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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 -
Life (Basel, Switzerland) Jul 2023As of December 2009, cystic fibrosis (CF) newborn screening (NBS) is performed in all 50 US states and the District of Columbia. Widespread implementation of CF newborn... (Review)
Review
As of December 2009, cystic fibrosis (CF) newborn screening (NBS) is performed in all 50 US states and the District of Columbia. Widespread implementation of CF newborn screening (CFNBS) in the US and internationally has brought about new and varied challenges. Immunoreactive trypsinogen (IRT) remains the first, albeit imperfect, biomarker used universally in the screening process. Advances in genetic testing have provided an opportunity for newborn screening programs to add CFTR sequencing tiers to their algorithms. This in turn will enable earlier identification of babies with CF and improve longer-term outcomes through prompt treatment and intervention. CFTR sequencing has led to the ability to identify infants with CF from diverse ethnic and racial backgrounds more equitably while also identifying an increasing proportion of infants with inconclusive diagnoses. Using the evolution of the New York State CF newborn screening program as a guide, this review outlines the basic steps in a universal CF newborn screening program, considers how to reduce bias, highlights challenges, offers guidance to address these challenges and provides recommendations for future consideration.
PubMed: 37629501
DOI: 10.3390/life13081646 -
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 Genetics 2023Acute pancreatitis (AP) is one of the most common acute abdominal diseases characterized by an injury and inflammatory disorder of the pancreas with complicated... (Review)
Review
Acute pancreatitis (AP) is one of the most common acute abdominal diseases characterized by an injury and inflammatory disorder of the pancreas with complicated pathological mechanisms. Long non-coding RNAs (lncRNAs) have been shown to play an important role in various physiological and pathological processes in humans, and they have emerged as potential biomarkers of diagnosis and therapeutic targets in various diseases. Recently, accumulating evidence has shown significant alterations in the expression of lncRNAs, which are involved in the pathogenesis of AP, such as premature trypsinogen activation, impaired autophagy, inflammatory response, and acinar cell death. Moreover, lncRNAs can be the direct target of AP treatment and show potential as biomarkers for the diagnosis. Thus, in this review, we focus on the role of lncRNAs in the pathogenesis, diagnosis, and therapy of AP and emphasize the future directions to study lncRNAs in AP, providing new insight into understanding the cellular and molecular mechanisms of AP and seeking novel biomarkers for the diagnosis and therapeutic targets to improve clinical management in the future.
PubMed: 37842644
DOI: 10.3389/fgene.2023.1257552 -
Annals of the American Thoracic Society Aug 2023Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for in a Phase 3... (Randomized Controlled Trial)
Randomized Controlled Trial
Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for in a Phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index (LCI), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). This Phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). The results from Part 1 are reported. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age -scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the chest MRI global score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. Fifty-one children were enrolled and received LUM/IVA ( = 35) or placebo ( = 16). For the change in chest MRI global score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference, <0; higher score indicates greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years of age. Clinical trial registered with www.clinicaltrials.gov (NCT03625466).
Topics: Humans; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Chlorides; Bayes Theorem; Aminophenols; Disease Progression; Mutation
PubMed: 36943405
DOI: 10.1513/AnnalsATS.202208-684OC -
Scientific Reports Aug 2023Lactoferrin, a multifunctional iron-binding protein containing 16 disulfides, is actively studied for its antibacterial and anti-carcinogenic properties. However, scarce...
Lactoferrin, a multifunctional iron-binding protein containing 16 disulfides, is actively studied for its antibacterial and anti-carcinogenic properties. However, scarce information is nowadays available about its oxidative folding starting from the reduced and unfolded status. This study discovers unusual properties when this protein is examined in its reduced molten globule-like conformation. Using kinetic, CD and fluorescence analyses together with mass spectrometry, we found that a few cysteines display astonishing hyper-reactivity toward different thiol reagents. In details, four cysteines (i.e. 668, 64, 512 and 424) display thousands of times higher reactivity toward GSSG but normal against other natural disulfides. The formation of these four mixed-disulfides with glutathione probably represents the first step of its folding in vivo. A widespread low pK decreases the reactivity of other 14 cysteines toward GSSG limiting their involvement in the early phase of the oxidative folding. The origin of this hyper-reactivity was due to transient lactoferrin-GSSG complex, as supported by fluorescence experiments. Lactoferrin represents another disulfide containing protein in addition to albumin, lysozyme, ribonuclease, chymotrypsinogen, and trypsinogen which shows cysteines with an extraordinary and specific hyper-reactivity toward GSSG confirming the discovery of a fascinating new feature of proteins in their nascent phase.
Topics: Glutathione Disulfide; Lactoferrin; Albumins; Anti-Bacterial Agents; Cysteine; Disulfides
PubMed: 37644064
DOI: 10.1038/s41598-023-41064-x -
International Journal of Neonatal... Aug 2023The aim of this study is to evaluate the strategy of the cystic fibrosis newborn screening (CFNBS) programme in Hungary based on the results of the first year of...
The aim of this study is to evaluate the strategy of the cystic fibrosis newborn screening (CFNBS) programme in Hungary based on the results of the first year of screening. A combined immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) CFNBS protocol (IRT/IRT×PAP/IRT) was applied with an IRT-dependent safety net (SN). Out of 88,400 newborns, 256 were tested screen-positive. Fourteen cystic fibrosis (CF) and two cystic fibrosis-positive inconclusive diagnosis (CFSPID) cases were confirmed from the screen-positive cases, and two false-negative cases were diagnosed later. Based on the obtained results, a sensitivity of 88% and a positive predictive value (PPV) of 5.9% were calculated. Following the recognition of false-negative cases, the calculation method of the age-dependent cut-off was changed. In purely biochemical CFNBS protocols, a small protocol change, even after a short period, can have a significant positive impact on the performance. CFNBS should be monitored continuously in order to fine-tune the screening strategy and define the best local practices.
PubMed: 37754773
DOI: 10.3390/ijns9030047 -
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 -
Journal of Community Genetics Dec 2023The South Carolina cystic fibrosis (CF) newborn screening (NBS) program changed in 2019 to include CFTR genotyping for babies with top 4% immunoreactive trypsinogen,...
The South Carolina cystic fibrosis (CF) newborn screening (NBS) program changed in 2019 to include CFTR genotyping for babies with top 4% immunoreactive trypsinogen, which improves sensitivity and timeliness but increases carrier detection. Carrier identification has genetic implications for the family and parents of NBS+ babies have increased emotional distress. Genetic counseling (GC) may increase parent understanding and reduce anxiety yet is not uniformly offered at CF centers. We report our early results after implementing GC for NBS+ families at the time of sweat chloride testing based on GC availability, which resulted in an unselected GC- control arm. Sixteen mothers (GC+ = 9, GC- = 7) participated in an online survey about their experience. Responses were analyzed in aggregate and for differences between GC+ and GC- groups. All-respondent sadness and anxiety increased with notification of the NBS+ result and decreased after sweat test results. Anxiety and sadness were greater in GC- compared to GC+ until after the diagnosis was resolved, though emotional differences between the groups were not statistically significant. On a scale of 0 = not at all to 10 = extremely, GC was rated very helpful (mean 9.0, range 5-10), informative (mean 8.9, range 4-10), comforting (mean 9.1, range 6-10), and minimally distracting (mean 1.8, range 0-9). All participants correctly identified that a risk for a child to have CF exists when both parents are (at least) carriers. Delivery of NBS results to respondents varied by timing, informant, and information given. The child's pediatrician notified 10 (62.5%) of the NBS+ result. Parents felt they were notified in a timely manner (68.8%), by someone knowledgeable about NBS (62.5%), the sweat test (62.5%), CF (43.8%), and genetics (43.8%) and who cared about them (81.3%). Parents felt worried (81.3%), confused (81.3%), empowered (25%), and other (sad, shocked, scared, overwhelmed, devastated, defeated). Data from this single-center study suggest benefit of GC, that families would value earlier contact with an expert, and that prompt diagnostic resolution may reduce duration of parental distress.
PubMed: 37656403
DOI: 10.1007/s12687-023-00666-8 -
Journal of Advanced Research Nov 2023Conventional hot-alkaline cocoon degumming techniques greatly weaken the physicochemical and mechanical properties of silk fibroin fiber, thus affecting the quality of...
INTRODUCTION
Conventional hot-alkaline cocoon degumming techniques greatly weaken the physicochemical and mechanical properties of silk fibroin fiber, thus affecting the quality of silk fabric. Moreover, it causes massive energy waste and serious environmental pollution.
OBJECTIVE
This study aims to establish a novel cocoon self-degumming method by genetic modification of silkworm varieties and silk fibers.
METHODS
The self-degummed cocoon material was generated by specifically overexpressing trypsinogen protein in the sericin layer of silk thread; the effect of cocoon self-degumming method was evaluated by the degumming rate of sericin protein, the cleanliness and equivalent diameter of silk fibroin fiber; the basic characteristics of silk fibroin fiber degummed by cocoon self-degumming method and conventional hot-alkaline degumming technique were determined by electron microscopy, Fourier infrared spectroscopy, X-ray diffraction and tensile tests; the composition and biological activity of degummed sericin protein was respectively analyzed by liquid chromatograph-mass spectrometry and cytological experiments.
RESULTS
The genetically engineered self-degumming cocoon containing trypsinogen protein was successfully created, and the content of trypsinogen protein in silk was 47.14 ± 0.90 mg/g. The sericin protein in the self-degumming cocoon was removed out in water or 1 mM Tris-HCl buffer (pH = 8.0). Compared to alkaline-degummed silk fibroin, self-degummed silk fibroin had better cleanliness, thicker equivalent diameter, more complete silk structure and better mechanical property. In addition, sericin protein degummed from self-degumming cocoons significantly promoted cell proliferation and caused no obvious cytotoxicity.
CONCLUSION
Compared to conventional hot-alkaline degumming technique, the cocoon self-degumming method by genetically overexpressing trypsinogen protein in sericin layer of silk thread can self-degummed in a mild degumming condition, and gain silk fiber with better quality and more biologically active sericin protein products. This strategy can not only reduce the environmental impact, but also generate greater economic value, which will accelerate its application in the silk and pharmaceutical industries.
Topics: Animals; Silk; Bombyx; Fibroins; Sericins; Trypsinogen
PubMed: 36572337
DOI: 10.1016/j.jare.2022.12.005