RESUMEN
Objectives: Osteoporosis (OP) is characterized by reduced bone mass and impaired bone microstructure. Paeoniflorin (PF) is isolated from peony root with anti-inflammatory, immunomodulatory, and bone-protective effects. Up to now, the mechanism of anti-OP in PF has not been completely clarified. Methods: The expression of MEDAG in osteoclasts, osteoblasts and adipocytes was detected by RT-qPCR. The OVX mouse model was constructed, and oral administration of PF was performed for 15 weeks. Bone microstructure was detected by H&E staining and a micro-CT system, and expression of signaling proteins examined by Western blot and immunohistochemical staining. ELISA and biochemical kits were used to quantify serum metabolite levels. Key findings: MEDAG were upregulated in osteoclasts and adipocytes, and downregulated in osteoblasts. PF administration effectively alleviated OVX-induced bone loss, and histological changes in femur tissues. Moreover, PF significantly reduced serum TRAP, CTX-1, P1NP, BALP, and LDL-C levels and increased HDL-C. In addition, PF inhibited the expression of MEDAG, cathepsin K, NFATc1, PPARγ, and C/EBPα and increased p-AMPKα, OPG and Runx2. Conclusions: MEDAG is a potential target for bone diseases, and PF might attenuate OVX-induced osteoporosis via MEDAG/AMPK/PPARγ signaling pathway.
RESUMEN
Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAGKD)-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAGKD cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAGOE) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes.
Asunto(s)
Neoplasias de la Mama , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Femenino , Glucosa/metabolismo , HumanosRESUMEN
BACKGROUND: Two gerbil species, sand rat (Psammomys obesus) and Mongolian jird (Meriones unguiculatus), can become obese and show signs of metabolic dysregulation when maintained on standard laboratory diets. The genetic basis of this phenotype is unknown. Recently, genome sequencing has uncovered very unusual regions of high guanine and cytosine (GC) content scattered across the sand rat genome, most likely generated by extreme and localized biased gene conversion. A key pancreatic transcription factor PDX1 is encoded by a gene in the most extreme GC-rich region, is remarkably divergent and exhibits altered biochemical properties. Here, we ask if gerbils have proteins in addition to PDX1 that are aberrantly divergent in amino acid sequence, whether they have also become divergent due to GC-biased nucleotide changes, and whether these proteins could plausibly be connected to metabolic dysfunction exhibited by gerbils. RESULTS: We analyzed ~ 10,000 proteins with 1-to-1 orthologues in human and rodents and identified 50 proteins that accumulated unusually high levels of amino acid change in the sand rat and 41 in Mongolian jird. We show that more than half of the aberrantly divergent proteins are associated with GC biased nucleotide change and many are in previously defined high GC regions. We highlight four aberrantly divergent gerbil proteins, PDX1, INSR, MEDAG and SPP1, that may plausibly be associated with dietary metabolism. CONCLUSIONS: We show that through the course of gerbil evolution, many aberrantly divergent proteins have accumulated in the gerbil lineage, and GC-biased nucleotide substitution rather than positive selection is the likely cause of extreme divergence in more than half of these. Some proteins carry putatively deleterious changes that could be associated with metabolic and physiological phenotypes observed in some gerbil species. We propose that these animals provide a useful model to study the 'tug-of-war' between natural selection and the excessive accumulation of deleterious substitutions mutations through biased gene conversion.