Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to ...evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin-dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21
mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21
mice, via relieved repression of CDK2AP1. Further, miR-21
mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis.
Delivering the promise of miRNA cancer therapeutics Pereira, Diane M.; Rodrigues, Pedro M.; Borralho, Pedro M. ...
Drug discovery today,
March 2013, 2013-Mar, 2013-3-00, 20130301, Letnik:
18, Številka:
5-6
Journal Article
Recenzirano
► Delivery strategies for miRNA modulators (miRNA mimics/inhibitors) in cancer. ► Local versus systemic delivery in vivo. ► Modified miRNA modulators. ► Carriers for miRNA modulators delivery in vivo ...(viral, non-viral, and targeted strategies).
MicroRNAs (miRNAs) are pivotal post-transcriptional gene expression regulators. These endogenous small non-coding RNAs aberrantly expressed in cancer have significant roles in tumorigenesis and progression. Currently, miRNAs are being pursued as diagnostic and prognostic biomarkers, and as therapeutic tools in cancer. miRNA modulation provides the unique ability to fine-tune multiple genes simultaneously, thereby regulating relevant signaling pathways involved in cell differentiation, proliferation and survival. This unique miRNA feature shifts the traditional one drug one target paradigm to a novel one drug multiple targets paradigm. We herein review in vivo strategies of miRNA modulator (mimic and/or inhibitor) delivery in cancer models, a subject that remains the key challenge to the establishment of this novel class of RNA therapeutics.
Hepatocyte cell death, inflammation and oxidative stress constitute key pathogenic mechanisms underlying non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of necroptosis in ...human and experimental NAFLD and its association with tumour necrosis factor α (TNF-α) and oxidative stress. Serum markers of necrosis, liver receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like (MLKL) were evaluated in control individuals and patients with NAFLD. C57BL/6 wild-type (WT) or RIP3-deficient (RIP3(-/-)) mice were fed a high-fat choline-deficient (HFCD) or methionine and choline-deficient (MCD) diet, with subsequent histological and biochemical analysis of hepatic damage. In primary murine hepatocytes, necroptosis and oxidative stress were also assessed after necrostatin-1 (Nec-1) treatment or RIP3 silencing. We show that circulating markers of necrosis and TNF-α, as well as liver RIP3 and MLKL phosphorylation were increased in NAFLD. Likewise, RIP3 and MLKL protein levels and TNF-α expression were increased in the liver of HFCD and MCD diet-fed mice. Moreover, RIP3 and MLKL sequestration in the insoluble protein fraction of NASH (non-alcoholic steatohepatitis) mice liver lysates represented an early event during stetatohepatitis progression. Functional studies in primary murine hepatocytes established the association between TNF-α-induced RIP3 expression, activation of necroptosis and oxidative stress. Strikingly, RIP3 deficiency attenuated MCD diet-induced liver injury, steatosis, inflammation, fibrosis and oxidative stress. In conclusion, necroptosis is increased in the liver of NAFLD patients and in experimental models of NASH. Further, TNF-α triggers RIP3-dependent oxidative stress during hepatocyte necroptosis. As such, targeting necroptosis appears to arrest or at least impair NAFLD progression.
Lytic cell death in metabolic liver disease Gautheron, Jérémie; Gores, Gregory J.; Rodrigues, Cecília M.P.
Journal of hepatology,
08/2020, Letnik:
73, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Regulated cell death is intrinsically associated with inflammatory liver disease and is pivotal in governing outcomes of metabolic liver disease. Different types of cell death may coexist as ...metabolic liver disease progresses to inflammation, fibrosis, and ultimately cirrhosis. In addition to apoptosis, lytic forms of hepatocellular death, such as necroptosis, pyroptosis and ferroptosis elicit strong inflammatory responses due to cell membrane permeabilisation and release of cellular components, contributing to the recruitment of immune cells and activation of hepatic stellate cells. The control of liver cell death is of fundamental importance and presents novel opportunities for potential therapeutic intervention. This review summarises the underlying mechanism of distinct lytic cell death modes and their commonalities, discusses their relevance to metabolic liver diseases of different aetiologies, and acknowledges the limitations of current knowledge in the field. We focus on the role of hepatocyte necroptosis, pyroptosis and ferroptosis in non-alcoholic fatty liver disease, alcohol-associated liver disease and other metabolic liver disorders, as well as potential therapeutic implications.
Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is ...controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD.
RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or
-deficient (
) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks.
RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly,
deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in
mice. Furthermore,
3 deficiency hampered tumourigenesis. Intriguingly,
mice displayed increased body weight gain, while lipidomics showed that deletion of
shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in
mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis.
Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.
In the 20th century, the development, licensing and implementation of vaccines as part of large, systematic immunization programs started to address health inequities that existed globally. However, ...at the time of writing, access to vaccines that prevent life-threatening infectious diseases remains unequal to all infants, children and adults in the world. This is a problem that many individuals and agencies are working hard to address globally. As clinicians and biomedical scientists we often focus on the health benefits that vaccines provide, in the prevention of ill-health and death from infectious pathogens. Here we discuss the health, economic and social benefits of vaccines that have been identified and studied in recent years, impacting all regions and all age groups. After learning of the emergence of SARS-CoV-2 virus in December 2019, and its potential for global dissemination to cause COVID-19 disease was realized, there was an urgent need to develop vaccines at an unprecedented rate and scale. As we appreciate and quantify the health, economic and social benefits of vaccines and immunization programs to individuals and society, we should endeavor to communicate this to the public and policy makers, for the benefit of endemic, epidemic, and pandemic diseases.
Colite lymphocytaire associee a l'entacapone Rodrigues, David M; Hsieh, Eugene; Bernstein, Michael ...
CMAJ. Canadian Medical Association journal,
01/2023, Letnik:
195, Številka:
3
Journal Article
Microplastics (particles with a size<5mm), one of the most emerging aquatic pollutants, are of particular concern since they can reach high densities and interact with biotic and abiotic environment. ...The occurrence of microplastics in freshwater systems is less understood than in marine environment. Hence, the present study aims to provide new insights into microplastics abundances and distribution in Antuã River (Portugal) by applying the isolation method of wet peroxide oxidation with addition of zinc chloride to water and sediment samples collected in March and October 2016, in three sampling sites. The abundance of microplastics in water ranged from 5 to 8.3mgm−3 or 58–193itemsm−3 in March and from 5.8–51.7mgm−3 or 71–1265itemsm−3 in October. In sediments, the abundance ranged from 13.5–52.7mgkg−1 or 100–629itemskg−1 in March and from 2.6–71.4mgkg−1 or 18–514itemskg−1 in October. The water and sediment samples with the greatest abundances were from São João da Madeira and Aguincheira, respectively. Spatio-temporal distribution showed different pattern according to methodological approaches, seasonal and hydrodynamic conditions and the proximity to urban/industry areas. Analysis of plastics by Fourier transform infrared spectroscopy underline polyethylene and polypropylene as the most common polymer types identified in this work. The low medium high oxidation ratio was 56:22:22 (%) in March and 61:31:8 (%) in October. Foams and fibers were the most abundant type in São João da Madeira, while fibers and fragments were the most abundant in Aguincheira and Estarreja in water and sediment samples, respectively. This study emphasizes the importance of rivers as carriage systems of microplastics. Further studies should be performed to identify point sources in order to mitigate the microplastics contamination in aquatic systems.
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•Antuã River is severely affected by microplastics, especially in water column.•Spatial and temporal distributions show different pattern of abundance of MPs.•Sampling sites were areas with intensive anthropogenic activities.•Methodologies, seasonal and hydrodynamic conditions cause these variations.•Polyethylene and polypropylene are the most common polymers detected.
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