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1.
Int J Biol Macromol ; 253(Pt 7): 127415, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37848113

RESUMO

MicroRNAs (miRNAs) are a class of RNA macromolecules that play regulatory roles in follicle development by inhibiting protein translation through binding to the 3'UTR of its target genes. Granulosa cell (GC) proliferation, steroidogenesis, and lipid metabolism have indispensable effect during folliculogenesis. In this study, we found that miR-22-3p was highly expressed in the hierarchical follicles of the chickens, which indicated that it may be involved in follicle development. The results obtained suggested that miR-22-3p promoted proliferation, hormone secretion (progesterone and estrogen), and the content of lipid droplets (LDs) in the chicken primary GC. The results from the bioinformatics analysis, luciferase reporter assay, qRT-PCR, and Western blotting, confirmed that PTEN was directly targeted to miR-22-3p. Subsequently, it was revealed that PTEN inhibited proliferation, hormone secretion, and the content of LDs in GC. Therefore, this study showed that miR-22-3p could activate PI3K/Akt/mTOR pathway via targeting PTEN. Taken together, the findings from this study indicated that miR-22-3p was highly expressed in the hierarchical follicles of chickens, which promotes GC proliferation, steroidogenesis, and lipid metabolism by repressing PTEN to activate PI3K/AKT/mTOR pathway.


Assuntos
Galinhas , MicroRNAs , Animais , Galinhas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Metabolismo dos Lipídeos/genética , Transdução de Sinais/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células/genética , Hormônios
2.
Chin J Physiol ; 66(4): 200-208, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37635479

RESUMO

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. This study was aimed at exploring the improving effects of miR-22-3p on the symptoms of POF in mice by inhibiting chemokine-like receptor 1 (CMKLR1) expression. Female mice were intraperitoneally injected with cyclophosphamide to construct POF mice models. Lentiviral vectors containing miR-22-3p, short hairpin RNA (sh)-CMKLR1, and overexpression (oe)-CMKLR1, respectively, or in combination, were injected into the ovaries of both sides of POF mice. miR-22-3p and CMKLR1 expression in ovarian tissues of mice was assessed, and the targeting relationship between miR-22-3p and CMKLR1 was predicted and verified. Serum estradiol (E2), anti-Mullerian hormone, and follicle-stimulating hormone levels were assessed. Ovarian weight was weighed, and pathological changes and the number of primordial follicles, primary follicles, secondary follicles, and atresia follicles were observed. Apoptosis of ovarian tissues was determined. In ovarian tissues of POF mice, miR-22-3p expression was decreased while CMKLR1 expression was increased. miR-22-3p up-regulation or CMKLR1 down-regulation restored sex hormone levels, improved ovarian weight and the number of primordial follicles, primary follicles, and secondary follicles, and reduced the number of atresia follicle and ovarian granulosa cell apoptosis in POF mice. miR-22-3p targeted CMKLR1, and overexpressing CMKLR1 reversed the ameliorative effects of miR-22-3p overexpression on POF mice. Our research highlights that overexpressed miR-22-3p down-regulates CMKLR1 to ameliorate the symptoms of POF in mice. Therefore, the miR-22-3p/CMKLR1 axis could improve the symptoms of POF.


Assuntos
MicroRNAs , Insuficiência Ovariana Primária , Adulto , Feminino , Camundongos , Humanos , Animais , Insuficiência Ovariana Primária/patologia , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Ciclofosfamida/farmacologia , MicroRNAs/metabolismo , Receptores de Quimiocinas
3.
Eur Thyroid J ; 12(4)2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37074673

RESUMO

Objective: Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters. Methods: Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed. Results: We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3',5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins. Conclusions: Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.


Assuntos
Transportadores de Ânions Orgânicos , Peixe-Zebra , Humanos , Camundongos , Animais , Filogenia , Peixe-Zebra/metabolismo , Sulfatos/metabolismo , Hormônios Tireóideos , Proteínas de Membrana Transportadoras/genética , Transportadores de Ânions Orgânicos/genética
4.
J Biochem Mol Toxicol ; 37(7): e23367, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37009741

RESUMO

2,2-Bis(4-hydroxyphenyl)propane (bisphenol A; BPA) is an environmental endocrine-disrupting chemical. It mimics the effects of estrogen at multiple levels by activating estrogen receptors (ERs); however, BPA also affects the proliferation of human breast cancer cells independent of ERs. Although BPA inhibits progesterone (P4) signaling, the toxicological significance of its effects remain unknown. Tripartite motif-containing 22 (TRIM22) has been identified as a P4-responsive and apoptosis-related gene. Nevertheless, it has not yet been established whether exogenous chemicals change TRIM22 gene levels. Therefore, the present study investigated the effects of BPA on P4 signaling and TRIM22 and TP53 expression in human breast carcinoma MCF-7 cells. In MCF-7 cells incubated with various concentrations of P4, TRIM22 messenger RNA (mRNA) levels increased in a dose-dependent manner. P4 induced apoptosis and decreased viability in MCF-7 cells. The knockdown of TRIM22 abolished P4-induced decreases in cell viability and P4-induced apoptosis. P4 increased TP53 mRNA expression and p53 knockdown decrease the basal level of TRIM22 and P4 increased TRIM22 mRNA expression independent of p53 expression. BPA attenuated P4-induced increases in the ratio of cell apoptosis in a concentration-dependent manner, and the P4-induced decreases in cell viability was abolished in the presence of 100 nM and higher BPA concentrations. Furthermore, BPA inhibited P4-induced TRIM22 and TP53 expression. In conclusion, BPA inhibited P4-induced apoptosis in MCF-7 cells via the inhibition of P4 receptor transactivation. TRIM22 gene has potential as a biomarker for investigating the disruption of P4 signaling by chemicals.


Assuntos
Neoplasias da Mama , Progesterona , Humanos , Feminino , Progesterona/farmacologia , Células MCF-7 , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ativação Transcricional , Neoplasias da Mama/patologia , Compostos Benzidrílicos/farmacologia , Apoptose
5.
Mol Brain ; 16(1): 18, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36732798

RESUMO

A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.


Assuntos
Linfócitos T CD8-Positivos , Núcleo Hipotalâmico Paraventricular , Núcleo Hipotalâmico Paraventricular/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Hipotálamo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Corticosterona , Neurônios/metabolismo , RNA Mensageiro/metabolismo
6.
Genes (Basel) ; 14(2)2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36833418

RESUMO

Phelan-McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials.


Assuntos
Hormônio do Crescimento Humano , Fator de Crescimento Insulin-Like I , Recém-Nascido , Humanos , Fator de Crescimento Insulin-Like I/genética , Hormônio do Crescimento Humano/genética , Fenótipo , Proteínas do Tecido Nervoso/genética
7.
Mater Today Bio ; 14: 100223, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35243298

RESUMO

Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.

8.
Ital J Pediatr ; 47(1): 49, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663540

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS), also known as 22q13.3 deletion syndrome, is a rare neurodevelopmental syndrome resulting from a deletion of the distal long arm of chromosome 22. CASE PRESENTATION: We report a case of a 21 months old Chinese girl presenting with global developmental delay, regression of language skills, unable to understand a few words or walk independently, insomnia, and autism-like behaviors. Copy number variation (CNV) analysis showed a heterozygous loss of SHANK3 gene in the 22q13 region, consistent with a diagnosis of PMS. After treatment with recombinant human growth hormone (rhGH), this patient had an improvement in motor skills and social behaviors. No side effects from rhGH therapy were reported. CONCLUSIONS: This is the first report of using rhGH to treat a Chinese girl diagnosed with PMS. We speculate rhGH could be a reasonable alternative choice for PMS treatment with similar clinical outcomes in comparison to insulin-like growth factor-1(IGF-1). However, further clinical trials are needed to confirm this hypothesis.


Assuntos
Transtornos Cromossômicos/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , China , Deleção Cromossômica , Cromossomos Humanos Par 22 , Feminino , Humanos , Lactente
9.
Fetal Pediatr Pathol ; 40(5): 486-492, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31997693

RESUMO

BACKGROUND: The 17q22 contiguous microdeletion syndrome is a recently described chromosomal disorder. Clinical features are heterogeneous because of variable deletion sizes. Clinical report: We present a child with delayed psychomotor development, dysmorphic features (prominent posterior rotated ears, upturned nose, thin upper lip, smooth philtrum, high palate), vesicoureteral reflux and growth hormone deficiency. 1.53 Mb loss at the 17q22 chromosome region in the proband was the responsible for the phenotype. Conclusion: In the few cases of interstitial 17q22 deletion in the literature, this is the first with growth hormone deficiency. This may contribute to the phenotypic spectrum of 17q22 microdeletion syndrome. As the reported cases increase, we believe that genotype-phenotype correlation will be better illuminated.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Hormônio do Crescimento Humano/deficiência , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Humanos , Fenótipo , Síndrome
10.
Int J Mol Sci ; 20(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731788

RESUMO

Polyamines are multifaceted compounds which play a role in regulating plant growth and stress tolerance in interactions with plant hormones. The aim of the present study was to reveal how exogenous polyamines influence the synthesis of salicylic acid, with a special emphasis on the effect of salicylic acid deficiency on the polyamine metabolism and polyamine-induced changes in other plant hormone contents. Our hypothesis was that the individual polyamines induced different changes in the polyamine and salicylic acid metabolism of the wild type and salicylic acid-deficient Arabidopsis mutants, which in turn influenced other hormones. To our knowledge, such a side-by-side comparison of the influence of eds5-1 and sid2-2 mutations on polyamines has not been reported yet. To achieve our goals, wild and mutant genotypes were tested after putrescine, spermidine or spermine treatments. Polyamine and plant hormone metabolism was investigated at metabolite and gene expression levels. Individual polyamines induced different changes in the Arabidopsis plants, and the responses were also genotype-dependent. Polyamines upregulated the polyamine synthesis and catabolism, and remarkable changes in hormone synthesis were found especially after spermidine or spermine treatments. The sid2-2 mutant showed pronounced differences compared to Col-0. Interactions between plant hormones may also be responsible for the observed differences.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Poliaminas/farmacologia , Arabidopsis/genética , Transferases Intramoleculares/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Mutação/genética , Reguladores de Crescimento de Plantas/metabolismo , Ácido Salicílico/metabolismo
11.
Mol Syndromol ; 10(3): 147-153, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31191203

RESUMO

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is due to heterozygous FOXL2 intragenic mutations in about 70% of the patients, whereas total or partial gene deletions account for a minority of cases. Alteration of FOXL2 regulatory elements has been rarely described in patients with BPES. In this study, a prepubertal girl with BPES due to a 197-kb de novo deletion of the regulatory elements upstream of FOXL2 is reported. This girl presented with additional clinical features such as a soft cleft palate and microcephaly; thus, this copy number variant might have other somatic effects. The present deletion encompasses 2 coding genes (MRPS22 and COPB2), whose homozygous mutations have been associated with microcephaly. In our case, the sequences of the non-deleted allele were normal, ruling out a compound genetic defect. Normal levels of new biomarkers of ovarian reserve (anti-müllerian hormone, inhibin B) likely indicate an early diagnosis of type 2 BPES, but an evolutive gonadal damage will be excluded only by long-term follow-up. Additional reports of microdeletions upstream of FOXL2 are needed to better define the underlying genetic mechanism and the related phenotypic spectrum; the ability of the new hormonal markers to predict ovarian function in adolescence and adulthood should be confirmed.

12.
Front Immunol ; 10: 642, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001262

RESUMO

A synthetic progestin, medroxyprogesterone acetate (MPA), was used in a novel study to determine progestin effects on human purified macrophages and Th1, Th2, Th17, Th22 cells. MPA concentrations were equivalent to those in the serum of women after 6 and 9 months of progestin use. MPA has no effect on the proliferation of PBMCs and CD4+ T cell clones induced by immobilized anti-CD3 antibodies or by antigen (streptokinase). However, MPA decreases production and mRNA expression of IL-5, IL-13, IFN-γ, T-bet, RORC, and IL-17A but increases production and mRNA expression of IL-22 by CD4+ Th22 cell clones and decreases IL-22 production by Th17 cells. MPA inhibits RORC, but not T-bet and AHR, by Th17 cells but increases AHR mRNA and T-bet expression of established CD4+ Th22 cell clones. This suggests that MPA, at concentrations equivalent to those found in the serum of women after treatment for contraception and hormone replacement therapy, can directly inhibit Th1 responses (against intracellular bacteria and viruses), Th17 (against extracellular bacteria and fungi), Th2 (against parasites) but MPA therapy increases IL-22 produced by Th22 cells mediated by an increased expression of AHR and T-bet controlling inflammation. MPA could be responsible for the tissue damage limited by IL-22 in absence of IL-17A.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Macrófagos/patologia , Acetato de Medroxiprogesterona/farmacologia , Receptores de Hidrocarboneto Arílico/imunologia , Transdução de Sinais/efeitos dos fármacos , Células Th1/imunologia , Células Th17/imunologia , Adulto , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Citocinas/imunologia , Suscetibilidade a Doenças , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Macrófagos/imunologia , Masculino , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fatores Sexuais , Transdução de Sinais/imunologia , Proteínas com Domínio T/imunologia , Células Th1/patologia , Células Th17/patologia , Viroses/imunologia , Viroses/patologia
13.
Ecotoxicol Environ Saf ; 169: 778-785, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597776

RESUMO

Metal pyrithiones (MePTs) are frequently used antifouling biocides in marine coatings. Their main degradation product, 2,2'-dithiobis-pyridine ((PS)2), has been widely detected in seawater and may pose potential ecological risks. In the present study, sexually mature guppies (Poecilia reticulata) were exposed to (PS)2 at concentrations of 0, 20, 200, and 2000 ng/L for 28 days to investigate its reproductive toxicity. The results showed that (PS)2 significantly reduced testosterone (T) levels, spermatogenic cyst number and sperm motility, impeded spermatogenic cell differentiation in male guppies and delayed embryo development in females. These results indicated that (PS)2 could cause reproductive toxicity in guppies. We also examined mRNA expression of indices involved in the hypothalamic-pituitary-gonadal axis and reproductive behaviors. We found that 200 and 2000 ng/L (PS)2 decreased T synthesis by downregulating 17ßHSD and CYP17 mRNA levels, and upregulating the mRNA level of CYP19a1a, which converted T to 17ß-estradiol. (PS)2 also upregulated GnRH1, FSHß, LHß, and LHR mRNA levels, a positive feedback regulation due to the decrease of T levels in male guppies. Furthermore, (PS)2 significantly decreased CYP19a1b mRNA levels in all three exposure groups and thus reduced the display frequency of male guppies. This study was the first to report that (PS)2 could induce reproductive toxicity, which would provide a basis for future assessment of its ecological risk.


Assuntos
2,2'-Dipiridil/análogos & derivados , Desinfetantes/toxicidade , Dissulfetos/toxicidade , Poecilia/fisiologia , Reprodução/efeitos dos fármacos , 2,2'-Dipiridil/toxicidade , Animais , Diferenciação Celular , Estradiol/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Diferenciação Sexual , Maturidade Sexual/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testosterona/metabolismo , Testes de Toxicidade
14.
EBioMedicine ; 40: 67-76, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30639417

RESUMO

BACKGROUND: Bariatric surgery leads to early and long-lasting remission of type 2 diabetes (T2D). However, the mechanisms behind this phenomenon remain unclear. Among several factors, gut hormones are thought to be crucial mediators of this effect. Unlike GLP-1, the role of the hormone peptide tyrosine tyrosine (PYY) in bariatric surgery in humans has been limited to appetite regulation and its impact on pancreatic islet secretory function and glucose metabolism remains under-studied. METHODS: Changes in PYY concentrations were examined in obese patients after bariatric surgery and compared to healthy controls. Human pancreatic islet function was tested upon treatment with sera from patients before and after the surgery, in presence or absence of PYY. Alterations in intra-islet PYY release and insulin secretion were analysed after stimulation with short chain fatty acids (SCFAs), bile acids and the cytokine IL-22. FINDINGS: We demonstrate that PYY is a key effector of the early recovery of impaired glucose-mediated insulin and glucagon secretion in bariatric surgery. We establish that the short chain fatty acid propionate and bile acids, which are elevated after surgery, can trigger PYY release not only from enteroendocrine cells but also from human pancreatic islets. In addition, we identify IL-22 as a new factor which is modulated by bariatric surgery in humans and which directly regulates PYY expression and release. INTERPRETATION: This study shows that some major metabolic benefits of bariatric surgery can be emulated ex vivo. Our findings are expected to have a direct impact on the development of new non-surgical therapy for T2D correction.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Peptídeo YY/metabolismo , Animais , Cirurgia Bariátrica , Biomarcadores , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Células Enteroendócrinas/metabolismo , Feminino , Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Interleucinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Peptídeo YY/sangue , Peptídeo YY/genética , Ratos
15.
Toxicol Rep ; 6: 10-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30510908

RESUMO

Kummerowia striata (K. striata) is used as a traditional medicine for inflammation-related therapy. To determine whether it has beneficial anti-melanogenic and anti-oxidant activities, we investigated the biological activities of the ethanol extract of Kummerowia striata (EKS) using a variety of in vitro and cell culture model systems. The anti-melanogenic activity was assessed in B16F10 melanoma cells in terms of melanin synthesis and in vitro tyrosinase inhibitory activity. The anti-oxidant assays were performed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). EKS showed strong anti-oxidant activities in DPPH and ABTS assays. The mRNA transcription levels and protein expression levels of tyrosinase, tyrosinase-related protein 1, tyrosinase-related protein 2, and microphthalmia-associated transcription factor decreased in a dose-dependent manner with EKS treatment. Additionally, EKS did not affect cell viability at different concentrations used in this study, indicating that the mechanism of action of EKS-mediated inhibition of melanin synthesis does not involve cytotoxicity. Also, we confirmed that p-coumaric acid and quercetin are important compounds for anti-melanogenesis and antioxidant properties of EKS. Collectively, our findings demonstrate for the first time that EKS possesses anti-melanogenic and anti-oxidant activities. Further evaluation and development of EKS as a functional supplement or cosmetic may be useful for skin whitening and reducing wrinkles.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30181896

RESUMO

The measurement of circulating concentrations of growth hormone (GH) is an indispensable tool in the diagnosis of both GH deficiency and GH excess. GH is a heterogeneous protein composed of several molecular isoforms, but the physiological role of these different isoforms has not yet been fully understood. The 22KD GH (22 K-GH) is the main isoform in circulation, followed by 20KD GH (20 K-GH) and other rare isoforms. Studies have been performed to better understand the biological actions of the different isoforms as well as their importance in pathological conditions. Generally, the non-22 K- and 20 K-GH isoforms are secreted in parallel to 22 K-GH, and only very moderate changes in the ratio between isoforms have been described in some pituitary tumors or during exercise. Therefore, in a diagnostic approach, concentrations of 22 K-GH accurately reflect total GH secretion. On the other hand, the differential recognition of GH isoforms by different GH immunoassays used in clinical routine contributes to the known discrepancy in results from different GH assays. This makes the application of uniform decision limits problematic. Therefore, the worldwide efforts to standardize GH assays include the recommendation to use 22 K-GH specific GH assays calibrated against the pure 22 K-GH reference preparation 98/574. Adoption of this recommendation might lead to improvement in diagnosis and follow-up of pathological conditions, and facilitate the comparison of results from different laboratories.

17.
Biochem Biophys Rep ; 11: 130-137, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28955777

RESUMO

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human hepatocytes (JHH5, JHH7, and HepG2) to experimental IH or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction (RT-PCR), and found that IH significantly increased the mRNA levels of selenoprotein P (SELENOP) - a hepatokine - and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) - one of REG (Regenerating gene) family. We next investigated promoter activities of both genes and discovered that they were not increased by IH. On the other hand, a target mRNA search of micro RNA (miRNA) revealed that both mRNAs have a potential target sequence for miR-203. The miR-203 level of IH-treated cells was significantly lower than that of normoxia-treated cells. Thus, we introduced miR-203 inhibitor and a non-specific control RNA (miR-203 inhibitor NC) into HepG2 cells and measured the mRNA levels of SELENOP and HIP/PAP. The IH-induced expression of SELENOP and HIP/PAP was abolished by the introduction of miR-203 inhibitor but not by miR-203 inhibitor NC. These results demonstrate that IH stress up-regulates the levels of SELENOP in human hepatocytes to accelerate insulin resistance and up-regulates the levels of HIP/PAP mRNAs to proliferate such hepatocytes, via the miR-203 mediated mechanism.

18.
Toxicol Rep ; 3: 414-426, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28959563

RESUMO

Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others; animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date.

19.
J Neurosurg ; 123(3): 813-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26047408

RESUMO

OBJECT: Pituitary adenomas are well suited to resection by a minimal-access endoscopic technique. Validation of this approach requires prospective outcome studies to determine the impact on quality of life (QOL). This study aims to assess the effect of endoscopic pituitary adenoma resection on site-specific and sinonasal-related QOL before and after endoscopic surgery using validated instruments. METHODS: Consecutive adult patients undergoing endoscopic endonasal resection of pituitary adenoma were prospectively enrolled from a single tertiary care center. All patients completed the Anterior Skull Base Questionnaire (ASBQ) and the 22-Item Sino-Nasal Outcome Test (SNOT-22) preoperatively and then at regular intervals after surgery to assess their perceived QOL with regard to hormonal, surgical, and anatomical factors. RESULTS: Eighty-one of 114 patients were eligible for study; median follow-up was 16 months. This cohort included 24 (29.6%) nonsecreting macroadenomas and 57 (70.4%) hypersecreting tumors. There was significant improvement in the mean ASBQ score at 12 weeks, 6 months, and 1 year after surgery (p < 0.05), while postoperative SNOT-22 scores, at the same time points, showed no significant difference from preoperative scores. Both ASBQ and SNOT-22 scores showed transient worsening at 3 weeks postoperatively. Subtotal resection correlated with worse QOL, both overall and among patients with hypersecreting tumors (p < 0.05). Extrasellar tumor extension, intraoperative CSF leakage, and a reconstruction technique during surgery did not impact postoperative QOL. Visual disturbances did not significantly alter QOL. There were no postoperative CSF leaks in this series. CONCLUSIONS: Endoscopic resection of pituitary adenoma is associated with long-term improvements in site-specific QOL and stability in sinonasal QOL when assessed pre- and postoperatively with validated instruments. Subtotal resection was the only factor that negatively impacted postoperative QOL. Therefore, gross-total resection should be attempted for all patients to optimize QOL after surgery.


Assuntos
Adenoma/cirurgia , Endoscopia/métodos , Seios Paranasais/cirurgia , Neoplasias Hipofisárias/cirurgia , Qualidade de Vida , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento
20.
Prog Neurobiol ; 113: 6-39, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24172649

RESUMO

Progesterone is commonly considered as a female reproductive hormone and is well-known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of γ-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain.


Assuntos
Encéfalo/metabolismo , Pregnanolona/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Animais , Feminino , Humanos , Masculino , Proto-Oncogene Mas
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