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1.
Hum Reprod ; 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38915267

RESUMEN

STUDY QUESTION: What is the pathological mechanism involved in a thin endometrium, particularly under ischaemic conditions? SUMMARY ANSWER: Endometrial dysfunction in patients with thin endometrium primarily results from remodelling in cytoskeletons and cellular junctions of endometrial epithelial cells under ischemic conditions. WHAT IS KNOWN ALREADY: A healthy endometrium is essential for successful embryo implantation and subsequent pregnancy; ischemic conditions in a thin endometrium compromise fertility outcomes. STUDY DESIGN, SIZE, DURATION: We recruited 10 patients with thin endometrium and 15 patients with healthy endometrium. Doppler ultrasound and immunohistochemical results confirmed the presence of insufficient endometrial blood perfusion in patients with thin endometrium. Organoids were constructed using healthy endometrial tissue and cultured under oxygen-glucose deprivation (OGD) conditions for 24 h. The morphological, transcriptomic, protein expression, and signaling pathway changes in the OGD organoids were observed. These findings were validated in both thin endometrial tissue and healthy endometrial tissue samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial thickness and blood flow were measured during the late follicular phase using transvaginal Doppler ultrasound. Endometrial tissue was obtained via hysteroscopy. Fresh endometrial tissues were used for the generation and culture of human endometrial organoids. Organoids were cultured in an appropriate medium and subjected to OGD to simulate ischemic conditions. Apoptosis and cell death were assessed using Annexin-V/propidium iodide staining. Immunofluorescence analysis, RNA sequencing, western blotting, simple westerns, immunohistochemistry, and electron microscopy were conducted to evaluate cellular and molecular changes. MAIN RESULTS AND THE ROLE OF CHANCE: Patients with thin endometrium showed significantly reduced endometrial thickness and altered blood flow patterns compared to those with healthy endometrium. Immunohistochemical staining revealed fewer CD34-positive blood vessels and glands in the thin endometrium group. Organoids cultured under OGD conditions exhibited significant morphological changes, increased apoptosis, and cell death. RNA-seq identified differentially expressed genes related to cytoskeletal remodeling and stress responses. OGD induced a strong cytoskeletal reorganization, mediated by the RhoA/ROCK signaling pathway. Additionally, electron microscopy indicated compromised epithelial integrity and abnormal cell junctions in thin endometrial tissues. Upregulation of hypoxia markers (HIF-1α and HIF-2α) and activation of the RhoA/ROCK pathway were also observed in thin endometrial tissues, suggesting ischemia and hypoxia as underlying mechanisms. LARGE SCALE DATA: none. LIMITATIONS AND REASONS FOR CAUTION: The study was conducted in an in vitro model, which may not fully replicate the complexity of in vivo conditions. WIDER IMPLICATIONS OF THE FINDINGS: This research provides a new three-dimensional in vitro model of thin endometrium, as well as novel insights into the pathophysiological mechanisms of endometrial ischaemia in thin endometrium, offering potential avenues for identifying therapeutic targets for treating fertility issues related to thin endometrium. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (81925013); National Key Research and Development Project of China (2022YFC2702500, 2021YFC2700303, 2021YFC2700601); the Capital Health Research and Development Project (SF2022-1-4092); the National Natural Science Foundation of China (82288102, 81925013, 82225019, 82192873); Special Project on Capital Clinical Diagnosis and Treatment Technology Research and Transformation Application (Z211100002921054); the Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation(TFJC2023010001). The authors declare that no competing interests exist.

2.
J Ovarian Res ; 17(1): 100, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734641

RESUMEN

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder with multiple metabolic abnormalities. Most PCOS patients have concomitant metabolic syndromes such as insulin resistance and obesity, which often lead to the development of type II diabetes and cardiovascular disease with serious consequences. Current treatment of PCOS with symptomatic treatments such as hormone replacement, which has many side effects. Research on its origin and pathogenesis is urgently needed. Although improving the metabolic status of the body can alleviate reproductive function in some patients, there is still a subset of patients with metabolically normal PCOS that lacks therapeutic tools to address ovarian etiology. METHODS: The effect of IL-22 on PCOS ovarian function was verified in a non-metabolic PCOS mouse model induced by dehydroepiandrosterone (DHEA) and rosiglitazone, as well as granulosa cell -specific STAT3 knockout (Fshrcre+Stat3f/f) mice (10 groups totally and n = 5 per group). Mice were maintained under controlled temperature and lighting conditions with free access to food and water in a specific pathogen-free (SPF) facility. Secondary follicles separated from Fshrcre+Stat3f/f mice were cultured in vitro with DHEA to mimic the hyperandrogenic environment in PCOS ovaries (4 groups and n = 7 per group) and then were treated with IL-22 to investigate the specific role of IL-22 on ovarian function. RESULTS: We developed a non-metabolic mice model with rosiglitazone superimposed on DHEA. This model has normal metabolic function as evidenced by normal glucose tolerance without insulin resistance and PCOS-like ovarian function as evidenced by irregular estrous cycle, polycystic ovarian morphology (PCOM), abnormalities in sex hormone level. Supplementation with IL-22 improved these ovarian functions in non-metabolic PCOS mice. Application of DHEA in an in vitro follicular culture system to simulate PCOS follicular developmental block and ovulation impairment. Follicles from Fshrcre+Stat3f/f did not show improvement in POCS follicle development with the addition of IL-22. In DHEA-induced PCOS mice, selective ablation of STAT3 in granulosa cells significantly reversed the ameliorative effect of IL-22 on ovarian function. CONCLUSION: IL-22 can improve non-metabolic PCOS mice ovarian function. Granulosa cells deficient in STAT3 reverses the role of IL-22 in alleviating ovary dysfunction in non-metabolic PCOS mice.


Asunto(s)
Modelos Animales de Enfermedad , Interleucina-22 , Ovario , Síndrome del Ovario Poliquístico , Animales , Femenino , Ratones , Deshidroepiandrosterona/farmacología , Células de la Granulosa/metabolismo , Interleucina-22/farmacología , Interleucinas/metabolismo , Interleucinas/genética , Ratones Noqueados , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patología , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Factor de Transcripción STAT3/metabolismo
3.
Exp Neurol ; 375: 114730, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38401853

RESUMEN

Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.


Asunto(s)
Enfermedades Desmielinizantes , Exosomas , Animales , Ratones , Enfermedades Desmielinizantes/terapia , Enfermedades Desmielinizantes/tratamiento farmacológico , Oligodendroglía , Ligandos , Exosomas/metabolismo , Triyodotironina/metabolismo , Triyodotironina/farmacología , Triyodotironina/uso terapéutico , Cuprizona/toxicidad , Ratones Endogámicos C57BL , Vaina de Mielina/patología , Modelos Animales de Enfermedad
4.
J Ovarian Res ; 17(1): 69, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38539230

RESUMEN

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic condition in women of childbearing age and a major cause of anovulatory infertility. The pathophysiology of PCOS is complex. Recent studies have reported that apart from hyperandrogenism, insulin resistance, systemic chronic inflammation, and ovarian dysfunction, gut microbiota dysbiosis is also involved in PCOS development and may aggravate inflammation and metabolic dysfunction, forming a vicious cycle. As naturally occurring plant secondary metabolites, polyphenols have been demonstrated to have anticancer, antibacterial, vasodilator, and analgesic properties, mechanistically creating putative bioactive, low-molecular-weight metabolites in the human gut. Here, we summarize the role of gut microbiota dysbiosis in the development of PCOS and demonstrate the ability of different polyphenols - including anthocyanin, catechins, and resveratrol - to regulate gut microbes and alleviate chronic inflammation, thus providing new insights that may assist in the development of novel therapeutic strategies to treat women with PCOS.


Asunto(s)
Microbioma Gastrointestinal , Hiperandrogenismo , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Femenino , Humanos , Síndrome del Ovario Poliquístico/complicaciones , Microbioma Gastrointestinal/fisiología , Polifenoles/farmacología , Polifenoles/uso terapéutico , Disbiosis/complicaciones , Resistencia a la Insulina/fisiología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo
5.
Nat Metab ; 6(5): 947-962, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38769396

RESUMEN

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.


Asunto(s)
Agmatina , Microbioma Gastrointestinal , Síndrome del Ovario Poliquístico , Receptores Citoplasmáticos y Nucleares , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Animales , Femenino , Ratones , Agmatina/farmacología , Agmatina/metabolismo , Agmatina/uso terapéutico , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a la Insulina , Bacteroides/efectos de los fármacos , Humanos , Carboxiliasas/metabolismo
6.
Neoplasia ; 37: 100882, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36791577

RESUMEN

Microorganisms play very important roles in carcinogenesis, tumor progression, and resistance upon treatment. Due to the challenge of accurately acquiring samples and quantifying low-biomass tissue microorganisms, most studies have focused on the effect of gut microorganisms on cancer treatments, especially the efficacy of immunotherapy. Although recent publications reveal the potential interactions between intratumor microorganisms and the immune microenvironment, whether and to what extent the intratumor microorganism could affect progression and treatment outcome remain controversial. This study is aiming to evaluate the associations among intratumor microorganisms, DNA methylation cancer driver genes, immune response, and clinical outcomes from a pan-cancer perspective, using 6,876 TCGA samples across 21 cancer types. We revealed that tumor microorganism dysbiosis is closely associated with the abnormal tumor methylome and/or tumor microenvironment, which might serve to enhance the proliferation ability and fitness for the therapy of tumors. These findings shed the light on a better understanding of the interactions between tumor cells and carcinogens during and after tumor formation, as well as microorganism-associated methylation alterations that could further serve as biomarkers for clinical outcome assessment.


Asunto(s)
Metilación de ADN , Neoplasias , Humanos , Neoplasias/patología , Epigenoma , Inmunoterapia , Oncogenes , Microambiente Tumoral
7.
Front Endocrinol (Lausanne) ; 13: 815968, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35237237

RESUMEN

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age. Ovarian dysfunction including abnormal steroid hormone synthesis and follicular arrest play a vital role in PCOS pathogenesis. Hyperandrogenemia is one of the important characteristics of PCOS. However, the mechanism of regulation and interaction between hyperandrogenism and ovulation abnormalities are not clear. To investigate androgen-related metabolic state in granulosa cells of PCOS patients, we identified the transcriptome characteristics of PCOS granulosa cells by RNA-seq. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs) revealed that genes enriched in lipid metabolism pathway, fatty acid biosynthetic process and ovarian steroidogenesis pathway were abnormally expressed in PCOS granulosa cells in comparison with that in control. There are close interactions among these three pathways as identified by analysis of the protein-protein interaction (PPI) network of DEGs. Furthermore, in vitro mouse follicle culture system was established to explore the effect of high androgen and its related metabolic dysfunction on follicular growth and ovulation. RT-qPCR results showed that follicles cultured with dehydroepiandrosterone (DHEA) exhibited decreased expression levels of cumulus expansion-related genes (Has2, Ptx3, Tnfaip6 and Adamts1) and oocyte maturation-related genes (Gdf9 and Bmp15), which may be caused by impaired steroid hormone synthesis and lipid metabolism, thus inhibited follicular development and ovulation. Furthermore, the inhibition effect of DHEA on follicle development and ovulation was ameliorated by flutamide, an androgen receptor (AR) antagonist, suggesting the involvement of AR signaling. In summary, our study offers new insights into understanding the role of androgen excess induced granulosa cell metabolic disorder in ovarian dysfunction of PCOS patients.


Asunto(s)
Andrógenos , Síndrome del Ovario Poliquístico , Andrógenos/farmacología , Animales , Deshidroepiandrosterona , Femenino , Células de la Granulosa , Humanos , Ratones , Síndrome del Ovario Poliquístico/metabolismo , Esteroides
8.
Biomater Sci ; 10(3): 714-727, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-34928285

RESUMEN

Demyelination is a critical neurological disease, and there is still a lack of effective treatment methods. In the past two decades, stem cells have emerged as a novel therapeutic effector for neural regeneration. However, owing to the existence of the blood-brain barrier (BBB) and the complex microenvironment, targeted therapy still faces multiple challenges. Targeted exosome carriers for drug delivery may be considered a promising therapeutic method. Exosomes were isolated from mice neural stem cells. To develop targeting exosomes, we generated a lentivirus armed PDGFRα ligand that could anchor the membrane. Exosome targeting tests were carried out in vitro and in vivo. The modified exosomes showed an apparent ability to target OPCs in the lesion area. Next, the exosomes were loaded with Bryostatin-1 (Bryo), and the cuprizone-fed mice were administered with the targeting exosomes. The data show that Bryo exhibits a powerful therapeutic effect compared with Bryo alone after exosome encapsulation. Specifically, this novel exosome-based targeting delivery of Bryo significantly improves the protection ability of the myelin sheath and promotes remyelination. Moreover, it blocks astrogliosis and axon damage, and also has an inhibitory effect on pro-inflammatory microglia. The results of this investigation provide a straightforward strategy to produce targeting exosomes and indicate a potential therapeutic approach for demyelinating disease.


Asunto(s)
Enfermedades Desmielinizantes , Exosomas , Esclerosis Múltiple , Células-Madre Neurales , Fármacos Neuroprotectores , Remielinización , Animales , Brioestatinas/farmacología , Cuprizona/farmacología , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Neuroprotección , Fármacos Neuroprotectores/farmacología , Oligodendroglía
9.
Front Endocrinol (Lausanne) ; 12: 667422, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34122341

RESUMEN

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. PCOS patients are characterized by hyperandrogenemia, anovulation, and metabolic dysfunction. Hypothalamus-pituitary-ovary axis imbalance is considered as an important pathophysiology underlying PCOS, indicating that central modulation, especially the abnormal activation of hypothalamic GnRH neurons plays a vital role in PCOS development. Increased GnRH pulse frequency can promote LH secretion, leading to ovarian dysfunction and abnormal sex steroids synthesis. By contrast, peripheral sex steroids can modulate the action of GnRH neurons through a feedback effect, which is impaired in PCOS, thus forming a vicious cycle. Additionally, hypothalamic GnRH neurons not only serve as the final output pathway of central control of reproductive axis, but also as the central connection point where reproductive function and metabolic state inter-regulate with each other. Metabolic factors, such as insulin resistance and obesity in PCOS patients can regulate GnRH neurons activity, and ultimately regulate reproductive function. Besides, gut hormones act on both brain and peripheral organs to modify metabolic state. Gut microbiota disturbance is also related to many metabolic diseases and has been reported to play an essential part in PCOS development. This review concludes with the mechanism of central modulation and the interaction between neuroendocrine factors and reproductive or metabolic disorders in PCOS development. Furthermore, the role of the gut microenvironment as an important part involved in the abnormal neuronal-reproductive-metabolic circuits that contribute to PCOS is discussed, thus offering possible central and peripheral therapeutic targets for PCOS patients.


Asunto(s)
Enfermedades Metabólicas/fisiopatología , Neuronas/patología , Síndrome del Ovario Poliquístico/patología , Reproducción , Femenino , Humanos , Síndrome del Ovario Poliquístico/etiología
10.
J Endocrinol ; 245(2): 281-289, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32163914

RESUMEN

Polycystic ovary syndrome (PCOS) is a complex syndrome involving both endocrine and metabolic disorders. Gut microbiota and the intestinal immune factor IL-22 play an important role in the pathogenesis of PCOS. However, the therapeutic role of IL-22 in high androgen-induced PCOS mice is not clear. We aimed to determine the therapeutic effects of IL-22 on the DHEA-induced PCOS mouse model and to explore the possible mechanism of IL-22 in regulating hyperandrogenism-associated PCOS. Insulin resistance levels and ovarian functions were investigated in DHEA-induced PCOS mice with or without additional IL-22 treatment. We found that IL-22 could reverse insulin resistance, disturbed estrous cycle, abnormal ovary morphology, and decreased embryo number in DHEA mice. Mechanistically, IL-22 upregulated the browning of white adipose tissue in DHEA mice. This study demonstrated that IL-22-associated browning of white adipose tissue regulated insulin sensitivity and ovarian functions in PCOS, suggesting that IL-22 may be of value for the treatment of PCOS with a hyperandrogenism phenotype.


Asunto(s)
Interleucinas/farmacología , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Andrógenos , Animales , Modelos Animales de Enfermedad , Ciclo Estral/efectos de los fármacos , Femenino , Hiperandrogenismo/inducido químicamente , Hiperandrogenismo/complicaciones , Resistencia a la Insulina/fisiología , Ratones , Ovario/fisiopatología , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/fisiopatología , Interleucina-22
11.
J Diabetes Complications ; 32(9): 876-884, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30049445

RESUMEN

Prolonged hyperglycemia leads to a non-enzymatic glycation of proteins, and produces Amadori products, such as glycated albumin (GA) and glycated hemoglobin (HbA1c). The utility of HbA1c in the setting of chronic kidney disease (CKD) may be problematic since altered lifespan of red blood cells, use of iron and/or erythropoietin therapy, uremia and so on. Therefore, as an alternative marker, GA has been suggested as a more reliable and sensitive glycemic index in patients with CKD. In addition to the mean plasma glucose concentration, GA also reflects postprandial plasma glucose and glycemic excursion. Besides, with a half-life of approximately 2-3 weeks, GA may reflect the status of blood glucose more rapidly than HbA1c. GA is also an early precursor of advanced glycation end products (AGEs), which cause alterations in various cellular proteins and organelles. Thus, high GA levels may correlate with adverse outcomes of patients with CKD. In this review, the clinical usefulness of GA was discussed, including a comparison of GA with HbA1c, the utility and limitations of GA as a glycemic index, its potential role in pathogenesis of diabetic nephropathy and the correlations between GA levels and outcomes, specifically in patients with diabetes and CKD.


Asunto(s)
Diabetes Mellitus/diagnóstico , Nefropatías Diabéticas/diagnóstico , Técnicas de Diagnóstico Endocrino , Insuficiencia Renal Crónica/diagnóstico , Albúmina Sérica/análisis , Biomarcadores/análisis , Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus/sangre , Nefropatías Diabéticas/sangre , Técnicas de Diagnóstico Endocrino/normas , Técnicas de Diagnóstico Endocrino/tendencias , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Productos Finales de Glicación Avanzada/sangre , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Albúmina Sérica/metabolismo , Albúmina Sérica Glicada
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