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The purpose of this study was to explore the effect of Semaglutide on intrauterine adhesions and discover new drugs for such adhesions. In this study, the cell model was simulated by TGF-ß1-induced human endometrial epithelial cells, and the animal model was established through mechanical curettage and inflammatory stimulation. After co-culturing with TGF-ß1 with or without different concentrations of Semaglutide for 48 h, cells were collected for RT-qPCR and Western blotting analyses. Three doses were subcutaneously injected into experimental mice once a day for two weeks, while the control group received sterile ddH2O. The serum and uterine tissues of the mice were collected. HE and Masson staining were used for the uterine histomorphological and pathological analyses. RT-qPCR and Western blotting were used for mRNA and protein expression analyses. Serum indicators were detected using ELISA kits. The results showed that Semaglutide significantly reduced the mRNA levels of fibrosis indicators ACTA2, COL1A1, and FN and inflammatory indicators TNF-α, IL-6, and NF-κB in the two models. Semaglutide improved endometrium morphology, increased the number of endometrial glands, and reduced collagen deposition in IUA mice. The results also showed that Semaglutide could inhibit vimentin, E-Cadherin, and N-Cadherin in the two models. In summary, Semaglutide can ameliorate fibrosis and inflammation of intrauterine adhesions as well as inhibit epithelial-mesenchymal transition in IUA models.
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Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Fibrosis , Péptidos Similares al Glucagón , Animales , Femenino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/metabolismo , Adherencias Tisulares/patología , Adherencias Tisulares/prevención & control , Ratones , Péptidos Similares al Glucagón/farmacología , Humanos , Endometrio/efectos de los fármacos , Endometrio/patología , Endometrio/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Útero/efectos de los fármacos , Útero/patología , Útero/metabolismoRESUMEN
Background: Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies. Objective: We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC. Methods: In vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing. Results: PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs. Conclusion: ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Antineoplásicos Hormonales , Mitotano , Pruebas de Farmacogenómica , Humanos , Mitotano/uso terapéutico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Femenino , Masculino , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/farmacología , Persona de Mediana Edad , Adulto , Anciano , FarmacogenéticaRESUMEN
Context: The prevalence of unilateral primary aldosteronism (UPA) with cortisol co-secretion varies geographically. Objective: To investigate the prevalence and clinical characteristics of UPA with cortisol co-secretion in a Chinese population. Design: Retrospective cohort study. Methods: We recruited 580 patients with UPA who underwent cosyntropin stimulation test (CST) after the 1-mg dexamethasone suppression test (DST) and retrospectively analyzed the clinical characteristics and postoperative outcomes of UPA with and without cortisol co-secretion. Results: UPA with cortisol co-secretion (1 mg DST>1.8 ug/dL) was identified in 65 of 580 (11.2%) patients. These patients were characterized by older age, longer duration of hypertension, higher concentration of plasma aldosterone and midnight cortisol, lower adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS), larger tumor diameter, and more history of diabetes mellitus. Cortisol and aldosterone levels were higher and DHEAS level was lower in UPA with cortisol co-secretion at 0-120 min after CST. Among 342 UPA patients with KCNJ5 gene sequencing and follow-up results, the complete clinical success rate was lower in UPA with cortisol co-secretion (33.3% vs. 56.4%, P<0.05); the complete biochemical success rate and KCNJ5 mutation did not differ between the two groups. Age, tumor size, and ACTH were independent predictors of UPA with cortisol co-secretion. Sex, BMI, duration of hypertension, KCNJ5 mutation, and cortisol co-secretion were independent predictors for complete clinical success in UPA after surgery. Conclusions: UPA with cortisol co-secretion is not uncommon in China, but the clinical features were distinctly different from those without co-secretion. Cortisol co-secretion is an independent risk factor for incomplete clinical success after surgery in UPA.
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Hidrocortisona , Hiperaldosteronismo , Humanos , Hiperaldosteronismo/cirugía , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/sangre , Masculino , Femenino , Persona de Mediana Edad , Hidrocortisona/sangre , Estudios Retrospectivos , Adulto , Aldosterona/sangre , Adrenalectomía , China/epidemiología , Resultado del Tratamiento , Hormona Adrenocorticotrópica/sangre , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Estudios de Seguimiento , PronósticoRESUMEN
Bisphenol A (BPA), an environmental endocrine disruptor (EDC), has been implicated in impairing intestinal and male reproductive dysfunction. The efficacy of gut microbiota modulation for BPA-exposed testicular dysfunction has yet to be verified through research. Therefore, this study explored the potential of mixed probiotics in restoring spermatogenesis damage through the gut-testis axis under BPA exposure. We selected two probiotics strains (Lactobacillus rhamnosus and Lactobacillus plantarum) with BPA removal properties in vitro and the BPA-exposed male mice model was established. The probiotics mixture effectively reduced BPA residue in the gut, serum, and testis in mice. Through 16 S rDNA-seq and metabolomics sequencing, we uncovered that vitamin D metabolism and bile acid levels in the gut was abolished under BPA exposure. This perturbation was linked to an increased abundance of Faecalibaculum and decreased abundance of Lachnospiraceae_NK4A136_group and Ligilactobacillus. The probiotics mixture restored this balance, enhancing intestinal barrier function and reducing oxidative stress. This improvement was accompanied by a restored balance of short-chain fatty acids (SCFAs). Remarkably, the probiotics ameliorated testicular dysfunction by repairing structures of seminiferous tubules and reversing arrested spermiogenesis. Further, the probiotics mixture enhanced testosterone-driven increases in spermatogonial stem cells and all stages of sperm cells. Testicular transcriptome profiling linked these improvements to fatty acid degradation and peroxisome pathways. These findings suggest a significant interplay between spermatogenesis and gut microbiota, demonstrating that probiotic intake could be a viable strategy for combating male subfertility issues caused by BPA exposure.
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Microbioma Gastrointestinal , Fenoles , Probióticos , Masculino , Ratones , Animales , Semen , Espermatogénesis , Compuestos de Bencidrilo/toxicidad , Probióticos/farmacologíaRESUMEN
CONTEXT: Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. OBJECTIVE: The objective of this work is to examine the alteration of gut microbiota in patients with CS. METHODS: We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. RESULTS: We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. CONCLUSION: This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.
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Síndrome de Cushing , Disbiosis , Heces , Microbioma Gastrointestinal , Hidrocortisona , Humanos , Disbiosis/microbiología , Disbiosis/metabolismo , Masculino , Femenino , Microbioma Gastrointestinal/fisiología , Síndrome de Cushing/microbiología , Síndrome de Cushing/metabolismo , Hidrocortisona/metabolismo , Persona de Mediana Edad , Adulto , Heces/microbiología , Estudios de Casos y Controles , Clostridiales/aislamiento & purificación , Clostridiales/metabolismoRESUMEN
INTRODUCTION: Despite radiotherapy being one of the major treatments for triple-negative breast cancer (TNBC), new molecular targets for its treatment are still required due to radioresistance. CDK2 plays a critical role in TNBC. However, the mechanism by which CDK2 promotes TNBC radioresistance remains to be clearly elucidated. OBJECTIVES: We aimed to elucidate the relationship between CDK2 and TRIM32 and the regulation mechanism in TNBC. METHODS: We performed immunohistochemical staining to detect nuclear TRIM32, CDK2 and STAT3 on TNBC tissues. Western blot assays and PCR were used to detect the protein and mRNA level changes. CRISPR/Cas9 used to knock out CDK2. shRNA-knockdown and transfection assays also used to knock out target genes. GST pull-down analysis, immunoprecipitation (IP) assay and in vitro isomerization analysis also used. Tumorigenesis studies also used to verify the results in vitro. RESULTS: Herein, tripartite motif-containing protein 32 (TRIM32) is revealed as a substrate of CDK2. Radiotherapy promotes the binding of CDK2 and TRIM32, thus leading to increased CDK2-dependent phosphorylation of TRIM32 at serines 328 and 339. This causes the recruitment of PIN1, involved in cis-trans isomerization of TRIM32, resulting in importin α3 binding to TRIM32 and contributing to its nuclear translocation. Nuclear TRIM32 inhibits TC45-dephosphorylated STAT3, Leading to increased transcription of STAT3 and radioresistance in TNBC. These results were validated by clinical prognosis confirmed by the correlative expressions of the critical components of the CDK2/TRIM32/STAT3 signaling pathway. CONCLUSIONS: Our findings demonstrate that regulating the CDK2/TRIM32/STAT3 pathway is a promising strategy for reducing radioresistance in TNBC.
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Context: Adrenal incidentaloma (AI) is commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion is the most common functional disorder detected in AI. Objective: To delineate the association between radiological characteristics of benign adrenocortical tumors and hypothalamus-pituitary-adrenal (HPA) axis. Methods: In the study, 494 patients diagnosed with benign unilateral adrenocortical tumors were included. Mild autonomous cortisol secretion (MACS) was diagnosed when cortisol after 1mg-dexamethasone suppression test (1-mg DST) was in the range of 1.8-5ug/dl. Non-functional adrenocortical tumor (NFAT) was diagnosed as cortisol following 1-mg DST less than 1.8ug/dL. We performed Logistics regression and causal mediation analyses, looking for associations between radiological characteristics and the HPA axis. Results: Of 494 patients, 352 (71.3%) with NFAT and 142 (28.7%) with MACS were included. Patients with MACS had a higher tumor diameter, thinner contralateral adrenal gland, and lower plasma ACTH and serum DHEAS than those with NFAT. ACTH (OR 0.978, 0.962-0.993) and tumor diameter (OR 1.857, 95%CI, 1.357-2.540) were independent factors associated with decreased serum DHEAS (all P<0.05). ACTH was also associated with decreased contralateral adrenal diameter significantly (OR 0.973, 95%CI, 0.957-0.988, P=0.001). Causal mediation analysis showed ACTH mediated the effect significantly for the association between 1-mg DST results and DHEAS level (Pmediation<0.001, proportion=22.3%). Meanwhile, we found ACTH mediated 39.7% of the effects of 1-mg DST on contralateral adrenal diameter (Pmediation=0.012). Conclusions: Patients with MACS had thinner contralateral adrenal glands and disturbed HPA axes compared with NFAT. ACTH may partially be involved in mediating the mild autonomous cortisol secretion to DHEAS and the contralateral adrenal gland.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Humanos , Hidrocortisona , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Neoplasias de la Corteza Suprarrenal/diagnóstico , Deshidroepiandrosterona , Sulfato de Deshidroepiandrosterona , Hormona AdrenocorticotrópicaRESUMEN
Background: Idiopathic hyperaldosteronism (IHA) is one of the most common types of primary aldosteronism (PA), an important cause of hypertension. Although high dietary sodium is a major risk factor for hypertension, there is no consensus on the recommended dietary sodium intake for IHA. Objective: This study investigated the effect of a low-sodium diet on hemodynamic variables and relevant disease biomarkers in IHA patients, with the aim of providing a useful reference for clinical treatment. Methods: Fifty IHA patients were evenly randomized into two groups and provided, after a 7-day run-in period (100 mmol/d sodium), either a low-sodium diet (50 mmol/d sodium) or a normal sodium diet (100 mmol/d sodium) for an additional 7 days. After the 14-day intervention (conducted without potassium supplementation), changes in blood pressure (BP) and serum potassium were evaluated in both groups. Results: After the dietary intervention, the low sodium group exhibited, compared to the normal sodium group, decreased BP (SBP: 121.8 ± 12.8 vs. 129.9 ± 12.1 mmHg, p < 0.05; DBP: 82.6 ± 7.6 vs. 86.4 ± 8.2 mmHg, p < 0.05; MAP: 95.7 ± 8.8 vs. 100.9 ± 8.4 mmHg, p < 0.05) and increased serum potassium levels (3.38 ± 0.33 vs. 3.07 ± 0.27 mmol/L, p < 0.001). The low sodium group showed also better control of both BP and serum potassium: BP <140/90 mmHg in 70.0% of total patients (76.0% vs. 64.0%, in the low and normal sodium groups, respectively; p > 0.05), BP <130/85 mmHg in 38.0% of total patients (56.0% vs. 20.0%, p < 0.05), BP <120/80 mmHg in 28.0% of total patients (44.0% vs. 12.0%, p < 0.05); serum potassium ≥3.5 mmol/L in 22.0% of total patients (32.0% vs. 12.0% in the low and normal sodium groups, respectively; p = 0.088). There were differences between the controlled BP group (<120/80 mmHg) and the non-controlled BP group (≥120/80 mmHg) in gender, BP at baseline, and type of diet (low vs. normal sodium). Female gender and low-sodium diet were protective factors for BP control. Conclusions: A low-sodium diet is effective in lowering BP and elevating serum potassium in IHA patients. Female patients on a low-sodium diet are more likely to achieve BP control (<120/80 mmHg). We advocate a dietary sodium intake of 50 mmol/d for IHA patients. Clinical trial registration: https://clinicaltrials.gov, Identifier NCT05649631.
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Hiperaldosteronismo , Hipertensión , Sodio en la Dieta , Humanos , Femenino , Dieta Hiposódica , Hipertensión/etiología , Hipertensión/tratamiento farmacológico , Sodio , Sodio en la Dieta/uso terapéutico , Potasio , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/tratamiento farmacológicoRESUMEN
The development of efficient, stable, and economic electrocatalysts are key to the large-scale application of electrochemical energy conversion. Porous carbon-based non-precious metal electrocatalysts are considered to be the most promising materials to replace Pt-based catalysts, which are limited in large-scale applications due to high costs. Because of its high specific surface area and easily regulated structure, a porous carbon matrix is conducive to the dispersion of active sites and mass transfer, showing great potential in electrocatalysis. This review will focus on porous carbon-based non-precious metal electrocatalysts and summarize their new progress, focusing on the synthesis and design of porous carbon matrix, metal-free carbon-based catalysts, non-previous metal monatomic carbon-based catalyst, and non-precious metal nanoparticle carbon-based catalysts. In addition, current challenges and future trends will be discussed for better development of porous carbon-based non-precious metal electrocatalysts.
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Introduction: Pheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumors and can secrete catecholamine. Previous studies have found that SDHB immunohistochemistry (IHC) can predict SDHB germline gene mutation, and SDHB mutation is closely associated with tumor progression and metastasis. This study aimed to clarify the potential effect of SDHB IHC as a predictive marker for tumor progression in PCC/PGL patients. Methods: We included PCC/PGL patients diagnosed in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from 2002 to 2014 for retrospective analysis and discovered that SDHB (-) staining patients had poorer prognoses. Then we examined SDHB protein expression by IHC on all tumors in the prospective series, which was composed of patients from 2015 to 2020 in our center. Results: In the retrospective series, the median follow-up was 167 months, and during follow-up, 14.4% (38/264) patients developed metastasis or recurrence, and 8.0% (22/274) patients died. Retrospective analysis revealed that 66.7% (6/9) of participants in the SDHB (-) group and 15.7% (40/255) of those in the SDHB (+) group developed progressive tumors (OR: 10.75, 95% CI: 2.72-52.60, P=0.001), and SDHB (-) was independently associated with poor outcomes after adjusting by other clinicopathological parameters (OR: 11.68, 95% CI: 2.58-64.45, P=0.002). SDHB (-) patients had shorter disease-free survival (DFS) and overall survival (OS) (P<0.001) and SDHB (-) was significantly associated with shorter median DFS (HR: 6.89, 95% CI: 2.41-19.70, P<0.001) in multivariate cox proportional hazard analysis. In the prospective series, the median follow-up was 28 months, 4.7% (10/213) patients developed metastasis or recurrence, and 0.5% (1/217) patient died. For the prospective analysis, 18.8% (3/16) of participants in the SDHB (-) group had progressive tumors compared with 3.6% (7/197) in the SDHB (+) group (RR: 5.28, 95% CI: 1.51-18.47, P=0.009), statistical significance remained (RR: 3.35, 95% CI: 1.20-9.38, P=0.021) after adjusting for other clinicopathological factors. Conclusions: Our findings demonstrated patients with SDHB (-) tumors had a higher possibility of poor outcomes, and SDHB IHC can be regarded as an independent biomarker of prognosis in PCC/PGL.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Inmunohistoquímica , Estudios Retrospectivos , China , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patología , Pronóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismoRESUMEN
CONTEXT: Preoperative inflammatory markers, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR), have recently been proposed as prognostic markers in different tumors. However, their predictive values in patients with pheochromocytomas and paragangliomas (PPGLs) are uncertain. OBJECTIVE: This study aimed to investigate the prognostic significance of inflammatory biomarkers in PPGL patients. METHODS: Data from 1247 consecutive PPGL patients between 2002 and 2020 were evaluated. The preoperative inflammatory markers were evaluated. The prognostic roles were identified by X-tile software, Kaplan-Meier curves, and Cox regression models. RESULTS: A total of 728 patients were included in the analysis, with a median follow-up of 63 months (IQR, 31-111 months); 31 individuals died, 28 patients developed metastases, and 12 patients developed recurrence. Our study showed that deaths were observed significantly more frequently in patients with high NLR(≥3.5) and high PLR (≥217.4) than those with low NLR (<3.5) (P = .003) and low PLR (<217.4) (P = .005). Elevated NLR (≥3.5) and elevated PLR (≥217.4) was significantly associated with decreased overall survival (OS) (P = .005), and elevated PLR (≥238.3) was significantly associated with decreased metastasis-free survival (MFS) (P = .021). Cox models illustrated that NLR and PLR were independent prognostic factors for OS, and PLR was an independent prognostic factor for MFS. CONCLUSION: Both elevated NLR and PLR are associated with poor prognosis in PPGLs. They are convenient predictive markers that could be used in daily clinical practice.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , Neutrófilos , Pronóstico , Feocromocitoma/diagnóstico , Linfocitos , Plaquetas , Paraganglioma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Estudios RetrospectivosRESUMEN
Context: Adrenocortical carcinoma (ACC) is rare and have high rates of recurrence and mortality. The role of adjuvant radiation therapy (RT) in localized ACC was controversial. Methods: We conducted a retrospective study in our center between 2015 and 2021 to evaluate the efficacy and safety of adjuvant RT in localized ACC. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to estimate the independent risk factors. Adverse events associated with RT were documented according to the toxicity criteria of the radiation therapy oncology group (RTOG) and the common terminology criteria for adverse events (CTCAE v5.0). Results: Of 105 patients with localized ACC, 46 (43.8%) received adjuvant RT after surgery. The median radiation dose was 45.0Gy (range:30.0-50.4) and median follow up time was 36.5 (IQR: 19.7-51.8) months. In comparison to the no adjuvant RT group, patients with adjuvant RT had better 3-year OS (87.9% vs 79.5%, P=0.039), especially for patients with ENSAT I/II stage (P=0.004). Adjuvant RT also improved the median DFS time from 16.5months (95%CI, 12.0-20.9) to 34.6months (95%CI, 16.1-53.0). Toxicity of RT was generally mild and moderate with six grade 3 events. Conclusions: Postoperative adjuvant RT significantly improved OS and DFS compared with the use of surgery alone in resected ACC patients. Although this retrospective study on RT in localized ACC indicates that RT is effective in ACC, its findings need to be prospectively confirmed.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Carcinoma Corticosuprarrenal/radioterapia , Carcinoma Corticosuprarrenal/cirugía , Radioterapia Adyuvante , Estudios Retrospectivos , Supervivencia sin Enfermedad , Neoplasias de la Corteza Suprarrenal/radioterapia , Neoplasias de la Corteza Suprarrenal/cirugíaRESUMEN
OBJECTIVE: To explore the prevalence and clinical significance of newly diagnosed diabetes mellitus (DM) in patients with primary aldosteronism (PA). Investigating the risk factors for cardiocerebrovascular disease (CCVD) will guide strategies for reducing CCVD in patients with PA. METHODS: We retrospectively included 729 PA patients without DM and conducted oral glucose tolerance tests. RESULTS: We found that 15.0% of PA patients had newly diagnosed DM. The DM prevalence increased with elevated aldosterone levels [OR = 3.20 (1.77, 5.78), P value < 0.001]. The rate of CCVD in newly diagnosed diabetic PA patients was higher than that in nondiabetic PA patients at diagnosis (11.9% vs. 5.0%, P = 0.005). Furthermore, multivariate logistic analysis revealed that HT duration [1.055 (1.002,1.111), P = 0.041] and newly diagnosed DM [2.600 (1.072,6.303), P = 0.034] were significantly associated with CCVD in PA patients. CONCLUSION: The prevalence of newly diagnosed DM in PA patients was higher than that in the general population. Aldosterone level was an independent risk factor for DM not for CCVD. CCVD was correlated with longer HT duration and newly diagnosed DM. Therefore, it is crucial to screen DM at the diagnosis in PA patients.
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Diabetes Mellitus , Hiperaldosteronismo , Aldosterona , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Humanos , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiología , Prevalencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Adrenal incidentalomas are the most frequent human neoplasms. Recent genomic investigations on functional adrenocortical tumors have demonstrated that somatic mutations in PRKACA and KCNJ5 responsible for the development of adrenocortical adenomas (ACAs) are associated with hypercortisolism and aldosteronism, respectively. Several studies have identified CTNNB1 mutations in ACAs and have been mostly involved in the tumorigenesis of non-functional ACA (NFACA). However, integrated genomic characterization of NFACAs is lacking. In the current study, we utilized pan-genomic methods to comprehensively analyze 60 NFACA samples. A total of 1264 somatic mutations in coding regions among the 60 samples were identified, with a median of 15 non-silent mutations per tumor. Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1. We also identified several somatic mutations in genes of the cAMP/PKA pathway and KCNJ5. Histone modification genes (KMT2A, KMT2C, and KMT2D) were altered in 10% of cases. Germline mutations of MEN1 and RET were also found. Finally, by comparison of our transcriptome data with those available in the TCGA, we illustrated the molecular characterization of NFACA. We revealed the genetic profiling and molecular landscape of NFACA. Wnt/ß-catenin pathway activation as shown ssby nuclear and/or cytoplasmic ß-catenin accumulation is frequent, occurring in about one-third of ACA cases. cytochrome P450 enzymes could be markers to reveal the functional status of adrenocortical tumors. These observations strongly suggest the involvement of the Wnt/ß-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion.
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Neoplasias de la Corteza Suprarrenal , Neoplasias de las Glándulas Suprarrenales , Adenoma Corticosuprarrenal , Neoplasias de la Corteza Suprarrenal/patología , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Carcinogénesis , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Humanos , Mutación , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Nutrition and lifestyle have a great impact on reproduction and infertility in humans, as they are essential for certain processes such as implantation, placental growth, angiogenesis, and the transfer of nutrients from the mother to the fetus. The aim of this review is to provide the interconnection between nutrition and reproductive health through the insight of omics approaches (including metabolomics and nutrigenomics). The effect of various macronutrients, micronutrients, and some food-associated components on male and female reproduction was discussed. Recent research work was collected through database search from 2010 to 2020 to identify eligible studies. Alterations of metabolic pathways in pregnant women were deliberated with an emphasis on different strategies of lifestyle and dietary interventions. Several nutritional methods, which are important for embryonic and child neurological development, nutritional supplements to lactation, and improved gestational length along with birth weight have been emphasized. Considerable advances in omics strategies show potential technological development for improving human reproductive health.
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Objective: Unilateral primary aldosteronism (PA) includes aldosterone-producing adenoma (APA), unilateral adrenal hyperplasia, and unilateral multiple nodules. The correlation of multiple nodules, especially genotypic and pathological characteristics, remains unknown. KCNJ5 mutation accounts for 60-80% of unilateral PA, so we aimed to explore the correlation of KCNJ5 somatic mutation and CYP11B1/CYP11B2 staining in multiple nodules in unilateral PA. Design and Methods: A total of 56 microdissected nodules from 24 patients with unilateral PA were included. We assessed somatic KCNJ5 mutations, immunohistochemistry for aldosterone synthase (CYP11B2)/cortisol synthase (CYP11B1), and histological cellular composition of nodules together with adjacent adrenal cortical statements. Results: KCNJ5 mutations were identified in 17 (17/56, 30.4%) nodules from 11 adrenals (11/24, 45.8%). All KCNJ5-mutant nodules were positive for CYP11B2 staining, 6 cases (6/11) had only one KCNJ5-mutant nodular, and the other 5 cases (5/11) had more than one KCNJ5-mutant nodules. Three cases (3/11) had different KCNJ5 mutations in individual nodules. Compared with KCNJ5-positive adrenals, the cortices adjacent to the nodules in KCNJ5-negative adrenals showed significant proliferation (p = 0.004). CYP11B2/CYP11B1 expression patterns revealed great heterogeneity in intensity and range both in KCNJ5-mutant nodules and KCNJ5-WT ones. Conclusion: There is great heterogeneity among nodules from patients with unilateral PA. Countable nodules could be considered as multiple APAs, featuring somatic KCNJ5 mutation, positive CYP11B2 staining, and lack of adjacent cortical proliferation in unilateral multiple nodules.
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Developing cost-effective and stable non-noble electrocatalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is now the critical issue for large-scale application of zinc-air batteries. Here, we presented a simple method to synthesize highly dispersed cobalt manganate spinel nanodots in-situ embedded in amine-functionalized carbon black. Silane coupling agent 3-aminopropyltriethoxysilane (APTES) played dual roles in the preparation: (1) to achieve amine-functionalization of carbon support; (2) as weak alkali to precipitate metal hydroxides which were then converted to spinel nanodots after mild calcination. The hydrophilicity of the carbon substrate was enhanced by amine modification from APTES to disperse metal oxide evenly, and the electrochemical activity was promoted through the strong interface interaction between embedded spinel nanodots and carbon substrate during the calcination process. As expected, the CoMn2O4/C-NH2-300 catalyst exhibited satisfactory bifunctional catalytic performance for both ORR and OER with an ΔE (E1/2-Ej10)â¯=â¯0.75â¯V, which was lower than most state-of-the-art catalysts. In addition, CoMn2O4/C-NH2-300 as a cathode also exhibited remarkable zinc-air battery performance in alkaline solution. This strategy of APTES as a bifunctional coupling agent provided a novel way to design and explore highly active, durable, and cost-effective catalysts for renewable energy conversion and storage.
RESUMEN
Background: Primary aldosteronism is caused by aldosterone overproduction. While conventional hematoxylin-eosin staining can demonstrate morphological abnormality, it cannot provide any functional histopathological information. We aimed to identify the diagnostic, functional and prognostic value of CYP11B2, CYP11B1, and ß-catenin immunostaining in unilateral hyperaldosteronism. Method: A total of 134 patients with unilateral hyperaldosteronism were recruited in our study. The expression of CYP11B2, CYP11B1, and ß-catenin was evaluated semiquantitatively on 134 patients' sections using immunohistochemistry technology and the relationship with clinical data was assessed. Results: Patients were classified into four subtypes based on CYP11B2 staining as below: (1)118 patients with unilateral single aldosterone-producing adenoma (APA), (2)11 with unilateral multiple APA, (3)four with aldosterone-producing cell cluster (APCC), and (4)one with an undefined source. Adjusted CYP11B2 H-score was correlated with serum aldosterone, aldosterone to renin ratio (ARR), and serum potassium. In the abnormal ß-catenin staining group, hypertension duration, aldosterone, ARR, cortisol, tumor diameter, tumor area, and CYP11B2 H-score were significantly higher than those of the wild-type group. Serum potassium level was significantly lower in the abnormal ß-catenin staining group. Age, gender, BMI, family history of hypertension, adjusted CYP11B2 and CYP11B1 H-scores differed significantly between complete clinical success and incomplete clinical success groups. Age, gender and family history of hypertension were independently associated with complete clinical success based on multivariate logistic regression analysis. Conclusion: CYP11B2 immunostaining could improve the differential diagnosis of unilateral hyperaldosteronism. Adjusted CYP11B2 H-score could be used as a histopathological marker to reflect the severity of unilateral APA. Dysregulation of Wnt/ß-catenin signaling and impaired ß-catenin degradation may provoke the proliferation and enhance the steroidogenic ability of APA tumor cells, indicating that the Wnt pathway might be a potential, actionable, therapeutic target in the treatment of hyperaldosteronism. Age, sex and family history of hypertension were independent predictors of clinical outcome after adrenalectomy for unilateral hyperaldosteronism.
RESUMEN
OBJECTIVE: The purpose of this study was to explore the effect of dulaglutide on DHEA induced PCOS rats and its mechanism, to provide new drugs and research directions for clinical treatment of PCOS. METHODS: In this study, the PCOS model was established by giving female SD rats subcutaneous injection of DHEA for 21 consecutive days. After modeling, the treatment group was injected subcutaneously with three doses of dulaglutide for 3 weeks. The model group was injected with sterile ultrapure water, and the normal group did not get any intervention. The body weight changes of rats in each group were recorded from the first day when rats received the administration of dulaglutide. Three weeks later, the rats were fasted the night after the last treatment, determined fasting insulin and fasting glucose the next day. After the rats were anesthetized by chloral hydrate, more blood was collected from the heart of the rat. The serum insulin, testosterone and sex hormone binding globulin (SHBG) levels were detected by the enzyme-linked immunoassay method. After removing the adipose tissue, the obtained rat ovary tissue was used for subsequent experimental detection, using HE staining for morphology and follicular development analysis; qRT-PCR for the detection of 3ßHSD, CYP17α1, CYP19α1, and StAR gene expression in ovarian tissue; and western blotting analysis of CYP17α1, CYP19α1, StAR protein expression and insulin level to verify whether dulaglutide has a therapeutic effect on PCOS in rats. RESULTS: After treated with different concentrations of dulaglutide, we found that the body weight of rats in the treatment groups were reduced. Compared with the rats in PCOS group, the serum androgen level of rats in the treatment groups was significantly decreased, and the serum sex hormone binding protein content was significantly increased, and there was statistically significant difference between these groups and PCOS group. In terms of protein expression and gene regulation, the expression of 3ßHSD, CYP19α1 and StAR in the ovarian tissue of rats in treatment groups were decreased significantly after received the treatment of dulaglutide, and there was statistically significant difference between these groups and PCOS group. In addition, dulaglutide reduced the insulin content in the ovarian tissue of PCOS rats. CONCLUSION: Dulaglutide may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3ßHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats. In addition, dulaglutide may reduce the weight of PCOS rats, further reducing the level of high androgen in PCOS rats, and improving the morphology of their polycystic ovaries.