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1.
Int J Mol Sci ; 24(13)2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37445704

RESUMO

Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR < 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = -6.22 and Z = -6.45, respectively). Compared to previously published datasets of interleukin-1ß and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.


Assuntos
Neoplasias Pulmonares , Glândula Tireoide , Humanos , Animais , Camundongos , Glândula Tireoide/metabolismo , Transcriptoma , Receptor de Morte Celular Programada 1 , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Anticorpos/genética , Análise de Sequência de RNA
2.
Front Endocrinol (Lausanne) ; 13: 1032262, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568088

RESUMO

Introduction: Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice. Methods: To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ ) and their wild type (WT) counterparts. Results: In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton. Discussion: These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.


Assuntos
Osso Cortical , Receptor alfa de Estrogênio , Osteoporose , Sirtuína 1 , Animais , Feminino , Masculino , Camundongos , Osso Cortical/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Camundongos Endogâmicos C57BL , Porosidade , Sirtuína 1/genética , Osteoporose/genética , Osteoporose/metabolismo
3.
Mol Metab ; 60: 101482, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35364299

RESUMO

OBJECTIVE: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged. METHODS: 9-week-old C57BL/6 J female mice were subjected to ovariectomy (OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery. RESULTS: Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16, Fitm1 as well as Il18, Rares2, Retn, Rbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = -0.7 p < 0.001) and liver triglyceride content (r = -0.4, p = 0.04), with a similar trend for serum adropin. In vitro, Enho expression was tripled by 17ß-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16. CONCLUSIONS: OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement.


Assuntos
Estrogênios , Fígado , Animais , Estrogênios/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Triglicerídeos/metabolismo , Aumento de Peso
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