RESUMEN
Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called "minimum information for cellular senescence experimentation in vivo" (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.
Asunto(s)
Senescencia Celular , Humanos , Animales , Biomarcadores/metabolismo , Guías como Asunto , Neoplasias/patologíaRESUMEN
Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Animales , Ratones , Biopelículas , Pulmón/microbiología , Pulmón/patología , Mycobacterium tuberculosis/fisiología , Tuberculosis/microbiología , Tuberculosis/patología , Virulencia , Fenómenos BiomecánicosRESUMEN
Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
Asunto(s)
Envejecimiento/genética , Biomarcadores , Senescencia Celular/genética , Enfermedades Genéticas Congénitas/genética , Puntos de Control del Ciclo Celular/genética , Cromatina/genética , Regulación de la Expresión Génica/genética , Enfermedades Genéticas Congénitas/terapia , HumanosRESUMEN
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Asunto(s)
Envejecimiento , Interleucina-11 , Longevidad , Transducción de Señal , Animales , Femenino , Masculino , Ratones , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Fragilidad/genética , Fragilidad/metabolismo , Fragilidad/prevención & control , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-11/antagonistas & inhibidores , Interleucina-11/deficiencia , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/deficiencia , Longevidad/efectos de los fármacos , Longevidad/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Humanos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiologíaRESUMEN
Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Asunto(s)
Antagonistas de Receptores Androgénicos , Antineoplásicos , Quimiotaxis , Resistencia a Antineoplásicos , Células Mieloides , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Quimiotaxis/efectos de los fármacos , Progresión de la Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/patología , Antígeno Lewis X/metabolismo , Células Mieloides/efectos de los fármacos , Células Mieloides/patología , Metástasis de la Neoplasia , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.
Asunto(s)
Senescencia Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Carioferinas/genética , Carioferinas/metabolismo , Proteína de Unión al GTP ran/genética , Proteína de Unión al GTP ran/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Neoplasias/fisiopatología , Proteína 2 de Unión a Repeticiones Teloméricas/genéticaRESUMEN
Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay aging and limit dysfunction, known as "senotherapy," is gaining momentum. While drugs that selectively kill senescent cells, termed "senolytics" are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarize the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary or an alternative to current senolytic approaches.
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Envejecimiento/patología , Senescencia Celular/genética , Susceptibilidad a Enfermedades/terapia , Quimioterapia , Envejecimiento/genética , Desarrollo de Medicamentos , Epigénesis Genética , Regulación de la Expresión Génica , Humanos , Preparaciones Farmacéuticas/química , Vías Secretoras , Transducción de SeñalRESUMEN
The mammalian liver possesses a unique capacity for regeneration. However, this regenerative potential declines with age due to unknown mechanisms. In this issue of Genes & Development, Ritschka and colleagues (pp. 489-494). compare liver regeneration upon partial hepatectomy in young and adult mice. Partial hepatectomy causes a transient increase in p21 in a subpopulation of hepatocytes that persists in adult mice. Remarkably, treatment with the BCL-2 family inhibitor ABT-737 blunts p21 expression, enhancing liver regeneration.
Asunto(s)
Hepatectomía , Regeneración Hepática , Animales , Hepatocitos , Hígado , RatonesRESUMEN
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16INK4a, p21CIP1, and p15INK4b, preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes.
Asunto(s)
Reprogramación Celular , Senescencia Celular , Perfilación de la Expresión Génica , ARN Interferente Pequeño , Análisis de Secuencia de ARN , Serina-Treonina Quinasas TOR/fisiología , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Factor 4 Similar a Kruppel , Ratones , Análisis de la Célula Individual , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
BACKGROUND: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. METHODS: We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline. RESULTS: Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs. CONCLUSIONS: Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.
Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Ratones , Ratas , Animales , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Células Endoteliales/metabolismo , Monocrotalina/metabolismo , Senoterapéuticos , Arteria Pulmonar , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipoxia/metabolismo , Senescencia Celular , Factores de Transcripción Forkhead/metabolismoRESUMEN
The tumor microenvironment influences cancer progression and therapy outcome by mechanisms not yet fully understood. In this issue of Genes & Development, Bent and colleagues (pp. 1811-1821) show how chemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells do not mount a typical senescence-associated secretory phenotype but instead acutely secrete IL-6, promoting chemoresistance. This study unveils a physiological switch involving PI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit the detrimental consequences of persistent inflammation.
Asunto(s)
Senescencia Celular/genética , Fosfatidilinositol 3-Quinasas/genética , Resistencia a Antineoplásicos , Humanos , Interleucina-6/genética , FenotipoRESUMEN
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
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Carcinoma Hepatocelular/genética , Senescencia Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Hepáticas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Apirasa/metabolismo , Carcinoma Hepatocelular/enzimología , Línea Celular , Línea Celular Tumoral , Epigénesis Genética/genética , Femenino , Humanos , Neoplasias Hepáticas/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , ARN Interferente Pequeño/genéticaRESUMEN
Advancements in polymer science and nanotechnology hold significant potential for addressing the increasing demands of food security, by enhancing the shelf life, barrier properties, and nutritional quality of harvested fruits and vegetables. In this context, biopolymer-based delivery systems present themselves as a promising strategy for encapsulating bioactive compounds, improving their absorption, stability, and functionality. This study provides an exploration of the synthesis, characterization, and postharvest protection applications of nanocarriers formed through the complexation of chitosan oligomers, carboxymethylcellulose, and alginate in a 2:2:1 molar ratio. This complexation process was facilitated by methacrylic anhydride and sodium tripolyphosphate as cross-linking agents. Characterization techniques employed include transmission electron microscopy, energy-dispersive X-ray spectroscopy, infrared spectroscopy, thermal analysis, and X-ray powder diffraction. The resulting hollow nanospheres, characterized by a monodisperse distribution and a mean diameter of 114 nm, exhibited efficient encapsulation of carvacrol, with a loading capacity of approximately 20%. Their suitability for phytopathogen control was assessed in vitro against three phytopathogens-Botrytis cinerea, Penicillium expansum, and Colletotrichum coccodes-revealing minimum inhibitory concentrations ranging from 23.3 to 31.3 µg·mL-1. This indicates a higher activity compared to non-encapsulated conventional fungicides. In ex situ tests for tomato (cv. 'Daniela') protection, higher doses (50-100 µg·mL-1, depending on the pathogen) were necessary to achieve high protection. Nevertheless, these doses remained practical for real-world applicability. The advantages of safety, coupled with the potential for a multi-target mode of action, further enhance the appeal of these nanocarriers.
Asunto(s)
Quitosano , Cimenos , Solanum lycopersicum , Carboximetilcelulosa de Sodio , AlginatosRESUMEN
The glycogenin knockout mouse is a model of Glycogen Storage Disease type XV. These animals show high perinatal mortality (90%) due to respiratory failure. The lungs of glycogenin-deficient embryos and P0 mice have a lower glycogen content than that of wild-type counterparts. Embryonic lungs were found to have decreased levels of mature surfactant proteins SP-B and SP-C, together with incomplete processing of precursors. Furthermore, non-surviving pups showed collapsed sacculi, which may be linked to a significantly reduced amount of surfactant proteins. A similar pattern was observed in glycogen synthase1-deficient mice, which are devoid of glycogen in the lungs and are also affected by high perinatal mortality due to atelectasis. These results indicate that glycogen availability is a key factor for the burst of surfactant production required to ensure correct lung expansion at the establishment of air breathing. Our findings confirm that glycogen deficiency in lungs can cause respiratory distress syndrome and suggest that mutations in glycogenin and glycogen synthase 1 genes may underlie cases of idiopathic neonatal death.
Asunto(s)
Glucosiltransferasas/fisiología , Glucógeno Sintasa/fisiología , Glicoproteínas/fisiología , Surfactantes Pulmonares/metabolismo , Síndrome de Dificultad Respiratoria/patología , Animales , Animales Recién Nacidos , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
Autophagy is a conserved intracellular catabolic pathway that removes cytoplasmic components to contribute to neuronal homeostasis. Accumulating evidence has increasingly shown that the induction of autophagy improves neuronal health and extends longevity in several animal models. Therefore, there is a great interest in the identification of effective autophagy enhancers with potential nutraceutical or pharmaceutical properties to ameliorate age-related diseases, such as neurodegenerative disorders, and/or promote longevity. Queen bee acid (QBA, 10-hydroxy-2-decenoic acid) is the major fatty acid component of, and is found exclusively in, royal jelly, which has beneficial properties for human health. It is reported that QBA has antitumor, anti-inflammatory, and antibacterial activities and promotes neurogenesis and neuronal health; however, the mechanism by which QBA exerts these effects has not been fully elucidated. The present study investigated the role of the autophagic process in the protective effect of QBA. We found that QBA is a novel autophagy inducer that triggers autophagy in various neuronal cell lines and mouse and fly models. The beclin-1 (BECN1) and mTOR pathways participate in the regulation of QBA-induced autophagy. Moreover, our results showed that QBA stimulates sirtuin 1 (SIRT1), which promotes autophagy by the deacetylation of critical ATG proteins. Finally, QBA-mediated autophagy promotes neuroprotection in Parkinson's disease in vitro and in a mouse model and extends the lifespan of Drosophila melanogaster. This study provides detailed evidences showing that autophagy induction plays a critical role in the beneficial health effects of QBA.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Humanos , Abejas , Animales , Neuroprotección , Drosophila melanogaster , Autofagia , Línea Celular , Fármacos Neuroprotectores/farmacologíaRESUMEN
Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
Asunto(s)
Senescencia Celular , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Transducción de Señal , Adenocarcinoma/metabolismo , Animales , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Línea Celular , Línea Celular Tumoral , Quimiocinas/metabolismo , Daño del ADN , Regulación hacia Abajo , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Ligandos , Neoplasias Pulmonares/metabolismo , Ratones , FN-kappa B/metabolismo , Lesiones Precancerosas/metabolismo , Interferencia de ARN , Receptores de Interleucina-8A/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Despite extensive research on the chemical composition of elderberries and their numerous uses in pharmaceutical, beverage, and food production, there is still a lack of knowledge about Sambucus nigra leaves and flowers' antimicrobial activity against plant pathogens. In this study, the phytoconstituents of their aqueous ammonia extracts were first characterized by infrared spectroscopy and gas chromatography-mass spectrometry. The major phytocompounds identified in the flower extract were octyl 2-methylpropanoate; 3,5-dihydroxy-6-methyl-2,3-dihydropyran-4-one; propyl malonic acid; adenine; and 1-methyl-2-piperidinemethanol. Concerning the leaf extract, 1,6-anhydro-ß-D-glucopyranose; oleic acid; 2,1,3-benzothiadiazole; 2,3-dihydro-benzofuran; and 4-((1E)-3-hydroxy-1-propenyl)-2-methoxyphenol and other phenol derivatives were the main constituents. The potential of the extracts to act as bioprotectants was then investigated against three almond tree pathogens: Diaporthe amygdali, Phytophthora megasperma, and Verticillium dahliae. In vitro tests showed higher activity of the flower extract, with EC90 values in the 241-984 µg·mL-1 range (depending on the pathogen) vs. 354-1322 µg·mL-1 for the leaf extract. In addition, the flower extract led to full protection against P. megasperma at a dose of 1875 µg·mL-1 in ex situ tests on artificially-infected excised almond stems. These inhibitory concentrations were lower than those of commercial fungicides. These findings suggest that S. nigra aerial organs may be susceptible to valorization as an alternative to synthetic fungicides for the protection of this important crop.
Asunto(s)
Antiinfecciosos , Fungicidas Industriales , Prunus dulcis , Sambucus nigra , Sambucus nigra/química , Extractos Vegetales/química , Fungicidas Industriales/análisis , Antiinfecciosos/farmacología , Antiinfecciosos/análisis , Fitoquímicos/farmacología , Fitoquímicos/análisis , Flores/químicaRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein ß (C/EBPß) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPß was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPß overexpression increased TFAM promoter activity. However, downregulation of C/EBPß in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPß. Then, we concluded that C/EBPß is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.
Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Porción Compacta de la Sustancia Negra/metabolismo , Neuronas Dopaminérgicas/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Autofagia/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismoRESUMEN
Helichrysum stoechas is a singular halophyte that has been shown to have anti-inflammatory, antioxidant, and allelopathic properties. In the work presented herein, we have characterized its inflorescences hydromethanolic extract and assessed its antifungal activity for the pre- and postharvest management of tomato crop diseases. Gas chromatography-mass spectrometry characterization of the extract showed that 4-ethenyl-1,3-benzenediol, 2,3-dihydro-benzofuran, quinic acid, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-1-benzopyran-4-one, 1,6-anhydro-ß-D-glucopyranose, catechol, scopoletin, and maltol were the main constituents. The co-occurrence of pyranones, benzenediols, and quinic acids as phytoconstituents of H. stoechas extract resulted in promising in vitro minimum inhibitory concentrations of 500, 375, 500, 187.5, 187.5, and 375 µg·mL-1 against mycelia of Alternaria alternata, Colletotrichum coccodes, Fusarium oxysporum f. sp. lycopersici, Rhizoctonia solani, Sclerotinia sclerotiorum, and Verticillium dahliae, respectively. Further, to assess the potential of H. stoechas inflorescence extract for postharvest tomato crop protection, ex situ tests were conducted against C. coccodes, obtaining high protection at a dose of 750 µg·mL-1. Taking into consideration that the demonstrated activity is among the highest reported to date for plant extracts and comparable to that of the synthetic fungicides tested as positive controls, H. stoechas inflorescence extract may be put forward as a promising biorational and may deserve further testing in field-scale studies.