RESUMEN
Antibody affinity maturation occurs in germinal centers (GCs), where B cells cycle between the light zone (LZ) and the dark zone. In the LZ, GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from helper T cells, which promotes their rapid proliferation. Here we found that the RNA-binding protein PTBP1 was needed for the progression of GC B cells through late S phase of the cell cycle and for affinity maturation. PTBP1 was required for proper expression of the c-MYC-dependent gene program induced in GC B cells receiving T cell help and directly regulated the alternative splicing and abundance of transcripts that are increased during positive selection to promote proliferation.
Asunto(s)
Linfocitos B/inmunología , Selección Clonal Mediada por Antígenos/inmunología , Centro Germinal/inmunología , Ribonucleoproteínas Nucleares Heterogéneas/inmunología , Activación de Linfocitos/inmunología , Proteína de Unión al Tracto de Polipirimidina/inmunología , Animales , Afinidad de Anticuerpos/inmunología , Diferenciación Celular/inmunología , Proliferación Celular , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
To ameliorate or even prevent signatures of aging in ultimately humans, we here report the identification of a previously undescribed polyacetylene contained in the root of carrots (Daucus carota), hereafter named isofalcarintriol, which we reveal as potent promoter of longevity in the nematode C. elegans. We assign the absolute configuration of the compound as (3 S,8 R,9 R,E)-heptadeca-10-en-4,6-diyne-3,8,9-triol, and develop a modular asymmetric synthesis route for all E-isofalcarintriol stereoisomers. At the molecular level, isofalcarintriol affects cellular respiration in mammalian cells, C. elegans, and mice, and interacts with the α-subunit of the mitochondrial ATP synthase to promote mitochondrial biogenesis. Phenotypically, this also results in decreased mammalian cancer cell growth, as well as improved motility and stress resistance in C. elegans, paralleled by reduced protein accumulation in nematodal models of neurodegeneration. In addition, isofalcarintriol supplementation to both wild-type C57BL/6NRj mice on high-fat diet, and aged mice on chow diet results in improved glucose metabolism, increased exercise endurance, and attenuated parameters of frailty at an advanced age. Given these diverse effects on health parameters in both nematodes and mice, isofalcarintriol might become a promising mitohormesis-inducing compound to delay, ameliorate, or prevent aging-associated diseases in humans.
Asunto(s)
Caenorhabditis elegans , Daucus carota , Humanos , Animales , Ratones , Caenorhabditis elegans/metabolismo , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , Envejecimiento , Longevidad , Poliinos/metabolismo , MamíferosRESUMEN
The use of carbon ion therapy for cancer treatment is becoming more widespread due to the advantages of carbon ions compared with Xrays. Breast cancer patients may benefit from these advantages, as the surrounding healthy tissues receive a lower dose, and the increased biological effectiveness of carbon ions can better control radioresistant cancer cells. Accumulating evidence indicates that the Hedgehog (Hh) pathway is linked to the development and progression of breast cancer, as well as to resistance to Xirradiation and the migratory capacity of cancer cells. Hence, there is an increasing interest in targeting the Hh pathway in combination with radiotherapy. Several studies have already investigated this treatment strategy with conventional radiotherapy. However, to the best of our knowledge, the combination of Hh inhibitors with particle therapy has not yet been explored. The aim of the present study was to investigate the potential of the Hh inhibitor GANT61 as an effective modulator of radiosensitivity and migration potential in MCF7 breast cancer cells, and compare potential differences between carbon ion irradiation and Xray exposure. Although Hh targeting was not able to radiosensitise cells to any radiation type used, the combination of GANT61 with Xrays or carbon ions (energy: 95 MeV/n; linear energy transfer: 73 keV/µm) was more effective in decreasing MCF7 cell migration compared with either radiation type alone. Gene expression of the Hh pathway was affected to different degrees in response to Xray and carbon ion irradiation, as well as in response to the combination of GANT61 with irradiation. In conclusion, combining Hh inhibition with radiation (Xrays or carbon ions) more effectively decreased breast cancer cell migration compared with radiation treatment alone.