44,864 research outputs found

    Determinantes genéticos de resistência cruzada entre a terapêutica da malaria com novos compostos

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    Tese de doutoramento em Envelhecimento e Doen√ßas Cr√≥nicasIn 2019, malaria caused half a million deaths worldwide, being elimination hampered by the ability of Plasmodium falciparum to evolve antimalarial resistance. The efficacy of artemisinin-based combination therapies (ACT) helped to reduce malaria mortality, however, resistance is a reality. Being ACT efficacy threatened, efforts to define the molecular basis of multidrug resistance and the search for new compound, ideally with new mechanisms of action, are urgently in need. Within the parasite, most of the available antimalarials act at the host‚Äôs intraerythrocytic stage. Here, many drugs are housed in the digestive vacuole of the parasite with flux promoted by transporter proteins, such as the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1), a well-known ACT resistance player. We explored the interplay of known pfmdr1 resistance markers, namely, gene copy number variation with N86Y and Y184F single nucleotide polymorphisms to unravel the complex traits that might serve to maximize ACT resistance. Using genomic epidemiology, a global prevalence and temporal changes of pfmdr1 polymorphisms were assessed and, taking into account the information from this database, through a gene editing approach, we create in vitro edited parasite lines to evaluate the impact of these polymorphisms in the kinetics of the transporter. This data provided evidence of specific multicopy PfMDR1 with N86/184F haplotype, geographic selection and expansion in Southeast Asia. The genetic tools created could help on finding drugs with potential of reverting a multidrug resistance phenotype, as the herein explored synthetic compounds derived from steroids, a class of molecules with relevant biological activities. Structure‚Äďactivity relationship led to the synthesis of steroid derivatives with promising antimalarial activity against the blood stage of the parasite‚Äôs life cycle with high selectivity and independent of PfMDR1. Exploring possible mechanisms of action of the best compound, revealed induction of oxidative stress inside the parasite and interference with the metabolic process that leads to hemozoin formation inside the digestive vacuole of the parasite. Overall, the findings presented could help tailor and optimize present antimalarial drug usage by taking into account the regional prevalence of pfmdr1 polymorphisms and highlights the high potential of the newly developed compounds, thereby underscoring the possibility to develop new antimalarial drugs based on steroids.Em 2019, a mal√°ria causou meio milh√£o de mortes mundialmente, sendo a elimina√ß√£o dificultada pela capacidade do Plasmodium falciparum desenvolver resist√™ncia aos antimal√°ricos atuais. A efic√°cia da terapia de combina√ß√£o baseadas em artemisinina (ACT) ajudou a reduzir a mortalidade provocada pela mal√°ria, no entanto, a resist√™ncia √© uma realidade. A efic√°cia do ACT est√° comprometida, as tentativas para definir as bases moleculares da multirresist√™ncia e a procura por novos compostos, idealmente com novos mecanismos de a√ß√£o, s√£o urgentes. No parasita, a maioria dos antimal√°ricos atua no estadio intra-eritroc√≠tico. Muitos s√£o alojados no vac√ļolo digestivo do parasita atrav√©s do fluxo promovido por prote√≠nas transportadoras, como a ‚ÄúPlasmodium falciparum multidrug resistance protein 1‚ÄĚ (PfMDR1), um fator envolvido na resist√™ncia aos ACTs. Neste trabalho foi explorada a intera√ß√£o de marcadores de resist√™ncia conhecidos no pfmdr1, ou seja, varia√ß√£o do n√ļmero de c√≥pias do gene com polimorfismos no nucle√≥tido N86Y e Y184F para tentar descobrir as caracter√≠sticas que ajudam a maximizar a resist√™ncia aos ACTs. Usando epidemiologia gen√≥mica, a preval√™ncia e altera√ß√Ķes temporais dos polimorfismos no pfmdr1 foram avaliadas tendo em considera√ß√£o a informa√ß√£o obtida desta base de dados, atrav√©s de edi√ß√£o de genes, geramos in vitro parasitas editados para avaliar o impacto desses polimorfismos na cin√©tica do transportador. Isto desvendou evid√™ncias acerca do hapl√≥tipo espec√≠fico de multic√≥pias com N86/184F, sobre a sele√ß√£o geogr√°fica e expans√£o no Sudeste Asi√°tico. As ferramentas gen√©ticas criadas podem auxiliar na descoberta de f√°rmacos com potencial para reverter o fen√≥tipo de resist√™ncia, como os compostos sint√©ticos derivados de ester√≥ides explorados nesta tese, uma classe de mol√©culas com atividade biol√≥gica relevante. A rela√ß√£o estrutura-atividade levou √† s√≠ntese de ester√≥ides com uma atividade promissora contra o estadio intra-eritroc√≠tico do ciclo de vida do parasita com grande seletividade e independ√™ncia do PfMDR1. Os mecanismos de a√ß√£o do melhor composto foi tamb√©m explorados, revelando indu√ß√£o de stress oxidativo no parasita e uma interfer√™ncia no processo metab√≥lico que leva √† forma√ß√£o de hemozo√≠na. Concluindo, os resultados apresentados podem ajudar a adaptar e otimizar o uso dos antimal√°ricos atuais, tendo em considera√ß√£o a preval√™ncia regional dos polimorfismos no pfmdr1 e, destaca tamb√©m o grande potencial dos compostos recentemente desenvolvidos, demonstrando a possibilidade de desenvolver novos antimal√°ricos baseados em ester√≥ides.Financial support was provided by grants from the PD/BD/127826/2016, ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020; by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF

    Fucoidan de algas marinhas usado no desenvolvimento de abordagens terapêuticas para diabetes mellitus

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    Tese de Doutoramento em Engenharia de Tecidos, Medicina Regenerativa e C√©lulas EstaminaisDiabetes mellitus (DM) is a metabolic disorder that affects 450 million people worldwide, being the sixth most common cause of death. Therefore, it is crucial to develop new therapeutic strategies and relevant models for diabetes in order to accelerate the discovery of new treatments. In this perspective, marine origin polymers represent a relatively untapped source that can be used in the creation of platforms/models to attend these needs. Algae, for instance, synthesize sulfated polysaccharides with several bioactivity properties, which added to their structural role, open new avenues in biomaterials research. The main focus of this thesis consists in the demonstration of the potential of fucoidan on the development of therapeutic approaches for diabetes mellitus treatment. Fucoidan (Fu) is an underexploited sulfated polysaccharide extracted from brown algae, which has interesting chemical and biological properties. The major obstacle for using fucoidan on polymeric devices for biomedical applications is the higher solubility in water. In order to control the solubility of fucoidan in water and increase its processability, a chemical modification was studied, a methacrylation reaction, enabling its further gelation by photocrosslinking. Quasi-spherical hydrogel particles were thus prepared, supporting the culture of human pancreatic cells (1.1B4HP), as well as the sustained delivery of insulin. Moreover, alternative methodologies based in blends of fucoidan with other natural/synthetic polymers were also explored. In particular, attention was given to agarose, with attractive gelling properties mediated by temperature. The properties of the resulting hydrogel were assessed, envisaging its use on the encapsulation of pancreatic cells (1.1B4HP cells) as a system to protect those cells from the host immune system. As pancreatic cells and islets are highly vascularized, a platform device was developed based on fibrous meshes of PCL/fucoidan using airbrush technique, with capacity to promote angiogenesis. Additionally, the anti-oxidant effect of fucoidan on beta cells was also assessed, enabling to protect those cells from oxidative stress. This fucoidan was combined with alginate, developing hydrogels capable to support the encapsulation of pancreatic cells and islets with insulin secretion responsive to glucose concentration in medium. Altogether the results obtained under the scope of this thesis gave interesting insights on the use of the new fucoidan-based structures as functional biomaterials with a potential pivotal role for diabetes treatment.A diabetes mellitus (DM) √© um dist√ļrbio metab√≥lico que afeta cerca de 450 milh√Ķes de pessoas em todo o mundo, sendo a sexta causa de morte. Por conseguinte, √© crucial desenvolver novas estrat√©gias/modelos terap√™uticos para a diabetes levando √† descoberta de novos tratamentos. Nesta perspetiva, os pol√≠meros de origem marinha representam uma fonte relativamente inexplorada que pode ser usada na cria√ß√£o de plataformas/modelos para atender a essas necessidades. As algas, s√£o um exemplo, porque sintetizam uma grande variedade de pol√≠meros e compostos mais pequenos com v√°rias propriedades bioativas. O foco principal desta tese consiste na demonstra√ß√£o do potencial do fucoidan no desenvolvimento de novas abordagens terap√™uticas desenvolvidas para o tratamento da diabetes mellitus. Fucoidan (Fu) √© um polissacar√≠deo sulfatado extra√≠do de algas castanhas, com propriedades qu√≠micas e biol√≥gicas interessantes sendo pouco explorado. O principal obst√°culo para o uso de fucoidan em dispositivos polim√©ricos para aplica√ß√Ķes biom√©dicas √© ser bastante sol√ļvel em √°gua. Para controlar a solubilidade do Fu na √°gua e aumentar sua processabilidade, foi estudada uma modifica√ß√£o qu√≠mica, uma rea√ß√£o de metacrila√ß√£o, permitindo a sua gelifica√ß√£o atrav√©s da foto reticula√ß√£o. Desta forma, foram preparadas part√≠culas quase-esf√©ricas, permitindo o contacto direto com c√©lulas pancre√°ticas humanas (1.1B4HPc√©lulas) bem como o encapsulamento/liberta√ß√£o de insulina foram abordados. Al√©m disso, metodologias alternativas baseadas em misturas do Fu com outros pol√≠meros naturais/sint√©ticos tamb√©m foram exploradas. A agarose teve uma aten√ß√£o particular, com propriedades gelificantes atrativas dependentes da temperatura. As propriedades do hidrogel resultante foram avaliadas, antevendo a sua utiliza√ß√£o no encapsulamento de 1.1B4HP c√©lulas, para proteger essas c√©lulas do sistema imunit√°rio do hospedeiro. Como as c√©lulas pancre√°ticas e as ilhotas Langerhans s√£o altamente vascularizadas, foi desenvolvido um bicomposito de nanofibras PCL/Fu usando uma t√©cnica de aerografia, esse dispositivo/plataforma tinha a capacidade de promover a angiog√™nese. O efeito antioxidante do fucoidan nas c√©lulas beta tamb√©m foi avaliado, permitindo proteger as c√©lulas do stress oxidativo. Hidrog√©is de fucoidan e alginato foram desenvolvidos, sendo capazes de suportar o encapsulamento das ilhotas Langerhans e promover a secre√ß√£o √† insulina em resposta √† concentra√ß√£o de glucose presente no meio. Em conclus√£o, os resultados obtidos no √Ęmbito desta tese foram interessantes e promissores, demonstraram a capacidade do fucoidan a ser usado como base em estruturas e mecanismos que poder√£o ser fundamentais para o tratamento da diabetes.The authors especially acknowledge financial support from the Portuguese Foundation for Science FCT (Grant SFRH/BD/112139/2015), PTDC/CTM-CTM//29813/2017 with support from Fundo Social Europeu and the Programa Operacional de Potencial Humano and the research project EXPL/MAR BIO/0165/2013, from European Union with co-funding of INTERREG POCTEP projects 0330- IBEROMARE_1_P and 0687_NOVOMAR_1_P INTERREG Espanha Portugal 2014-2020 project 0302_CVMAR_I_1_P and Atlantic Area project 2011/1/164 MARMED, through ERDF as well as from Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through Structured projects NORTE-01-0145-FEDER-000021 and NORTE-01-0145-FEDER-000023

    Application of lactic acid bacteria for the biopreservation of meat products: A systematic review

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    .The increasing concern of consumers about food quality and safety and their rejection of chemical additives has promoted the breakthrough of the biopreservation field and the development of studies on the use of beneficial bacteria and their metabolites as potential natural antimicrobials for shelf life extension and enhanced food safety. Control of foodborne pathogens in meat and meat products represents a serious challenge for the food industry which can be addressed through the intelligent use of bio-compounds or biopreservatives. This article aims to systematically review the available knowledge about biological strategies based on the use of lactic acid bacteria to control the proliferation of undesirable microorganisms in different meat products. The outcome of the literature search evidenced the potential of several strains of lactic acid bacteria and their purified or semi-purified antimicrobial metabolites as biopreservatives in meat products for achieving longer shelf life or inhibiting spoilage and pathogenic bacteria, especially when combined with other technologies to achieve a synergistic effect.S

    Metabolic and nutritional triggers associated with increased risk of liver complications in SARS-CoV-2

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    Obesity, diabetes, cardiovascular and respiratory diseases, cancer and smoking are risk factors for negative outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can quickly induce severe respiratory failure in 5% of cases. Coronavirus disease-associated liver injury may occur during progression of SARS-CoV-2 in patients with or without pre-existing liver disease, and damage to the liver parenchyma can be caused by infection of hepatocytes. Cirrhosis patients may be particularly vulnerable to SARS-CoV-2 if suffering with cirrhosis-associated immune dysfunction. Furthermore, pharmacotherapies including macrolide or quinolone antibiotics and steroids can also induce liver damage. In this review we addressed nutritional status and nutritional interventions in severe SARS-CoV-2 liver patients. As guidelines for SARS-CoV-2 in intensive care (IC) specifically are not yet available, strategies for management of sepsis and SARS are suggested in SARS-CoV-2. Early enteral nutrition (EN) should be started soon after IC admission, preferably employing iso-osmolar polymeric formula with initial protein content at 0.8 g/kg per day progressively increasing up to 1.3 g/kg per day and enriched with fish oil at 0.1 g/kg per day to 0.2 g/kg per day. Monitoring is necessary to identify signs of intolerance, hemodynamic instability and metabolic disorders, and transition to parenteral nutrition should not be delayed when energy and protein targets cannot be met via EN. Nutrients including vitamins A, C, D, E, B6, B12, folic acid, zinc, selenium and ŌČ-3 fatty acids have in isolation or in combination shown beneficial effects upon immune function and inflammation modulation. Cautious and monitored supplementation up to upper limits may be beneficial in management strategies for SARS-CoV-2 liver patients

    Understanding interactions between Ramularia collo-cygni and barley leaf physiology to target improvements in host resistance and disease control strategy

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    Ramularia Leaf Spot (RLS) is an increasingly problematic disease of barley. Control options are limited as the causal fungus, Ramularia collo-cygni, has developed resistance to several of the major fungicide groups. Developing new methods for controlling this disease is therefore a priority. R. collo-cygni can grow systemically in barley plants from infected seed, without inducing visible symptoms. In the field, visible symptoms normally only appear after flowering. The relative contribution of the latent and symptomatic stages of the fungal lifecycle to reduction in barley yield is not currently known with any certainty. Two possibilities are that the effect of asymptomatic infection on pre-flowering photosynthetic activity, and the development of grain sink capacity, plays an important role; or that reduction in photosynthetic activity during grain filling, resulting from lesion development and loss of green leaf area, is the predominant factor. This research aimed to increase our understanding of the impact of different phases of the fungal lifecycle on barley photosynthesis and yield formation, to better target host resistance and disease control strategies. Controlled environment and field experiments were used to determine the relative effects of asymptomatic and symptom-expressing phases of R. collo-cygni infection on photosynthesis and yield formation in spring barley. In controlled environment experiments leaf photosynthetic activity was measured in seedlings inoculated with suspensions of R. collo-cygni mycelia. Measurements were made before and after visible symptom development using Infra-Red Gas Analysis (IRGA), chlorophyll fluorescence analysis and chlorophyll fluorescence imaging. No reduction in photosynthetic activity was observed in leaves infected with R. collo-cygni, compared to those of non- infected leaves, during the latent phase of infection. After the appearance of visible symptoms, photosynthetic activity within lesions reduced as the lesions developed. However, this did not lead to reductions in photosynthetic activity when measured across the whole leaf area, suggesting that for there to be a significant effect of disease on whole leaf photosynthetic activity, visible symptoms must develop into mature lesions and coalesce to cover larger areas of the leaf surface. In field experiments plots were treated with a full fungicide regime, left untreated, or inoculated with R. collo-cygni and treated with fungicide to which R. collo-cygni is resistant (the latter as a precaution against lack of natural RLS disease that year and/or other diseases developing on untreated plots). RLS was the only disease of significance that developed in untreated or inoculated plots. Symptoms first appeared after flowering, around Zadoks Growth Stage 72. Fungicide-treated plots remained free of disease. Chlorophyll fluorescence analysis of field plants showed no effect of infection on the maximum quantum efficiency of Photosystem II (Fv/Fm) before visible symptom development, consistent with results from controlled environment experiments. Grain yield of untreated and fungicide-treated plots was predicted from fixed common values of radiation use efficiency (RUE) and utilisation of soluble sugar reserves, and measured values of post-flowering healthy (green) leaf area light interception. Grain yields predicted from the difference in post-flowering light interception between fungicide-treated plants and untreated or inoculated plants displaying symptoms of RLS were comparable with the measured yield response to fungicide. This suggests that yield loss to RLS is primarily associated with a reduction in light capture during grain filling, resulting from lesion development and loss of green leaf area. Results from controlled environment and field experiments suggested that symptom expression was associated with leaf senescence. Further controlled environment experiments tested this relationship by using treatments to vary the onset and rate of leaf senescence. Seedlings that were treated with cytokinin to delay senescence after inoculation with suspensions of R. collo-cygni mycelia developed fewer lesions than control plants. Fungal growth, as measured by quantification of R. collo-cygni DNA in leaves, was also restricted in plants treated with cytokinin. Collectively these results suggest that prevention of visible symptom development, rather than prevention of asymptomatic growth, is the most important target for management of this disease. Control methods targeted at delaying senescence could be a useful avenue for further investigation

    Effects of soccer match-play on unilateral jumping and Inter-limb asymmetry: a repeated measures design

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    The aims of the present study were twofold: 1) determine the effects of repeated soccer match-play on unilateral jump performance and inter-limb asymmetries and, 2) examine associations between asymmetry and commonly reported external load variables collected during competition. Single leg countermovement jumps (SLCMJ) and drop jumps (SLDJ) were collected pre and immediately post five soccer matches in elite academy soccer players. GPS data was also collected each match as part of the routine match-day procedures. SLCMJ height and concentric impulse showed significant reductions post-matches (p 0.05; ES: -0.05 to -0.13). SLDJ height and reactive strength also showed significant reductions post-matches (p < 0.01; ES: -0.39 to -0.58). No meaningful reductions in asymmetry were present at the group level, but individual responses were highly variable. Significant associations between post-match reactive strength asymmetry and explosive distance (r = 0.29; p < 0.05), relative explosive distance (r = 0.34; p < 0.05), high speed running (r = 0.35; p < 0.05) and relative high speed running (r = 0.44; p < 0.01). These findings show that unilateral jump tests are more appropriate than asymmetry to detect real change post soccer competition and practitioners should be cautious about using asymmetry to inform decision-making during the temporal recovery period

    Exposure to particulate matter: direct and indirect role in the COVID-19 pandemic

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    Knowing the transmission factors and the natural environment that favor the spread of a viral infection is crucial to stop outbreaks and develop effective preventive strategies. This work aims to evaluate the role of Particulate Matter (PM) in the COVID-19 pandemic, focusing especially on that of PM as a vector for SARS-CoV-2. Exposure to PM has been related to new cases and to the clinical severity of people infected by SARS-CoV-2, which can be explained by the oxidative stress and the inflammatory response generated by these particles when entering the respiratory system, as well as by the role of PM in the expression of ACE-2 in respiratory cells in human hosts. In addition, different authors have detected SARS-CoV-2 RNA in PM sampled both in outdoor and indoor environments. The results of various studies lead to the hypothesis that the aerosols emitted by an infected person could be deposited in other suspended particles, sometimes of natural but especially of anthropogenic origin, that form the basal PM. However, the viability of the virus in PM has not yet been demonstrated. Should PM be confirmed as a vector of transmission, prevention strategies ought to be adapted, and PM sampling in outdoor environments could become an indicator of viral load in a specific area.‚ÄúThis work has been carried out within the framework of the project ‚ÄúAir pollution and COVID-19: what can we learn from this pandemic?‚ÄĚ of the Call for Grants from the BBVA Foundation to Scientific Research Teams in SARS-CoV-2 and COVID-19, in the area of Ecology and Veterinary Medicine

    Integrated Proteomic and Metabolomic Profiling of Phytophthora cinnamomi Attack on Sweet Chestnut (Castanea sativa) Reveals Distinct Molecular Reprogramming Proximal to the Infection Site and Away from It

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    Phytophthora cinnamomi is one of the most invasive tree pathogens that devastates wild and cultivated forests. Due to its wide host range, knowledge of the infection process at the molecular level is lacking for most of its tree hosts. To expand the repertoire of studied Phytophthora-woody plant interactions and identify molecular mechanisms that can facilitate discovery of novel ways to control its spread and damaging effects, we focused on the interaction between P. cinnamomi and sweet chestnut (Castanea sativa), an economically important tree for the wood processing industry. By using a combination of proteomics, metabolomics, and targeted hormonal analysis, we mapped the effects of P. cinnamomi attack on stem tissues immediately bordering the infection site and away from it. P. cinnamomi led to a massive reprogramming of the chestnut proteome and accumulation of the stress-related hormones salicylic acid (SA) and jasmonic acid (JA), indicating that stem inoculation can be used as an easily accessible model system to identify novel molecular players in P. cinnamomi pathogenicity.O

    Effect of salinity stress on antioxidant activity and grain yield of different wheat genotypes

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    In order to evaluate the antioxidant activity of wheat in salinity stress conditions, an experiment with 27 wheat genotypes grown on two types of soil was conducted: solonetz (increased salinity) and chernozem (control), during two vegetation seasons (2015/2016 and 2016/2017). Analysis of DPPH radical scavenging activity and phenolic content (PC) were performed in different phenophases of wheat (tillering, stem elongation and heading). Genotypes showed significantly higher DPPH radical scavenging activity (9.82 mg trolox equivalents (TE) per mg of dry matter (d.m.)) and PC (8.15 mg gallic acid equivalents (GAE) per mg d.m.) under salinity stress conditions compared to values obtained on control (8.52 mg TE mg-1 d.m. and 7.13 mg GAE mg-1 d.m., respectively). All analyzed factors (genotype, soil type and year) had the highly significant influence on phenotypic variation of grain yield. Salinity stress reduced grain yield by 30%, whereas drought stress in 2016/2017 vegetation season reduced grain yield by 20%. Highly significant and positive correlations are present between grain yield and parameters of antioxidant activity in all growth stages of wheat and both soil conditions. Therefore, it could be possible to select salinity tolerant genotypes in early growth stages. DPPH scavenging activity and total phenolic content are in highly significant and positive correlation in all growth stages, which indicates that antioxidant activity is highly derived by phenolics

    Molecular mechanisms of liver carcinogenesis related to metabolic syndrome

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    Global prevalence of non-alcoholic fatty liver disease (NAFLD) and of NAFLD-hepatocellular carcinoma (HCC) is estimated to grow in the next years. The burden of NAFLD and the evidence that NAFLD-HCC arises also in non-cirrhotic patients, explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression. Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines, an increase in oxidative stress, DNA damage, and the activation of multiple signaling pathways involved in cell proliferation. Moreover, a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system, dysbiosis, and alterations in bile acids metabolism. Several dietary, genetic, or combined mouse models have been used to study nonalcoholic steatohepatitis (NASH) development and its progression to HCC, but models that fully recapitulate the biological and prognostic features of human NASH are still lacking. In humans, four single nucleotide polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7) have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients, whereas HSD17B13 polymorphism has a protective effect. In addition, higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients. The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC
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