scholarly journals Recent insights into the cellular mechanisms of acute pancreatitis

2007 ◽  
Vol 21 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Laura I Cosen-Binker ◽  
Herbert Y Gaisano
Keyword(s):  
Acute Pancreatitis ◽  
Cell Injury ◽  
Enzyme Activation ◽  
High Morbidity ◽  
Lysosomal Hydrolases ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Cellular Events ◽  
Multiorgan Dysfunction Syndrome

In acute pancreatitis, initiating cellular events causing acinar cell injury includes co-localization of zymogens with lysosomal hydrolases, leading to premature enzyme activation and pathological exocytosis of zymogens into the interstitial space. This is followed by processes that accentuate cell injury; triggering acute inflammatory mediators, intensifying oxidative stress, compromising the microcirculation and activating a neurogenic feedback. Such localized events then progress to a systemic inflammatory response leading to multiorgan dysfunction syndrome with resulting high morbidity and mortality. The present review discusses some of the most recent insights into each of these cellular processes postulated to cause or propagate the process of acute pancreatitis, and also the role of alcohol and genetics.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

Anesthetic Agents and Neuronal Autophagy. What We Know and What We Don't.

2018 ◽  
Vol 25 (8) ◽  
pp. 908-916 ◽  
Author(s):  
Lili Xu ◽  
Jianjun Shen ◽  
Patrick M. McQuillan ◽  
Zhiyong Hu
Keyword(s):  
Cell Injury ◽  
Neuronal Cell ◽  
Volatile Anesthetic ◽  
Calcium Flux ◽  
Anesthetic Agent ◽  
General Anesthetic ◽  
Cellular Mechanisms ◽  
Anesthetic Agents ◽  
Neuronal Autophagy

Background: Ethanol is known to have both γ-Aminobutyric acid agonist and Nmethyl- D-aspartate antagonist characteristics similar to commonly used volatile anesthetic agents. Recent evidence demonstrates that autophagy can reduce the development of ethanol induced neurotoxicity. Recent studies have found that general anesthesia can cause longterm impairment of both mitochondrial morphogenesis and synaptic transmission in the developing rat brain, both of which are accompanied by enhanced autophagy activity. Autophagy may play an important role in general anesthetic mediated neurotoxicity. Methods: This review outlines the role of autophagy in the development of anesthetic related neurotoxicity and includes an explanation of the role of autophagy in neuronal cell survival and death, the relationship between anesthetic agents and neuronal autophagy, possible molecular and cellular mechanisms underlying general anesthetic agent induced activation of neuronal autophagy in the developing brain, and potential therapeutic approaches aimed at modulating autophagic pathways. Results: In a time- and concentration-dependent pattern, general anesthetic agents can disrupt intracellular calcium homeostasis which enhances both autophagy and apoptosis activation. The degree of neural cell injury may be ultimately determined by the interplay between autophagy and apoptosis. It appears likely that the increase in calcium flux associated with some anesthetic agents disrupts lysosomal function. This results in an over-activation of endosomal- lysosomal trafficking causing mitochondrial damage, reactive oxygen species upregulation, and lipid peroxidation. Conclusion: Autophagy may play a role in the development of anesthetic related neurotoxicity. Understanding this may lead to strategies or therapies aimed at preventing or ameliorating general anesthetic agent mediated neurotoxicity.

Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis

2007 ◽  
Vol 292 (6) ◽  
pp. G1738-G1746 ◽  
Author(s):  
Gijs J. D. Van Acker ◽  
Eric Weiss ◽  
Michael L. Steer ◽  
George Perides
Keyword(s):  
Acute Pancreatitis ◽  
Transcription Factors ◽  
Acinar Cell ◽  
Cathepsin B ◽  
Cell Injury ◽  
Experimental Pancreatitis ◽  
Causal Relationships ◽  
Zymogen Activation ◽  
Lysosomal Hydrolases ◽  
Early Stages

We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-κB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.

scholarly journals Glial Bridge Ecology: Cellular Mechanisms that Drive Spinal Cord Regeneration in Zebrafish

2018 ◽  
Author(s):  
Corbin J. Schuster ◽  
Robert M. Kao
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Cell Injury ◽  
Model Organism ◽  
Spinal Cord Regeneration ◽  
Cellular Mechanisms ◽  
Bridge Formation ◽  
Cellular Processes ◽  
Cord Injury ◽  
One Step

Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.

scholarly journals Prophylactic antibiotics in acute pancreatitis: endless debate

2017 ◽  
Vol 99 (2) ◽  
pp. 107-112 ◽  
Author(s):  
MM Mourad ◽  
RPT Evans ◽  
V Kalidindi ◽  
R Navaratnam ◽  
L Dvorkin ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Multiple Organ ◽  
Prophylactic Antibiotics ◽  
Morbidity And Mortality ◽  
Current Evidence ◽  
High Morbidity ◽  
Antibiotic Administration ◽  
Infected Necrosis ◽  
Pancreatic Infection

INTRODUCTION The development of pancreatic infection is associated with the development of a deteriorating disease with subsequent high morbidity and mortality. There is agreement that in mild pancreatitis there is no need to use antibiotics; in severe pancreatitis it would appear to be a logical choice to use antibiotics to prevent secondary pancreatic infection and decrease associated mortality. MATERIALS AND METHODS A non-systematic review of current evidence, meta-analyses and randomized controlled trials was conducted to assess the role of prophylactic antibiotics in acute pancreatitis and whether it might improve morbidity and mortality in pancreatitis. RESULTS Mixed evidence was found to support and refute the role of prophylactic antibiotics in acute pancreatitis. Most studies have failed to demonstrate much benefit from its routine use. Data from our unit suggested little benefit of their routine use, and showed that the mortality of those treated with antibiotics was significantly higher compared with those not treated with antibiotics (9% vs 0%, respectively, P = 0.043). In addition, the antibiotic group had significantly higher morbidity (36% vs 5%, respectively, P = 0.002). CONCLUSIONS Antibiotics should be used in patients who develop sepsis, infected necrosis-related systemic inflammatory response syndrome, multiple organ dysfunction syndrome or pancreatic and extra-pancreatic infection. Despite the many other factors that should be considered, prompt antibiotic therapy is recommended once inflammatory markers are raised, to prevent secondary pancreatic infection. Unfortunately, there remain many unanswered questions regarding the indications for antibiotic administration and the patients who benefit from antibiotic treatment in acute pancreatitis.

Edema and intrapancreatic trypsinogen activation precede glutathione depletion during caerulein pancreatitis

1996 ◽  
Vol 271 (1) ◽  
pp. G20-G26 ◽  
Author(s):  
T. Grady ◽  
A. Saluja ◽  
A. Kaiser ◽  
M. Steer
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cell ◽  
Digestive Enzyme ◽  
Pancreatic Acinar Cell ◽  
Enzyme Activation ◽  
Glutathione Depletion ◽  
Critical Event ◽  
Lysosomal Hydrolases ◽  
Trypsinogen Activation ◽  
Pancreatic Edema

Acute pancreatitis is characterized by hyperamylasemia, pancreatic edema, and the presence of activated digestive enzymes within the pancreas. The secretagogue-induced model of acute pancreatitis is also characterized by pancreatic acinar cell vacuolation, subcellular redistribution of lysosomal hydrolases, and a fall in pancreatic glutathione levels. We have performed time-dependence studies to determine the sequence with which these phenomena appear and to establish their cause-and-effect relationship. Evidence of lysosomal enzyme redistribution and trypsinogen activation within the pancreas could be detected within 10-15 min of the onset of supramaximal secretagogue stimulation, while hyperamylasemia (30 min), pancreatic edema (60 min), and acinar cell vacuolation (60 min) occurred at later times. Pancreatic glutathione levels were either unchanged (15 and 30 min) or elevated (60 min) during the early times of supramaximal stimulation and were only noted to be decreased at a later time. These results support the conclusion that intrapancreatic digestive enzyme activation, possibly occurring by a mechanism involving lysosomal hydrolase redistribution, is an early and likely a critical event in the evolution of secretagogue-induced pancreatitis but that glutathione depletion is neither early nor critical to the evolution of this model of pancreatitis.

scholarly journals Automating multimodal microscopy with NanoJ-Fluidics

2018 ◽  
Author(s):  
Pedro Almada ◽  
Pedro M. Pereira ◽  
Siân Culley ◽  
Ghislaine Caillol ◽  
Fanny Boroni-Rueda ◽  
...  
Keyword(s):  
Sample Preparation ◽  
Low Cost ◽  
Super Resolution ◽  
Actin Dynamics ◽  
Cellular Mechanisms ◽  
Cellular Events ◽  
Complex Sequences ◽  
Multiple Sample ◽  
Information Combining

AbstractFluorescence microscopy can reveal all aspects of cellular mechanisms, from molecular details to dynamics, thanks to approaches such as super-resolution and live-cell imaging. Each of its modalities requires specific sample preparation and imaging conditions to obtain high-quality, artefact-free images, ultimately providing complementary information. Combining and multiplexing microscopy approaches is crucial to understand cellular events, but requires elaborate workflows involving multiple sample preparation steps. We present a robust fluidics approach to automate complex sequences of treatment, labelling and imaging of live and fixed cells. Our open-source NanoJ-Fluidics system is based on low-cost LEGO hardware controlled by ImageJ-based software and can be directly adapted to any microscope, providing easy-to-implement high-content, multimodal imaging with high reproducibility. We demonstrate its capacity to carry out complex sequences of experiments such as super-resolved live-to-fixed imaging to study actin dynamics; highly-multiplexed STORM and DNA-PAINT acquisitions of multiple targets; and event-driven fixation microscopy to study the role of adhesion contacts in mitosis.

Mechanisms of Acinar Cell Injury in Acute Pancreatitis

2005 ◽  
Vol 94 (2) ◽  
pp. 89-96 ◽  
Author(s):  
M. G. T. Raraty ◽  
J. A. Murphy ◽  
E. McLoughlin ◽  
D. Smith ◽  
D. Criddle ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cell ◽  
Cell Injury ◽  
Research Effort ◽  
Cytosolic Calcium ◽  
Pancreatic Acinar Cell ◽  
Enzyme Activation ◽  
Cellular Damage ◽  
Extracellular Milieu ◽  
The Subject

Acute pancreatitis has many causes, all leading to a common pathway of changes within the pancreatic acinar cell. Key amongst these changes is premature intracellular activation of digestive enzymes but this is also accompanied by the appearance of cytosolic vacuoles, co-localization of digestive and lysosomal enzymes, activation of NF-kB, and release of pro-inflammatory cytokines. The exact mechanism responsible for enzyme activation remains the subject of much research effort and not a little debate, however it is clear that all of these changes are triggered by an abnormal, sustained rise in cytosolic calcium concentration, which is itself dependent both on release of calcium from endoplasmic reticulum stores and uptake from the extracellular milieu. Activated enzymes are directly damaging to the acinar cell themselves, but recruitment of circulating neutrophils leads to further cellular damage. Cytokines and neutrophil activation are also responsible for the systemic inflammatory response typically seen in severe acute pancreatitis.

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