Oncology research has received considerable attention in recent years due to the increasing prevalence of cancer in human and animal populations worldwide ....
Pannexin1 as mediator of inflammation and cell death Crespo Yanguas, Sara; Willebrords, Joost; Johnstone, Scott R. ...
Biochimica et biophysica acta. Molecular cell research,
01/2017, Letnik:
1864, Številka:
1
Journal Article
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Pannexins form channels at the plasma membrane surface that establish a pathway for communication between the cytosol of individual cells and their extracellular environment. By doing so, pannexin ...signaling dictates several physiological functions, but equally underlies a number of pathological processes. Indeed, pannexin channels drive inflammation by assisting in the activation of inflammasomes, the release of pro-inflammatory cytokines, and the activation and migration of leukocytes. Furthermore, these cellular pores facilitate cell death, including apoptosis, pyroptosis and autophagy. The present paper reviews the roles of pannexin channels in inflammation and cell death. In a first part, a state-of-the-art overview of pannexin channel structure, regulation and function is provided. In a second part, the mechanisms behind their involvement in inflammation and cell death are discussed.
•Pannexin1 channels permeate ions and molecules in the size range of 1.5kDa. Pannexin1 channels are identified as ATP release channels as well as anion selective-channels.•Pannexin1 channels drive inflammation by assisting in the activation of inflammasomes, the release of pro-inflammatory cytokines, and the activation and migration of leukocytes.•Pannexin1 channels facilitate cell death, including apoptosis, pyroptosis and autophagy.•Pannexin1 channels inhibition or activation is an attractive potential therapeutic target in a variety of diseases.
Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis ...regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin‐like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin‐based and pannexin‐based channels in noncancerous liver disease.
Summary Background & aims : Few clinical trials have addressed the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) on non-alcoholic steatohepatitis (NASH). We evaluated the effects ...of supplementation with omega-3 PUFAs from flaxseed and fish oils in patients with biopsy-proven NASH. Methods Patients received three capsules daily, each containing 0.315 g of omega-3 PUFAs (64% alpha-linolenic ALA, 16% eicosapentaenoic EPA, and 21% docosahexaenoic DHA acids; n-3 group, n = 27) or mineral oil (placebo group, n = 23). Liver biopsies were evaluated histopathologically by the NASH activity score (NAS). Plasma levels of omega-3 PUFAs were assessed as a marker of intake at baseline and after 6 months of treatment. Secondary endpoints included changes in plasma biochemical markers of lipid metabolism, inflammation, and liver function at baseline and after 3 and 6 months of treatment. Results At baseline, NAS was comparable between the groups ( p = 0.98). After intervention with omega-3 PUFAs, plasma ALA and EPA levels increased ( p ≤ 0.05). However in the placebo group, we also observed increased EPA and DHA ( p ≤ 0.05), suggesting an off-protocol intake of PUFAs. NAS improvement/stabilization was correlated with increased ALA in the n-3 group ( p = 0.02) and with increased EPA ( p = 0.04) and DHA ( p = 0.05) in the placebo group. Triglycerides were reduced after 3 months in the n-3 group compared to baseline ( p = 0.01). Conclusions In NASH patients, the supplementation of omega-3 PUFA from flaxseed and fish oils significantly impacts on plasma lipid profile of patients with NASH. Plasma increase of these PUFAs was associated with better liver histology. (ID 01992809)
Recent meta-analyses indicate that coffee consumption reduces the risk for digestive tract (oral, esophageal, gastric and colorectal) and, especially, liver cancer. Coffee bean-derived beverages, as ...the widely-consumed espresso and “common” filtered brews, present remarkable historical, cultural and economic importance globally. These drinks have rich and variable chemical composition, depending on factors that vary from “seeding to serving”. The alkaloids caffeine and trigonelline, as well as the polyphenol chlorogenic acid, are some of the most important bioactive organic compounds of these beverages, displaying high levels in both espresso and common brews and/or increased bioavailability after consumption. Thus, we performed a comprehensive literature overview of current knowledge on the effects of coffee beverages and their highly bioavailable compounds, describing: 1) recent epidemiological and experimental findings highlighting the beneficial effects against gastrointestinal/liver carcinogenesis, and 2) the main molecular mechanisms in these in vitro and in vivo bioassays. Findings predominantly address the protective effects of coffee beverages and their most common/bioavailable compounds individually on gastrointestinal and liver cancer development. Caffeine, trigonelline and chlorogenic acid modulate common molecular targets directly implicated in key cancer hallmarks, what could stimulate novel translational or population-based mechanistic investigations.
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•Caffeine, chlorogenic acid and trigonelline are major compounds of coffee drinks.•Coffee lowers gastrointestinal and, especially, liver cancer risk in humans.•Coffee/major compounds attenuate gastrointestinal and liver carcinogenesis in vivo.•Major compounds share many cancer hallmark-related molecular targets in vitro.•Interaction of major compounds must be considered for future translational assays.
Connexin-based channels play key roles in cellular communication and can be affected by deleterious chemicals. In this study, the effects of various genotoxic carcinogenic compounds, non-genotoxic ...carcinogenic compounds and non-carcinogenic compounds on the expression and functionality of connexin-based channels, both gap junctions and connexin hemichannels, were investigated in human hepatoma HepaRG cell cultures. Expression of connexin26, connexin32, and connexin43 was evaluated by means of real-time reverse transcription quantitative polymerase chain reaction analysis, immunoblot analysis and in situ immunostaining. Gap junction functionality was assessed via a scrape loading/dye transfer assay. Opening of connexin hemichannels was monitored by measuring extracellular release of adenosine triphosphate. It was found that both genotoxic and non-genotoxic carcinogenic compounds negatively affect connexin32 expression. However, no specific effects related to chemical type were observed at gap junction or connexin hemichannel functionality level.
Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose is the most common cause of drug-induced liver injury (DILI). Although the primary hepatic damage is induced by APAP-derived toxic intermediates ...resulting from cytochrome P450 metabolism, immune components also play an important role in DILI pathophysiology. Aedes aegypti saliva is a source of bioactive molecules with in vitro anti-inflammatory and immunomodulatory activities. However, evidences on the therapeutic use of Ae. aegypti salivary preparations in animal models of relevant clinical conditions are still scarce. Thus, the present study was designed to evaluate the protective role of Ae. aegypti saliva in a murine model of APAP-induced DILI. C57BL/6 mice were exposed to Ae. aegypti bites 2 hours after APAP overdose. Biochemical and immunological parameters were evaluated in blood and liver samples at different time points after APAP administration. Exposure to Ae. aegypti saliva attenuated liver damage, as demonstrated by reduced hepatic necrosis and serum levels of alanine aminotransferase in APAP-overdosed mice. The levels of hepatic CYP2E1, the major enzyme responsible for the bioactivation of APAP, were not changed in Ae. aegypti exposed animals, suggesting no effects in the generation of hepatotoxic metabolites. On the other hand, mice treated with Ae. aegypti saliva following APAP overdose presented lower serum concentration of TNF-α, IL-6, IL-1β and IL-10, as well as reduced frequency of inflammatory cell populations in the liver, such as NKT cells, macrophages and dendritic cells. These findings show that Ae. aegypti saliva has bioactive molecules with therapeutic properties and may represent a prospective source of new compounds in the management of DILI-associated inflammatory disorders and, perhaps, many other inflammatory/autoimmune diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cell junctions, including anchoring, occluding and communicating junctions, play an indispensable role in tissue architecture and homeostasis. Consequently, malfunctioning of cell junctions is linked ...with a wide range of disorders, including in liver. The present study was set up to investigate the effects of acute and chronic disease induced by chemical compounds on hepatic cell junctions in mice. Mice were either overdosed with paracetamol or repeatedly administered carbon tetrachloride followed by sampling at 24 hours or 8 weeks, respectively. mRNA and protein expression levels of adherens, gap and tight junction components were measured in liver using reverse transcription quantitative real-time polymerase chain reaction analysis and immunoblot techniques, respectively. It was found that protein levels of the adherens junction building blocks β-catenin and γ-catenin, the gap junction components Cx26 and Cx32, and the tight junction constituent zonula occludens 2 were decreased, while mRNA levels of the adherens junction building block E-cadherin, and the tight junction constituent zonula occludens 2 and claudin 1 were upregulated following paracetamol overdosing. Repeated administration of carbon tetrachloride increased protein levels of E-cadherin, β-catenin, Cx26, Cx32, Cx43 and claudin 1. The latter was reflected at the mRNA level. In conclusion, acute and chronic liver disease have different effects on cell junctions in liver.
Hepatocellular carcinoma causes ~10% of all cancer-related deaths worldwide, usually emerging in a background of liver fibrosis/cirrhosis (70%-90% of cases). Chemically-induced mouse models for ...fibrosis-associated hepatocarcinogenesis are widely-applied, resembling the corresponding human disease. Nonetheless, a long time is necessary for the development of preneoplastic/neoplastic lesions. Thus, we proposed an early fibrosis-associated hepatocarcinogenesis model for male and female mice separately, focusing on reducing the experimental time for preneoplastic/neoplastic lesions development and establishing standard models for both sexes. Then, two-week old susceptible C3H/HeJ male and female mice (n = 8 animals/sex/group) received a single dose of diethylnitrosamine (DEN, 10 or 50 mg/Kg). During 2 months, mice received 3 weekly doses of carbon tetrachloride (CCl4, 10% corn oil solution, 0.25 to 1.50 μL/g b.wt.) and they were euthanized at week 17. DEN/CCl4 protocols for males and females displayed clear liver fibrosis, featuring collagen accumulation and hepatic stellate cell activation (α-SMA). In addition, liver from males displayed increased CD68+ macrophage number, COX-2 protein expression and IL-6 levels. The DEN/CCl4 models in both sexes impaired antioxidant defense as well as enhanced hepatocyte proliferation and apoptosis. Moreover, DEN/CCl4-treated male and female developed multiple preneoplastic altered hepatocyte foci and hepatocellular adenomas. As expected, the models showed clear male bias. Therefore, we established standard and suitable fibrosis-associated hepatocarcinogenesis models for male and female mice, shortening the experimental time for the development of hepatocellular preneoplastic/neoplastic lesions in comparison to other classical models.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Liver cancer cell lines are frequently used in vitro tools to test candidate anti-cancer agents as well as to elucidate mechanisms of liver carcinogenesis. Among such mechanisms is cellular ...communication mediated by connexin-based gap junctions. The present study investigated changes in connexin expression and gap junction functionality in liver cancer in vitro. For this purpose, seven human liver cancer cell lines, as well as primary human hepatocytes, were subjected to connexin and gap junction analysis at the transcriptional, translational and activity level. Real-time quantitative reverse transcription polymerase chain reaction analysis showed enhanced expression of connexin43 in the majority of liver cancer cell lines at the expense of connexin32 and connexin26. Some of these changes were paralleled at the protein level, as evidenced by immunoblot analysis and in situ immunocytochemistry. Gap junctional intercellular communication, assessed by the scrape loading/dye transfer assay, was generally low in all liver cancer cell lines. Collectively, these results provide a full scenario of modifications in hepatocyte connexin production and gap junction activity in cultured liver cancer cell lines. The findings may be valuable for the selection of neoplastic hepatocytes for future mechanistic investigation and testing of anti-cancer drugs that target connexins and their channels.
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