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BACKGROUND & AIMS: Owing to the lack of genetic animal models that adequately recreate key clinical characteristics of cirrhosis, the molecular pathogenesis of cirrhosis has been poorly characterized, and treatments remain limited. Hence, we aimed to better elucidate the pathological mechanisms of cirrhosis using a novel murine model. METHODS: We report on the first murine genetic model mimicking human cirrhosis induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of non-specific lethal (NSL) and INO80 chromatin-modifier complexes. Using this genetic tool with other mouse models, cell culture and human samples, combined with quantitative proteomics, single nuclei/cell RNA sequencing and chromatin immunoprecipitation assays, we investigated mechanisms of cirrhosis. RESULTS: MCRS1 loss in mouse hepatocytes modulates the expression of bile acid (BA) transporters - with a pronounced downregulation of Na+-taurocholate cotransporting polypeptide (NTCP) - concentrating BAs in sinusoids and thereby activating hepatic stellate cells (HSCs) via the farnesoid X receptor (FXR), which is predominantly expressed in human and mouse HSCs. Consistently, re-expression of NTCP in mice reduces cirrhosis, and genetic ablation of FXR in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts histone deacetylase 1 from its histone H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays decreased nuclear MCRS1 and NTCP expression. CONCLUSIONS: Our data reveal a previously unrecognized function of MCRS1 as a critical histone acetylation regulator, maintaining gene expression and liver homeostasis. MCRS1 loss induces acetylation of BA transporter genes, perturbation of BA flow, and consequently, FXR activation in HSCs. This axis represents a central and universal signaling event in cirrhosis, which has significant implications for cirrhosis treatment. LAY SUMMARY: By genetic ablation of MCRS1 in mouse hepatocytes, we generate the first genetic mouse model of cirrhosis that recapitulates human features. Herein, we demonstrate that the activation of the bile acid/FXR axis in liver fibroblasts is key in cirrhosis development.
Assuntos
Histonas , Proteínas de Ligação a RNA , Receptores Citoplasmáticos e Nucleares , Acetilação , Animais , Ácidos e Sais Biliares/metabolismo , Proteínas de Transporte , Histonas/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Glicoproteínas de Membrana , Camundongos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Cancer-associated cachexia represents a multifactorial syndrome mainly characterized by muscle mass loss, which causes both a decrease in quality of life and anti-cancer therapy failure, among other consequences. The definition and diagnostic criteria of cachexia have changed and improved over time, including three different stages (pre-cachexia, cachexia, and refractory cachexia) and objective diagnostic markers. This metabolic wasting syndrome is characterized by a negative protein balance, and anti-cancer drugs like chemotherapy or immunotherapy exacerbate it through relatively unknown mechanisms. Due to its complexity, cachexia management involves a multidisciplinary strategy including not only nutritional and pharmacological interventions. Physical exercise has been proposed as a strategy to counteract the effects of cachexia on skeletal muscle, as it influences the mechanisms involved in the disease such as protein turnover, inflammation, oxidative stress, and mitochondrial dysfunction. This review will summarize the experimental and clinical evidence of the impact of physical exercise on cancer-associated cachexia.
RESUMO
Sublethal cell damage can trigger senescence, a complex adaptive program characterized by growth arrest, resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, verteporfin (VPF), selectively triggered apoptotic cell death largely by derepressing DDIT4, which in turn inhibited mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, triggering ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased the numbers of senescent cells in the organs of old mice and mice exhibiting doxorubicin-induced senescence. Moreover, VPF treatment reduced immune cell infiltration and pro-fibrotic transforming growth factor-ß signaling in aging mouse lungs, improving tissue homeostasis. We present an alternative senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.
Assuntos
Envelhecimento , Senescência Celular , Animais , Camundongos , Envelhecimento/genética , Sobrevivência Celular , Senescência Celular/genética , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteínas de Sinalização YAP/metabolismo , Fatores de Transcrição de Domínio TEA , Estresse do Retículo Endoplasmático/genéticaRESUMO
Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Senescência Celular , Animais , Humanos , Camundongos , Apoptose , Sobrevivência Celular , Senescência Celular/genética , LigantesRESUMO
The liver is one of the major metabolic organs in the body, susceptible to injury caused by various factors. In response to injury, sophisticated mechanisms are engaged to repair and regenerate the damaged liver, preventing its failure. When the damage is chronic, regeneration goes awry, impairing liver function and causing cirrhosis. Hence, cirrhosis may rather be a protective response to injury, where wound-healing processes are set to primarily repair the damaged liver. Although cirrhosis is clinically considered a risk factor for hepatocellular carcinoma (HCC), comprehensive population-based studies demonstrate a very modest incidence, refuting the idea that cirrhosis progresses to HCC. Here, we discuss and shed light on the provocative question of whether cirrhosis predisposes to HCC.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Regeneração Hepática/genética , Fígado/patologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Progressão da Doença , Predisposição Genética para Doença , Humanos , Cirrose Hepática/genética , Cirrose Hepática/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Fatores de Proteção , Fatores de RiscoRESUMO
Imidazo[1,2-b]pyridazine scaffold represents an important class of heterocyclic nucleus which provides various bioactives molecules. Among them, the successful kinase inhibitor ponatinib led to a resurgence of interest in exploring new imidazo[1,2-b]pyridazine-containing derivatives for their putative therapeutic applications in medicine. This present review intends to provide a state-of-the-art of this framework in medicinal chemistry from 1966 to nowadays, unveiling different aspects of its structure-activity relationships (SAR). This extensive literature surveil may guide medicinal chemists for the quest of novel imidazo[1,2-b]pyridazine compounds with enhanced pharmacokinetics profile and efficiency.
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Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Piridazinas/farmacologia , Anti-Infecciosos/química , Anti-Inflamatórios/química , Antineoplásicos/química , Química Farmacêutica , Humanos , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/químicaRESUMO
Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.
Assuntos
Adipócitos/efeitos dos fármacos , Interleucina-17/antagonistas & inibidores , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Tecido Adiposo Marrom/fisiologia , Animais , Quinase 5 Dependente de Ciclina/metabolismo , Dieta , Dieta Hiperlipídica , Digoxina/farmacologia , Metabolismo Energético/fisiologia , Fezes/química , Deleção de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Hipernutrição , PPAR gama/metabolismo , Fosforilação , Termogênese/fisiologiaRESUMO
All along the drug development process, one of the most frequent adverse side effects, leading to the failure of drugs, is the cardiac arrhythmias. Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel. The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years. In order to prevent the cardiac side effects, a great number of in silico, in vitro and in vivo assays have been performed. The main goal of these studies is to understand the reasons of these effects, and then to give information or instructions to scientists involved in drug development to avoid the cardiac side effects. To evaluate anticipated cardiovascular effects, early evaluation of hERG toxicity has been strongly recommended for instance by the regulatory agencies such as U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Thus, following an initial screening of a collection of compounds to find hits, a great number of pharmacomodulation studies on the novel identified chemical series need to be performed including activity evaluation towards hERG. We provide in this concise review clear guidelines, based on described examples, illustrating successful optimization process to avoid hERG interactions as cases studies and to spur scientists to develop safe drugs.
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Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/química , Humanos , Guias de Prática Clínica como AssuntoRESUMO
The phenomenon of aging has gained widespread attention in recent times. Although significant advances have been made to better understand aging and its related pathologies including cancer, there is not yet a clear mechanism explaining why diseases and cancer are inherent parts of the aging process. Finding a unifying equation that could bridge aging and its related diseases would allow therapeutic development and solve an immense human health problem to live longer and better. In this review, we discuss NAD+ reduction as the central mechanism that may connect aging to its related pathologies and cancer. NAD+ boosters would ensure and ameliorate health quality during aging.
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Envelhecimento/metabolismo , Longevidade , NAD/deficiência , Neoplasias/metabolismo , Complexo Vitamínico B/uso terapêutico , Envelhecimento/sangue , Humanos , Incidência , Expectativa de Vida/tendências , NAD/biossíntese , NAD/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Mononucleotídeo de Nicotinamida/uso terapêuticoRESUMO
The small GTPases from the rat sarcoma (Ras) superfamily are a heterogeneous group of proteins of about 21 kDa that act as molecular switches, modulating cell signaling pathways and controlling diverse cellular processes. They are active when bound to guanosine triphosphate (GTP) and inactive when bound to guanosine diphosphate (GDP). Ras homolog enriched in brain (Rheb) is a member of the Ras GTPase superfamily and a key activator of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). We recently determined that microspherule protein 1 (MCRS1) maintains Rheb at lysosomal surfaces in an amino acid-dependent manner. MCRS1 depletion promotes the formation of the GDP-bound form of Rheb, which is then delocalized from the lysosomal platform and transported to endocytic recycling vesicles, leading to mTORC1 inactivation. During this delocalization process, Rheb-GDP remains farnesylated and associated with cellular endomembranes. These findings provide new insights into the regulation of small GTPases, whose activity depends on both their GTP/GDP switch state and their capacity to move between different cellular membrane-bound compartments. Dynamic spatial transport between compartments makes it possible to alter the proximity of small GTPases to their activatory sites depending on the prevailing physiological and cellular conditions.
Assuntos
Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteínas Nucleares/metabolismo , Animais , Domínio Catalítico , Membrana Celular/metabolismo , Ativação Enzimática , Lisossomos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/química , Proteínas Nucleares/química , Transporte Proteico , RatosRESUMO
Resumen En Chile, el aumento sostenido de la inmigración extranjera ha impactado en la construcción de nuevas formas de relación social. Si bien los procesos aculturativos han sido estudiados desde la perspectiva de los inmigrantes por numerosas investigaciones, los miembros de las sociedades receptoras han recibido menor atención. Este trabajo tiene como propósito identificar las preferencias de aculturación de N=553 chilenos, y verificar sus relaciones con la percepción de amenaza y el bienestar social. Contrario a lo esperado, el individualismo aculturativo se asoció con un menor grado de amenaza percibida y una mejor evaluación del propio funcionamiento social que el integracionismo. Estos hallazgos son relacionados con la incorporación de modelos de ciudadanía promovidos por la ideología neoliberal en el Chile post-dictatorial.
Abstract In Chile, the sustained increase of migratory flows is producing an important impact on building new forms of social relations. Acculturation processes have been studied from immigrant's perspective by numerous studies, but host majority members has received less attention from scholars. This study aimed to verify relations between acculturation preferences of N=553 Chilean participants, their social well-being and perceived threat. Results showed that, contrary as expected, individualism was positively linked with better social functioning and less perceived threat than integrationism, suggesting the impact of neoliberal ideology on post-dictatorial Chilean culture.