RESUMEN
With aging, abnormalities during oocyte meiosis become more prevalent. However, the mechanisms of aging-related oocyte aneuploidy are not fully understood. Here we performed Hi-C and SMART-seq of oocytes from young and old mice and reveal decreases in chromosome condensation and disrupted meiosis-associated gene expression in metaphase I oocytes from aged mice. Further transcriptomic analysis showed that meiotic maturation in young oocytes was correlated with robust increases in mevalonate (MVA) pathway gene expression in oocyte-surrounding granulosa cells (GCs), which was largely downregulated in aged GCs. Inhibition of MVA metabolism in GCs by statins resulted in marked meiotic defects and aneuploidy in young cumulus-oocyte complexes. Correspondingly, supplementation with the MVA isoprenoid geranylgeraniol ameliorated oocyte meiotic defects and aneuploidy in aged mice. Mechanically, we showed that geranylgeraniol activated LHR/EGF signaling in aged GCs and enhanced the meiosis-associated gene expression in oocytes. Collectively, we demonstrate that the MVA pathway in GCs is a critical regulator of meiotic maturation and euploidy in oocytes, and age-associated MVA pathway abnormalities contribute to oocyte meiotic defects and aneuploidy.
Asunto(s)
Ácido Mevalónico , Oocitos , Femenino , Ratones , Animales , Ácido Mevalónico/metabolismo , Oocitos/metabolismo , Células de la Granulosa/metabolismo , Meiosis/genética , AneuploidiaRESUMEN
Non-obstructive azoospermia (NOA) severely affects male infertility, however, the deep mechanisms of this disease are rarely interpreted. In this study, we find that undifferentiated spermatogonial stem cells (SSCs) still exist in the basal compartment of the seminiferous tubules and the blood-testis barrier (BTB) formed by the interaction of neighbor Sertoli cells (SCs) is incomplete in NOA patients with spermatogenic maturation arrest. The adhesions between SCs and germ cells (GCs) are also broken in NOA patients. Meanwhile, the expression level of geranylgeranyl diphosphate synthase (Ggpps), a key enzyme in mevalonate metabolic pathway, is lower in NOA patients than that in obstructive azoospermia (OA) patients. After Ggpps deletion specifically in SCs, the mice are infertile and the phenotype of the SC-Ggpps-/- mice is similar to the NOA patients, where the BTB and the SC-GC adhesions are severely destroyed. Although SSCs are still found in the basal compartment of the seminiferous tubules, fewer mature spermatocyte and spermatid are found in SC-Ggpps-/- mice. Further examination suggests that the defect is mediated by the aberrant protein isoprenylation of RhoA and Ras family after Ggpps deletion. The exciting finding is that when the knockout mice are injected with berberine, the abnormal cell adhesions are ameliorated and spermatogenesis is partially restored. Our data suggest that the reconstruction of disrupted BTB is an effective treatment strategy for NOA patients with spermatogenic maturation arrest and hypospermatogenesis.
Asunto(s)
Azoospermia/metabolismo , Barrera Hematotesticular/metabolismo , Farnesiltransferasa/metabolismo , Complejos Multienzimáticos/metabolismo , Prenilación de Proteína , Espermatogénesis/genética , Proteínas ras/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Azoospermia/enzimología , Berberina/farmacología , Barrera Hematotesticular/efectos de los fármacos , Células Cultivadas , Farnesiltransferasa/genética , Células Germinativas/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Complejos Multienzimáticos/genética , Células de Sertoli/enzimología , Células de Sertoli/metabolismo , Espermatocitos/metabolismo , Espermatogénesis/efectos de los fármacos , Testículo/metabolismo , Uniones Estrechas/genética , Proteínas ras/química , Proteínas ras/genética , Proteína de Unión al GTP rhoA/química , Proteína de Unión al GTP rhoA/genéticaRESUMEN
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease that leads to progressive destruction of lung function. However, the mechanisms underlying the progression of LAM remain unknown. Recent studies demonstrated that miR1243p (hereinafter referred to as miR124) is a downregulated miRNA in tumors and it is still unclear whether miR124 participates in LAM. In the present study, it was revealed that miR124 was downregulated in LAM specimens and overexpression of miR124 resulted in the apoptosis of TSC2deficient cells via RXRα (retinoid X receptor α), while slightly influencing TSC2 wildtype cells. Furthermore, a xenograft model demonstrated that the miR124/RXRα axis regulated the growth and fatty acid oxidation genes in TSC2null cells. Altogether, our results revealed the suppressive functions and mechanisms of miR124 in LAM progression, providing novel therapeutic targets for LAM treatment.
Asunto(s)
Linfangioleiomiomatosis/patología , Receptor alfa X Retinoide/genética , Adulto , Anciano , Animales , Apoptosis , Línea Celular , Regulación hacia Abajo , Femenino , Humanos , Linfangioleiomiomatosis/genética , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/metabolismo , Persona de Mediana Edad , Receptor alfa X Retinoide/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aglinin A (1) is a mixture of C(24)-epimeric 20S,24-epoxy-24,25-dihydroxy-3,4-secodammar-4(28)-en-3-oic acid and present in plants of the family Meliaceae. The two epimers of 1 were resolved through an acetonide reaction, and the absolute configurations of two derivatives were deduced by the analysis of their (13)C NMR differences induced by γ-gauche or steric effect. Based on it, the (13)C NMR assignment of 24R-1 and 24S-1 was also established.
