Biomarkers of NRF2 signalling: Current status and future challenges.

The cytoprotective transcription factor NRF2 regulates the expression of several hundred genes in mammalian cells and is a promising therapeutic target in a number of diseases associated with oxidative stress and inflammation. Hence, an ability to monitor basal and inducible NRF2 signalling is vital for mechanistic understanding in translational studies. Due to some caveats related to the direct measurement of NRF2 levels, the modulation of NRF2 activity is typically determined by measuring changes in the expression of one or more of its target genes and/or the associated protein products.

Driver Mutations of Pancreatic Cancer Affect Ca Signaling and ATP Production.

Glandular pancreatic epithelia of the acinar or ductal phenotype may seem terminally differentiated, but they are characterized by remarkable cell plasticity. Stress-induced trans-differentiation of these cells has been implicated in the mechanisms of carcinogenesis. Current consensus links pancreatic ductal adenocarcinoma with onco-transformation of ductal epithelia, but under the presence of driver mutations in and , also with trans-differentiation of pancreatic acini.

Activation of pancreatic stellate cells attenuates intracellular Ca signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites.

Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative metabolites, fatty acid ethyl esters, generated from ethanol and fatty acids.

Transcriptomics and Network Pharmacology Reveal the Protective Effect of Chaiqin Chengqi Decoction on Obesity-Related Alcohol-Induced Acute Pancreatitis Oxidative Stress and PI3K/Akt Signaling Pathway.

Obesity-related acute pancreatitis (AP) is characterized by increasing prevalence worldwide and worse clinical outcomes compared to AP of other etiologies. Chaiqin chengqi decoction (CQCQD), a Chinese herbal formula, has long been used for the clinical management of AP but its therapeutic actions and the underlying mechanisms have not been fully elucidated. This study has investigated the pharmacological mechanisms of CQCQD in a novel mouse model of obesity-related alcohol-induced AP (OA-AP).

When healing turns into killing - the pathophysiology of pancreatic and hepatic fibrosis.

Disorders such as pancreatic or hepatic fibrosis are a cruel reminder that disruption of the delicate physiological balance could result in severe pathological consequences. Fibrosis is usually associated with chronic diseases and manifests itself as excessive deposition of the extracellular matrix, which gradually leads to the replacement of the cellular components by fibrotic lesions, significantly compromising normal tissue functions. The main cellular mediators of fibrosis are different populations of tissue fibroblasts, predominantly hepatic and pancreatic stellate cells in the liver and pancreas, respectively.

A microRNA checkpoint for Ca signaling and overload in acute pancreatitis.

Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca ([Ca]) overload; however, the underlying mechanisms in Ca overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca entry (SOCE) channel expression, Ca overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity.

Tyrophagus putrescentiae (Sarcoptiformes: Acaridae) in the in vitro cultures of slime molds (Mycetozoa): accident, contamination, or interaction?

Tyrophagus putrescentiae (Schrank), commonly known as the cereal mite, cheese mite, or ham mite, is a cosmopolitan species reported from various environments in the wild, including soil, plant material and vertebrate nests. It has also been recognized as a common pest of food storages, mycological collections as well as plant and invertebrate laboratory cultures. Laboratory observations indicate that T.

Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research.

Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging.

Electron paramagnetic resonance spectroscopy reveals alterations in the redox state of endogenous copper and iron complexes in photodynamic stress-induced ischemic mouse liver.

Divalent copper and iron cations have been acknowledged for their catalytic roles in physiological processes critical for homeostasis maintenance. Being redox-active, these metals act as cofactors in the enzymatic reactions of electron transfer. However, under pathophysiological conditions, owing to their high redox potentials, they may exacerbate stress-induced injury.

Pancreatic Cancer and Its Microenvironment-Recent Advances and Current Controversies.

Pancreatic ductal adenocarcinoma (PDAC) causes annually well over 400,000 deaths world-wide and remains one of the major unresolved health problems. This exocrine pancreatic cancer originates from the mutated epithelial cells: acinar and ductal cells. However, the epithelia-derived cancer component forms only a relatively small fraction of the tumor mass.

Signaling in the Physiology and Pathophysiology of Pancreatic Stellate Cells - Brief Review of Recent Advances.

The interest in pancreatic stellate cells (PSCs) has been steadily growing over the past two decades due mainly to the central role these cells have in the desmoplastic reaction associated with diseases of the pancreas, such as pancreatitis or pancreatic cancer. In recent years, the scientific community has devoted substantial efforts to understanding the signaling pathways that govern PSC activation and interactions with neoplastic cells. This mini review aims to summarize some very recent findings on signaling in PSCs and highlight their impact to the field.

Melanin presence inhibits melanoma cell spread in mice in a unique mechanical fashion.

Melanoma is a highly aggressive cancer that exhibits metastasis to various critical organs. Unlike any other cancer cells, melanoma cells can synthesize melanin in large amounts, becoming heavily pigmented. Until now the role of melanin in melanoma, particularly the effect of melanin presence on the abilities of melanoma cells to spread and metastasize remains unknown.

ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause Ca -signalling dysregulation or toxicity in pancreatic acinar cells.

Background And Purpose: Many cancer cells depend on anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins for their survival. Bcl-2 antagonism through Bcl-2 homology 3 (BH3) mimetics has emerged as a novel anti-cancer therapy. ABT-199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl-2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia.

BH4 domain peptides derived from Bcl-2/Bcl-XL as novel tools against acute pancreatitis.

Biliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IPR) and the ryanodine receptor (RyR) play major roles in intracellular Ca signaling.

On BH3 Mimetics and Ca Signaling.

Preclinical Research BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca homeostasis, including Ca release from the intracellular stores as well as Ca fluxes across the plasma membrane.

Biology of pancreatic stellate cells-more than just pancreatic cancer.

Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases.

BH3 mimetic-elicited Ca signals in pancreatic acinar cells are dependent on Bax and can be reduced by Ca-like peptides.

BH3 mimetics are small-molecule inhibitors of B-cell lymphoma-2 (Bcl-2) and Bcl-xL, which disrupt the heterodimerisation of anti- and pro-apoptotic Bcl-2 family members sensitising cells to apoptotic death. These compounds have been developed as anti-cancer agents to counteract increased levels of Bcl-2 proteins often present in cancer cells. Application of a chemotherapeutic drug supported with a BH3 mimetic has the potential to overcome drug resistance in cancers overexpressing anti-apoptotic Bcl-2 proteins and thus increase the success rate of the treatment.

Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake.

Key Points: Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3-sulfate primarily affects acinar cells.

Nitric oxide signals are interlinked with calcium signals in normal pancreatic stellate cells upon oxidative stress and inflammation.

The mammalian diffuse stellate cell system comprises retinoid-storing cells capable of remarkable transformations from a quiescent to an activated myofibroblast-like phenotype. Activated pancreatic stellate cells (PSCs) attract attention owing to the pivotal role they play in development of tissue fibrosis in chronic pancreatitis and pancreatic cancer. However, little is known about the actual role of PSCs in the normal pancreas.

Zinc-pheophorbide a-highly efficient low-cost photosensitizer against human adenocarcinoma in cellular and animal models.

Background: Our previous study has shown a prolonged retention and accumulation of Zn-pheophorbide a, a water-soluble derivative of chlorophyll a, in tumor tissue (Szczygiel et al. [19]). This prompted us to further evaluate the phototherapeutic potential of this photosensitizer of excellent physicochemical properties.

Nitrosylhemoglobin in photodynamically stressed human tumors growing in nude mice.

The role of nitric oxide in human tumor biology and therapy has been the subject of extensive studies. However, there is only limited knowledge about the mechanisms of NO production and its metabolism, and about the role NO can play in modern therapeutic procedures, such as photodynamic therapy. Here, for the first time, we report the presence of nitrosylhemoglobin, a stable complex of NO, in human lung adenocarcinoma A549 tumors growing in situ in nude mice.

Pulmonary metastases of the A549-derived lung adenocarcinoma tumors growing in nude mice. A multiple case study.

Lung adenocarcinoma is a leading human malignancy with fatal prognosis. Ninety percent of the deaths, however, are caused by metastases. The model of subcutaneous tumor xenograft in nude mice was adopted to study the growth of control and photodynamically treated tumors derived from the human A549 lung adenocarcinoma cell line.

Splenic melanosis during normal murine C57BL/6 hair cycle and after chemotherapy.

Cancer chemotherapy is associated with serious side effects, including temporary hair loss and impairment of pigmentation. We suspect that ectopic melanin deposition occurring due to chemotherapy may add to these effects worsening the already unpleasant symptoms. We associated the ectopic occurrence of follicular melanin after chemotherapy with splenic melanosis - an interesting example of extradermal melanin localization - and we expected an increase in splenic melanin deposition after chemotherapy.

Oxidative extraction versus total decomposition of soil in the determination of thallium.

An aqua regia extraction and a total decomposition of soil were compared in terms of thallium determination. A sequential extraction of soil, according to the BCR protocol, was also performed for additional information on thallium distribution in soil fractions. Certified reference material-soil GBW 07401 of Chinese origin, containing 1+/-0.