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INTRODUCTION: This study investigated changes in plasma microbial-derived extracellular vesicles (EVs) in patients with polycystic ovary syndrome and insulin resistance (PCOS-IR) before and after metformin treatment, and aimed to identify bacterial taxa within EVs that were biologically and statistically significant for diagnosis and treatment. METHODS: The case-control study was conducted at Xiamen Chang Gung Hospital, Hua Qiao University. Plasma samples were collected from five PCOS-IR patients of childbearing age before and after 3 months of metformin treatment, and the samples were sequenced. The diversity and taxonomic composition of different microbial communities were analyzed through full-length 16 S glycosomal RNA gene sequencing. RESULTS: After metformin treatment, fasting plasma glucose levels and IR degree of PCOS-IR patients were significantly improved. The 16 S analysis of plasma EVs from metformin-treated patients showed higher microbial diversity. There were significant differences in EVs derived from some environmental bacteria before and after metformin treatment. Notably, Streptococcus salivarius was more abundant in the metformin-treated group, suggesting it may be a potential probiotic. DISCUSSION: The study demonstrated changes in the microbial composition of plasma EVs before and after metformin treatment. The findings may offer new insights into the pathogenesis of PCOS-IR and provide new avenues for research.

Asunto(s)

Vesículas Extracelulares , Resistencia a la Insulina , Metformina , Síndrome del Ovario Poliquístico , Humanos , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/microbiología , Síndrome del Ovario Poliquístico/sangre , Metformina/farmacología , Metformina/uso terapéutico , Femenino , Vesículas Extracelulares/metabolismo , Adulto , Estudios de Casos y Controles , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Adulto Joven

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Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disease that affecting females in reproductive age. Insulin resistance (IR), an important molecular basis for PCOS, accounts for at least 75% of women carrying this syndrome. Although there have been many studies on PCOS-IR, the detailed mechanisms are not fully understood. As essential hub for energy generation, mitochondria are critical to insulin secretion and normal function, whereas mutations in mitochondrial DNA (mtDNA) result in mitochondrial dysfunctions contributing to the pathophysiology of PCOS-IR via the regulation of balance of oxidative stress (OS), energy deficiency, or hormone metabolism. In the current review, we summarize the clinical and molecular features of PCOS-IR and discuss molecular mechanisms related to mtDNA mutations.

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This study explored the possible connection between the insulin resistance-targeting protein adipokine lipocalin-2 (LCN-2) and NF-κB signaling pathway in the inflammatory microenvironment in PCOS-IR model rats to determine the pharmacological mechanism of modified Cangfu Daotan decoction (MCDD) intervention for PCOS-IR. We used a high-fat diet (42 days) combined with letrozole (1 mg/kg/day, 42 days) to establish a PCOS-IR rat model. From the third week after modeling, the rats were given continuous administration of MCDD (high dose with 31.68 g/kg, medium dose with 15.84 g/kg, and low dose with 7.92 g/kg) for 28 days. Serum, ovarian tissue, liver, and adipose tissue were collected after the last gavage. Enzyme-linked immunosorbent assay, hematoxylin-eosin (HE) staining, Masson staining, qRT-PCR, and Western blot experiments were performed to detect various indicators. Our results showed that MCDD could reduce body weight and abdominal fat weight; restore normal estrous cycle and ovarian function; alleviate fatty liver; regulate HOMA-IR and OGTT index; reduce serum inflammatory factor levels, LCN-2 level, and gene expression; and regulate the insulin signal transduction and NF-κB pathways in PCOS-IR rats. Thus, MCDD may play a role in improving ovarian function in PCOS-IR rats by downregulating NF-κB/LCN-2 proteins and upregulating the gene expression of Insr/Irs-1/Glut4 in the insulin signaling pathway in the inflammatory environment.

Asunto(s)

Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Humanos , Femenino , Ratas , Animales , Resistencia a la Insulina/genética , FN-kappa B/metabolismo , Lipocalina 2/metabolismo , Transducción de Señal , Insulina/metabolismo , Microambiente Tumoral

RESUMEN

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder affecting women of reproductive age. Insulin resistance (IR), a central component of this disease, occurs in 30%-40% of women with PCOS. To date, the molecular mechanism underlying PCOS-IR remains largely unknown. Most recently, increasing evidence has shown that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations plays important roles in the pathogenesis of PCOS-IR. To identify the contribution of mitochondrial tRNA (mt-tRNA) mutations in this disease, we screened 80 women with PCOS-IR and 50 healthy control participants for mt-tRNA mutations. After genetic amplification and direct sequencing, we identified nine mt-tRNA mutations that were potentially associated with PCOS-IR: mt-tRNALeu(UUR) A3302G and C3275A mutations, mt-tRNAGln T4363C and T4395C mutations, mt-tRNASer(UCN) C7492T mutation, mt-tRNAAsp A7543G mutation, mt-tRNALys A8343G mutation, mt-tRNAArg T10454C mutation and mt-tRNAGlu A14693G mutation. These mutations were localized at evolutionarily conserved nucleotides and altered the secondary structure of mt-tRNAs, thus resulting in failure of mt-tRNA metabolism. Moreover, molecular and biochemical analysis revealed that levels of 8-OHdG, malondialdehyde and reactive oxygen species were increased in patients with PCOS-IR carrying these mt-tRNA mutations compared with in healthy control participants, whereas superoxide dismutase levels, mitochondrial copy number, membrane potential and ATP levels were significantly reduced. Taken together, our data indicate that mt-tRNAs are key locations for pathogenic mutations associated with PCOS-IR. Mitochondrial dysfunction caused by mt-tRNA mutations may be involved in the pathogenesis of PCOS-IR. Thus, our findings provide novel insight into the pathophysiology of this disorder.