pancreatitis is often associated with pancreatic colonization by fungi, the molecular mechanisms linking fungus-induced immune responses to the development of severe acute pancreatitis are poorly understood. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that mediates innate immune responses to fungi and bacteria. Mutations in is a risk factor for Parkinson's disease and Crohn's disease, both of which are driven by innate immune responses to gut organisms.
DISCUSSION
In this Minireview article, we discuss how activation of LRRK2 by the recognition of fungi induces severe acute pancreatitis.
Topics: Humans; Pancreatitis; Leucine; Acute Disease; Trypsin; Pancreas
PubMed: 38440723
DOI: 10.3389/fimmu.2024.1364839 -
Frontiers in Microbiology 2023Acute pancreatitis is caused by trypsinogen activation in acinar cells caused by various injury forms (gallstone, high triglycerides, alcohol, etc.). Viral pancreatitis... (Review)
Review
Acute pancreatitis is caused by trypsinogen activation in acinar cells caused by various injury forms (gallstone, high triglycerides, alcohol, etc.). Viral pancreatitis is a clinically rare disease type, which is easily neglected by clinicians and causes serious adverse consequences. Viral pancreatitis involves the entry of viruses into pancreatic cells, triggering inflammation, immune response activation, and enzymatic autodigestion, leading to tissue damage and potential complications. At present, there are few available reports on viral pancreatitis, most of which are case reports. This review brings attention to clinicians by describing the incidence of viral pancreatitis to enhance clinical understanding and patient care.
PubMed: 38420214
DOI: 10.3389/fmicb.2023.1326837 -
BioRxiv : the Preprint Server For... Feb 2024Histopathological heterogeneity in human pancreas has been well documented; however, functional evidence at the tissue level is scarce. Herein we investigated...
Histopathological heterogeneity in human pancreas has been well documented; however, functional evidence at the tissue level is scarce. Herein we investigated glucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in no diabetes (ND, n=15), single islet autoantibody-positive (1AAb+, n=7), and type 1 diabetes donors (T1D, <14 months duration, n=5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features were comparable across the regions in ND. In T1D, insulin secretion and beta-cell volume were significantly reduced within all regions, while glucagon and enzymes were unaltered. Beta-cell volume was lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ were consistent across PH, PB and PT. This study supports low inter-regional variation in pancreas slice function and potentially, increased metabolic demand in 1AAb+.
PubMed: 38405840
DOI: 10.1101/2024.02.08.579175 -
DEN Open Apr 2024Few reports have explored the application of urinary trypsinogen-2 measurement in the early diagnosis of post-endoscopic retrograde cholangiopancreatography (ERCP)...
Noninvasive rapid urinary trypsinogen-2 dipstick test for early exclusion of post-endoscopic retrograde cholangiopancreatography pancreatitis within hours after endoscopic retrograde cholangiopancreatography: Clinical diagnosis and considerations.
OBJECTIVE
Few reports have explored the application of urinary trypsinogen-2 measurement in the early diagnosis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, and none have demonstrated the benefits of noninvasive testing. This study aimed to evaluate the clinical application of the rapid urinary trypsinogen-2 dipstick test (Nipro, Japan) compared with serum amylase and lipase levels for the early diagnosis of post-ERCP pancreatitis (PEP).
METHODS
A total of 100 consecutive patients (54 men and 46 women) who were admitted and underwent ERCP at Tokyo Medical University Hospital from August 2021 to December 2021 were recruited. All patients underwent rapid urinary trypsinogen-2 measurement using the dipstick test before and after ERCP. Measurements were taken 24 h before ERCP for pre-ERCP and 1-4 h after ERCP for post-ERCP. Additionally, serum amylase and lipase levels were measured at 8:00 a.m. of the day after ERCP (at least 8 h after ERCP), and their diagnostic abilities for PEP were compared and evaluated.
RESULTS
PEP occurred in 5/100 patients (5%). The sensitivity, specificity, positive predictive value, and negative predictive value of the dipstick test for diagnosing PEP were 100%, 83.2%, 23.8%, and 100%, respectively. These results were comparable to the diagnostic performance of serum amylase and lipase levels at 8:00 a.m. on the day after ERCP (at least 8 h after ERCP). However, false positives must be considered.
CONCLUSION
The dipstick test may be useful in clinical practice as a noninvasive screening test for the early prediction of PEP.
PubMed: 38389803
DOI: 10.1002/deo2.336 -
Paediatric Respiratory Reviews Jan 2024Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis... (Review)
Review
OBJECTIVES
Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID).
METHODS
This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed.
RESULTS
Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF.
CONCLUSIONS
CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up.
PubMed: 38309973
DOI: 10.1016/j.prrv.2024.01.001 -
Experimental and Therapeutic Medicine Dec 2023Acute pancreatitis (AP) is a severe inflammatory condition characterized by the activation of pancreatic enzymes within acinar cells, leading to tissue damage and...
Interleukin‑22 alleviates arginine‑induced pancreatic acinar cell injury via the regulation of intracellular vesicle transport system: Evidence from proteomic analysis.
Acute pancreatitis (AP) is a severe inflammatory condition characterized by the activation of pancreatic enzymes within acinar cells, leading to tissue damage and inflammation. Interleukin (IL)-22 is a potential therapeutic agent for AP owing to its anti-inflammatory properties and ability to promote tissue repair. The present study evaluated the differentially expressed proteins in arginine-induced pancreatic acinar cell injury following treatment with IL-22, and the possible mechanisms involved in IL-22-mediated alleviation of AP. AR42J cells were stimulated using L-arginine to establish an acinar cell injury model and the damaged cells were subsequently treated with IL-22. The characteristics of the model and the potential therapeutic effects of IL-22 were examined by CCK-8 assay, flow cytometry, TUNEL assay, transmission electron microscopy and ELISA. Differentially expressed proteins in cells induced by arginine and treated with IL-22 were assessed using liquid chromatography-mass spectrometry. The identified proteins were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis to elucidate their functional roles. The present study demonstrated that arginine-stimulated cells showed significant pathological changes resembling those in AP, which were alleviated after IL-22 treatment. Proteomic analysis then demonstrated that in IL-22-treated cells, proteins related to the formation and fusion of autophagosomes with lysosomes were significantly downregulated, whereas endocytosis related proteins were enriched in the upregulated proteins. After IL-22 treatment, western blotting demonstrated reduced expression of autophagy-associated proteins. In conclusion, by inhibiting the formation and fusion of autophagosomes with lysosomes, IL-22 may have mitigated premature trypsinogen activation, subsequently minimizing acinar cell injury induced by L-arginine. This was accompanied by concurrent upregulation of endocytosis, which serves a pivotal role in sustaining regular cellular material transport and signal propagation. This research underscored the potential of IL-22 in mitigating arginine-induced AR42J injury, which could be valuable in refining treatment strategies for AP.
PubMed: 38023358
DOI: 10.3892/etm.2023.12277