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1.
Chem Commun (Camb) ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643622

RESUMO

Serum N-glycan patterns from 50 Crohn's disease (CD) patients and 50 healthy controls were acquired using a carbon matrix, from which eight N-glycans with significant difference were screened out to reveal remarkale performance for CD diagnosis. This research is expected to help future glycan-based disease detection not limited to CD.

2.
Anim Biosci ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34530511

RESUMO

Objective: Spermatozoa are produced within the seminiferous tubules after sexual maturity. The expression levels of mRNAs and lncRNAs in testicular tissues are different at each stage of testicular development and are closely related to formation of the extracellular matrix and spermatogenesis. Therefore, we set out to study the expression of lncRNAs and mRNAs during the different developmental stages of the goat testis. Methods: We constructed 12 RNA libraries using testicular tissues from goats aged 3, 6, and 12 months, and studied the functions of mRNAs and lncRNAs using the Gene Ontogeny (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Relationships between differentially expressed genes (DEGs) were analyzed by lncRNA-mRNA co-expression network and protein-protein interaction network (PPI). Finally, the protein expression levels of matrix metalloproteinase 2 (MMP2), insulin-like growth factor 2 (IGF2), and insulin-like growth factor-binding protein 6 (IGFBP6) were detected by western blotting. Results: We found 23, 8, and 135 differentially expressed lncRNAs and 161, 12, and 665 differentially expressed mRNAs that were identified between 3 vs. 6, 6 vs. 12, and 3 vs. 12 months, respectively. GO, KEGG, and PPI analyses showed that the differential genes were mainly related to the extracellular matrix. Moreover, MMP2 was a hub gene and co-expressed with the lncRNA TCONS-0002139 and TCONS-00093342. The results of qRT-PCR verification were consistent with those of RNA-seq sequencing. The expression trends of MMP2, IGF2, and IGFBP6 protein were the same as that of mRNA, which all decreased with age. IGF2 and MMP2 were significantly different in the 3 vs. 6-month-old group (P < 0.05). Conclusion: These results improve our understanding of the molecular mechanisms involved in sexual maturation of the goat testis.

3.
J Mater Chem B ; 9(38): 8109-8120, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34494067

RESUMO

1T-phase niobium telluride (NbTe2) nanosheets are becoming increasingly important in emerging fields, such as spintronics, sensors and magneto-optoelectronics, due to their excellent physical and chemical properties. However, exploration on their biomedical applications are limited. Herein, ultrathin 1T-phase NbTe2 single-crystalline nanosheets with excellent photothermal performance, high drug-loading rate, near-infrared (NIR) light/acidic pH-triggered drug release, and low toxicity were developed for potentiated photothermal therapy. Importantly, they showed excellent biocompatibility in vivo and in vitro. NbTe2 nanosheets loaded with integrated stress response inhibitors (ISRIB) could achieve chemo-photothermal therapy of tumors through the ATF4-ASNS signaling axis. Ultrathin 1T-phase NbTe2 single-crystalline nanosheets with unique photothermal properties, drug loading rate and safety provide dramatic possibilities in biomedical applications, such as tissue imaging, photothermal therapeutics and pharmaceutics.

4.
Biol Reprod ; 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34363387

RESUMO

Previous studies reported that, with aging, Leydig cell intracellular antioxidants are reduced in concentration and intracellular ROS levels increase, suggesting that oxidant/antioxidant imbalance may contribute to the reduced testosterone production that characterizes the aging cells. As yet, little is known about how the Leydig cell oxidant/antioxidant environment is regulated. Sirt1, an enzyme that deacetylates transcription factors, and the transcription factor Nrf2, have been shown to be associated with cellular response to oxidative stress. We hypothesized that Sirt1 and/or Nrf2 might be involved in regulating the oxidant/antioxidant environment of Leydig cells, and therefore testosterone production. We found that Sirt1 and Nrf2 are present in the Leydig cells of Brown Norway rats, though reduced in aged cells. In MA-10 cells in which Sirt1 or Nrf2 were suppressed by nicotinamide (NAM) or ML385, respectively, or in which siRNAs were used for knockdown of Sirt1 or Nrf2, increased ROS levels and decreased progesterone production occurred. In rat Leydig cells, inhibition of Sirt1 by culturing the cells with NAM resulted in increased ROS and reduced testosterone production, and subsequent removal of NAM from the culture medium resulted in increased testosterone production. Activation of rat Leydig cells Sirt1 with honokiol or of Nrf2 with sulforaphane resulted in the maintenance of testosterone production despite the exposure of the cells to oxidizing agent. These results, taken together, suggest that Sirt1 and Nrf2 are involved in maintaining the Leydig cell oxidant/antioxidant environment, and thus in maintaining steroid production.

5.
Accid Anal Prev ; 161: 106330, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34419652

RESUMO

To ensure safety, it is necessary to test the connected vehicle (CV) technology before application. The goal of this study is to provide a case reference for the testing of the connected vehicle technology. The connected vehicle technology test platform is built based on the driving simulator. Taking fog zone, tunnel zone, and work zone as analysis cases, drivers were invited to participate in driving simulation experiments, related data was collected, and the impact of connected vehicle technology on driving behavior and safety was analyzed. The results of the fog zone imply that drivers have a high degree of compliance with the connected vehicle technology. However, it also increases the visual workload of drivers to a certain extent. The results of the tunnel zone indicate that the connected vehicle technology can enhance driving safety by enabling drivers to remain cautious. The results of the work zone demonstrate that the connected vehicle technology is able to promote drivers' ability of controlling speed and lane-changing. Overall, the results show that the connected vehicle technology has a positive effect on enhancing driving behavior and safety. The research framework and the development of the connected vehicle technology test platform based on the driving simulator given in the paper are dynamic and reproducible, which provides a reference for researchers in related fields, and the case analysis in this paper enriches the research of connected vehicle technology.


Assuntos
Acidentes de Trânsito , Condução de Veículo , Acidentes de Trânsito/prevenção & controle , Simulação por Computador , Humanos , Tecnologia
6.
Biomater Sci ; 9(18): 6023-6036, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34323260

RESUMO

Platinum-based anticancer drugs can inhibit the growth of cancer cells by disrupting DNA replication, which makes them widely applicable in clinics for treating tumors and cancers. However, owing to the intrinsic or acquired drug resistance and severe side effects caused in the treatment, their successful clinical applications have been limited. Various strategies have been used to address these challenges. Nanocarriers have been used for platinum drug delivery because they can be effectively deposited in tumor tissues to reduce the damage to normal organs for an enhanced permeability and retention (EPR) effect. Furthermore, for synergizing the function of platinum-based drugs with different mechanisms to decrease the toxicities, multicomponent chemotherapy has become an imperative strategy in clinical cancer treatments. This review aims to introduce the mechanisms of action and limitations of platinum-based drugs in clinics, followed by providing the current advancement of nanocarriers including lipids, polymers, dendrimers, micelles and albumin for platinum drug delivery in cancer treatments. In addition, multicomponent chemotherapy based on platinum drugs is introduced in detail. Finally, the prospects of multicomponent chemotherapy for cancer treatment are discussed as well.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Micelas , Neoplasias/tratamento farmacológico , Platina/uso terapêutico
7.
Chem Commun (Camb) ; 57(51): 6249-6252, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34059853

RESUMO

A hydrophilic probe is employed to enrich exosomes from three kinds of cancer cells by TiO2-phosphate interaction and exosomal glycoproteins by hydrophilic interaction in succession. The probe performs efficiently in both the enrichment processes. And the analytical results confirm that unique exosomal glycoproteins can distinguish parent exosomes from others.


Assuntos
Exossomos/metabolismo , Glicoproteínas/análise , Sondas Moleculares/metabolismo , Linhagem Celular Tumoral , Óxido Ferroso-Férrico/química , Glutationa/química , Glutationa/metabolismo , Glicoproteínas/metabolismo , Glicosilação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas de Magnetita/química , Sondas Moleculares/química , Proteômica/métodos , Titânio/química
8.
Nat Commun ; 12(1): 3876, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162856

RESUMO

Testicular development and function rely on interactions between somatic cells and the germline, but similar to other organs, regenerative capacity declines in aging and disease. Whether the adult testis maintains a reserve progenitor population remains uncertain. Here, we characterize a recently identified mouse testis interstitial population expressing the transcription factor Tcf21. We found that TCF21lin cells are bipotential somatic progenitors present in fetal testis and ovary, maintain adult testis homeostasis during aging, and act as potential reserve somatic progenitors following injury. In vitro, TCF21lin cells are multipotent mesenchymal progenitors which form multiple somatic lineages including Leydig and myoid cells. Additionally, TCF21+ cells resemble resident fibroblast populations reported in other organs having roles in tissue homeostasis, fibrosis, and regeneration. Our findings reveal that the testis, like other organs, maintains multipotent mesenchymal progenitors that can be potentially leveraged in development of future therapies for hypoandrogenism and/or infertility.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Homeostase/genética , Células-Tronco Mesenquimais/metabolismo , Regeneração/genética , Testículo/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem da Célula/genética , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Célula Única/métodos , Testículo/citologia
9.
Toxicol Appl Pharmacol ; 415: 115440, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33549592

RESUMO

Perfluoroundecanoic acid (PFUnA) is one of long-chain perfluoroalkyl carboxylic acids. However, the effect of PFUnA on pubertal development of Leydig cells remains unclear. The goal of this study was to investigate the effect of PFUnA on Leydig cell development in pubertal male rats. We orally dosed male Sprague-Dawley rats (age 35 days) with PFUnA at doses of 0, 1, 5, and 10 mg/kg/day from postnatal day (PND) 35 to PND 56. Serum testosterone and luteinizing hormone levels were remarkably reduced by PFUnA at ≥1 mg/kg while serum follicle-stimulating hormone levels were lowered at 5 and 10 mg/kg. PFUnA down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Hsd11b1, Insl3, Nr5a1, Fshr, Dhh, Sod1, and Sod2 and their proteins in the testis and the expression of Lhb and Fshb in the pituitary. PFUnA reduced Leydig cell number at 5 and 10 mg/kg. PFUnA induced oxidative stress and increased autophagy. These may result from the inhibition of phosphorylation of mTOR, AKT1, AKT2, and ERK1/2 in the testis. In conclusion, PFUnA exhibits inhibitory effects on pubertal Leydig cell development possibly via inducing oxidative stress and increasing autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Ácidos Graxos/toxicidade , Fluorcarbonetos/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fatores Etários , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Hormônio Foliculoestimulante/sangue , Regulação Enzimológica da Expressão Gênica , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Hormônio Luteinizante/sangue , Masculino , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Ratos Sprague-Dawley , Desenvolvimento Sexual , Transdução de Sinais , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testosterona/sangue
10.
Mol Cell Endocrinol ; 525: 111179, 2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33515640

RESUMO

Peritubular stem Leydig cells (SLCs) have been identified from rat testicular seminiferous tubules. However, no stem cells for peritubular myoid cells have been reported in the adult testis so far. In the present study, we tested the hypothesis that the peritubular SLCs are multipotent and able to form either Leydig or myoid cells. Using cultured tubules, we show that in the presence of PDGFAA and luteinizing hormone, SLCs became testosterone-producing Leydig cells, while in the presence of PDGFBB and TGFB, the cells formed α-smooth muscle actin-expressing myoid cells. This multipotency was also confirmed by culture of isolated CD90+ SLCs. These results suggest that these stem cells outside the myoid layer are multipotent and give rise to either Leydig or myoid cells, depending on the inducing factors. These cells may serve as a common precursor population for maintaining homeostasis of both Leydig and myoid cell populations in the adult testis.


Assuntos
Diferenciação Celular , Linhagem da Célula , Células Intersticiais do Testículo/citologia , Túbulos Seminíferos/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ratos Sprague-Dawley , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Antígenos Thy-1/metabolismo
11.
J Cell Physiol ; 236(4): 3073-3082, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32974910

RESUMO

Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.

12.
Environ Pollut ; 272: 115535, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33223333

RESUMO

Perfluorooctane sulfonate (PFOS) is a man-made fluorosurfactant widely used in industry and consumer products. Previous studies with rats suggested that gestational exposure to PFOS may affect the lung development in the offspring. The mechanism, however, is still unknown. In the present study, we have exposed 24 pregnant SD rats from gestational day 12-18 to different doses of PFOS (0, 1 or 5 mg/kg BW/day). The lungs of the offspring were analyzed at postnatal days 1, 3, 7 and 14. PFOS treatment appeared to reduce the alveolar numbers, resulting in simplified alveolar structure and thickened alveolar septa. Also, PFOS treated animals had increased lung inflammation with up-regulated inflammasome associated proteins NLRP3, ASC, Caspase-1 and GSDMD and increased inflammatory cytokines IL-18 and IL-1ß. At the same time, HIF-1α and VEGFA were significantly down-regulated. Since HIF-1α and VEGFA are critical factors promoting alveolar development and pulmonary angiogenesis, these results suggested that PFOS may also affect lung development by inhibiting HIF-1α and VEGFA expression. Our results here indicate that gestational exposure to PFOS may affect lung development in the offspring with pathological characteristics similar to bronchopulmonary dysplasia (BPD), a severe lung developmental defect. The results also suggest that environmental factors such as PFOS may contribute to the increasing incidence of developmental lung diseases, such as BPD, by elevating lung inflammation and inhibiting lung development.


Assuntos
Ácidos Alcanossulfônicos , Fluorcarbonetos , Ácidos Alcanossulfônicos/toxicidade , Animais , Feminino , Fluorcarbonetos/toxicidade , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Pulmão , Exposição Materna , Proteínas de Ligação a Fosfato , Gravidez , Ratos , Ratos Sprague-Dawley
13.
Chemosphere ; 262: 127855, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32799149

RESUMO

Studies have shown that phthalates are capable of affecting the development and functions of male reproductive system. The effect of phthalates on Leydig cell functions is well documented. However, little is known about their potential effects on the functions of stem Leydig cells (SLC). In the present study, we have examined the effects of mono-(2-ethylhexyl) phthalate (MEHP) on SLC functions in vitro by culturing seminiferous tubules and isolated SLCs. The results indicate that MEHP can significantly inhibit the proliferation and differentiation of SLCs in both the organ and cell culture systems. Interestingly, the minimal effective concentration that is able to affect SLC function was lower in the tubule culture system (1 µM) than in the isolated cells (10 µM), suggesting a possible involvement of the niche cells. Also, MEHP appeared to affect both the efficiency of SLCs to form Leydig cells and a selected group of Leydig cell-specific genes, including Lhcgr, Scarb1, Hsd3b1, Cyp17a1, Star, Srd5a1, Akr1c14, Insl3, Hao2 and Pah. Since SLCs are multipotent, we also tested the effect of MEHP on the differentiation of SLCs to adipocytes. Though MEHP by itself can not specify SLCs into adipocyte lineage, it indeed significantly increased the adipogenic activity of SLCs if used with an adipocyte inducing medium by up-regulation of multiple adipogenic-related genes, including Pparg and Cebpa. Overall, the results indicate that MEHP inhibits SLCs differentiating into Leydig lineage while stimulates the differentiating potential of SLCs to adipocytes.


Assuntos
Células Intersticiais do Testículo/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Adipócitos , Animais , Diferenciação Celular/efeitos dos fármacos , Dietilexilftalato/farmacologia , Masculino , Túbulos Seminíferos/citologia , Esteroide 17-alfa-Hidroxilase , Testosterona/farmacologia
14.
Sensors (Basel) ; 20(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228069

RESUMO

We are developing a social mobile robot that has a name calling function using a face memorization system. It is said that it is an important function for a social robot to call to a person by her/his name, and the name calling can make a friendly impression of the robot on her/him. Our face memorization system has the following features: (1) When the robot detects a stranger, it stores her/his face images and name after getting her/his permission. (2) The robot can call to a person whose face it has memorized by her/his name. (3) The robot system has a sleep-wake function, and a face classifier is re-trained in a REM sleep state, or execution frequencies of information processes are reduced when it has nothing to do, for example, when there is no person around the robot. In this paper, we confirmed the performance of these functions and conducted an experiment to evaluate the impression of the name calling function with research participants. The experimental results revealed the validity and effectiveness of the proposed face memorization system.

15.
J Hazard Mater ; 400: 123234, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32585522

RESUMO

Gallium is widely used in the field of semiconductors, and is mainly recovered as a by-product from other production processes utilizing metals such as aluminum and zinc. As a waste generated during the production of yellow phosphorus, yellow phosphorus flue dust is a potential resource for recovery of gallium. In this study, vacuum carbothermic reduction technology was applied to extract gallium from yellow phosphorus flue dust. Under the optimal conditions of 1323 K, 40 min holding time, 50 wt% carbon content, and 1-10 Pa, the recovery rate of gallium was 92.5 %. The condensate was analyzed and the enrichment area of gallium in the condensation zone was determined. No hazardous gases and materials were generated during the process. Compared with other methods of recovering gallium from yellow phosphorus flue dust by hydrometallurgical process, this study has the advantages of short process, easy collection of products, low energy consumption. Overall, this work demonstrates a new and environmentally friendly method for the recovery of gallium from yellow phosphorus flue dust, and also provides a reference value for the comprehensive utilization of this material.

16.
Biomaterials ; 255: 120158, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32544717

RESUMO

For successful treatment of EBV-associated tumors immune tolerance must be broken. While most studies of EBV-associated tumor vaccines have focused on augmenting tumor-specific effector T cells, the effects of these vaccines on the immune-suppressive tumor microenvironment have not been investigated. Here, we describe the manufacture of a nanovaccine using tannic acid (TA) and a newly constructed protein antigen for EBV-associated tumors with interferon-α (IFN-α) or CpG as adjuvants. TA as a biocompatible material from plant self-assembles with antigens and adjuvants via hydrogen bonding to form well-defined nanoparticulate vaccines by flash nanocomplexation, a scalable yet controllable technique. By targeting lymph nodes, the nanovaccine co-loaded with CpG adjuvant induces strong immune activation and exhibits efficient inhibition tumorigenesis. Moreover, the nanovaccine combining with anti-PD-L1 results a marked decrease in tumor size and prolonged survival of tumor-bearing mice by decreasing infiltration of regulatory T cells to the tumor lesion. This suggests that the nanovaccine can reverse immune checkpoint inhibitor resistance by remodeling the tumor microenvironment. Thus, this study shows a promising strategy for treatment of EBV-positive tumors in patients.


Assuntos
Vacinas Anticâncer , Neoplasias , Animais , Herpesvirus Humano 4 , Humanos , Imunoterapia , Camundongos , Microambiente Tumoral
17.
Gene ; 731: 144335, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31927007

RESUMO

Deleted in azoospermia-like (DAZL) is essential for mammalian spermatogenesis as it regulates proliferation, development, maturation and functional maintenance of male germ cells. Its expression and regulation vary with different species or in the same animal at different developmental stages, and despite its importance, very little is known about its roles in sheep, especially Tibetan sheep. To investigate the expression patterns and regulatory roles of DZAL in Tibetan sheep testis, testicular tissue was isolated from sheep at three crucial development stages: 3 months old, 1 year old and 3 years old. Using quantitative real-time PCR and Western blot, we found that DAZL mRNA first decreased and then increased with advancing age, while DAZL protein exhibited an opposite expression pattern, with first increased and subsequently decreased levels. Immunohistochemistry and immunofluorescence revealed that DAZL protein was located predominantly in the cytoplasm of Leydig cells and in both the cytoplasm and nucleus of spermatids. ELISA indicated that testosterone content within developing testes was first enhanced and then declined. Our results, taken together, demonstrate, for the first time, that DAZL gene is involved in Tibetan sheep spermatogenesis by regulating the development of spermatids in post-pubertal rams, along with a novel role in functional maintenance of Leydig cells in postnatal rams.


Assuntos
Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ovinos , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Animais , Feminino , Perfilação da Expressão Gênica/veterinária , Regulação da Expressão Gênica no Desenvolvimento , Células Intersticiais do Testículo/fisiologia , Masculino , Proteínas de Ligação a RNA/fisiologia , Diferenciação Sexual/genética , Maturidade Sexual/genética , Ovinos/genética , Ovinos/crescimento & desenvolvimento , Ovinos/metabolismo , Espermátides/fisiologia , Espermatogênese/genética , Testosterona/metabolismo , Tibet , Distribuição Tecidual
18.
Biol Reprod ; 102(2): 489-498, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31504200

RESUMO

The Leydig cells of the mammalian testis produce testosterone (T) in response to luteinizing hormone (LH). In rats and men with reduced serum T levels, T replacement therapy (TRT) will raise T levels, but typically with suppressive effects on sperm formation. The rate-determining step in T formation is the translocation of cholesterol to the inner mitochondrial membrane, mediated by protein-protein interactions of cytosolic and outer mitochondrial membrane proteins. Among the involved proteins is cholesterol-binding translocator protein (TSPO) (18 kDa TSPO). We hypothesized that in contrast to TRT, the administration of the TSPO agonist N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27), by stimulating the ability of the Leydig cells to produce T, would result in the elevation of serum T levels while maintaining intratesticular T concentration and therefore without suppression of spermatogenesis. Age-related reductions in both serum and intratesticular T levels were seen in old Brown Norway rats. Both exogenous T and FGIN-1-27 increased serum T levels. With exogenous T, serum LH and Leydig cell T formation were suppressed, and intratesticular T was reduced to below the concentration required to maintain spermatogenesis quantitatively. In contrast, FGIN-1-27 stimulated Leydig cell T formation, resulting in increased serum T without reductions in intratesticular T concentrations or in testicular sperm numbers. FGIN-1-27 also significantly increased serum and intratesticular T levels in rats made LH-deficient by treatment with the gonadotropin-releasing hormone antagonist cetrorelix. These results point to a possible approach to increasing serum T without negative effects on spermatogenesis, based upon stimulating T production by the Leydig cells themselves rather than administering T exogenously.


Assuntos
Células Intersticiais do Testículo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Envelhecimento/metabolismo , Animais , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Ácidos Indolacéticos/farmacologia , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/sangue , Masculino , Ratos , Contagem de Espermatozoides , Testículo/metabolismo , Testosterona/sangue
19.
J Magn Reson Imaging ; 51(6): 1810-1820, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31710413

RESUMO

BACKGROUND: It is difficult to prospectively differentiate between benign (World Health Organization [WHO] I) and nonbenign (WHO II and III) meningiomas. PURPOSE: To evaluate the feasibility of preoperative differentiation between benign and nonbenign meningiomas by using texture analysis from multiparametric MR data. STUDY TYPE: Retrospective. SUBJECTS: In all, 184 patients with meningioma (139 benign and 45 nonbenign) were included as the training cohort and 79 patients with meningioma (60 benign and 19 nonbenign) were included as the external validation cohort. FIELD STRENGTH/SEQUENCE: T1 -weighted, T2 -weighted, and contrast-enhanced T1 -weighted imaging were performed on 1.5 or 3.0T MR systems from two centers. ASSESSMENT: Tumor segmentation and radiological characteristic (RC) evaluation were performed by experienced radiologists. The texture features were extracted from preprocessed images and combined with RCs, and then the combined features were reduced by using a two-step feature selection. Three single-sequence models and a multiparametric MRI (the combination of single sequences) model were constructed and then evaluated with the external validation cohort. STATISTICAL TESTS: Area under receiver operating characteristic curve (AUC), accuracy (Acc), f1-score (F1), sensitivity (Sen), and specificity (Spec), were calculated to quantify the performance of the models. RESULTS: Among the four texture models, the multiparametric MRI model demonstrated the best performance for differentiating between benign and nonbenign meningiomas in both the training and external validation cohorts (AUC 0.91, Acc 89%, F1 0.88, Sen 0.93, and Spec 0.87 in the training cohort; AUC 0.83, Acc 80%, F1 0.77, Sen 0.84, and Spec 0.78 in the validation cohort). DATA CONCLUSION: Nonbenign meningiomas might be preoperatively differentiated from benign meningiomas by using texture analysis from multiparametric MR data. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1810-1820.


Assuntos
Neoplasias Meníngeas , Meningioma , Imageamento por Ressonância Magnética Multiparamétrica , Humanos , Meningioma/diagnóstico por imagem , Curva ROC , Estudos Retrospectivos
20.
Andrology ; 8(3): 719-730, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31738001

RESUMO

BACKGROUND: Cholesterol import into the mitochondria of steroid-producing cells is the rate-determining step in steroidogenesis. Numerous studies have provided evidence that the cholesterol-binding translocator protein (18 kDa TSPO) plays an important role in cholesterol translocation into mitochondria and that it also might act on cholesterol homeostasis. Several TSPO-specific ligands have been shown to increase steroid production in vitro and in vivo. OBJECTIVES: The present study assessed the effects of the TSPO drug ligand FGIN-1-27 on cholesterol accumulation and lipid droplet formation in relationship to steroid formation. MATERIALS AND METHODS: Using MA-10 and primary Leydig cells, immunocytochemical and molecular methods were used to examine cholesterol accumulation, the formation of lipid droplets, and steroid formation in response to LH and FGIN-1-27. Additionally, we determined the effects of Tspo knockout by CRISPR/Cas9, and of siRNA knockdowns of Tspo and Plin2 (Perilipin 2; also known as adipose differentiation-related protein, ADFP) on LH- and FGIN-1-27-induced steroidogenesis. RESULTS: In response to LH and FGIN-1-27, cultured MA-10 cells and primary Leydig cells increased steroid formation, cholesterol accumulation, and lipid droplet formation. Cholesterol accumulation in the lipid droplets also was increased in Tspo knockout cells. Knockout of Tspo or its knockdown in MA-10 cells resulted in reduced progesterone formation in response to both LH and FGIN-1-27, as did knockdown of Plin2. Steroid production also was inhibited by the cholesteryl ester hydrolase inhibitor diethylumbelliferyl phosphate. DISCUSSION AND CONCLUSION: These results support the conclusion that FGIN-1-27 stimulates steroid formation by increasing TSPO-mediated cholesterol translocation into the inner mitochondria for steroidogenesis, as well as into the cytosol for lipid droplet formation. FGIN-1-27 also increased steroid formation at least in part by inducing the conversion of cholesteryl ester located in lipid droplets to cholesterol, thus making available more substrate for steroid formation.


Assuntos
Proteínas de Transporte/metabolismo , Colesterol/metabolismo , Células Intersticiais do Testículo/metabolismo , Gotículas Lipídicas/metabolismo , Receptores de GABA-A/metabolismo , Esteroides/biossíntese , Animais , Masculino , Ratos , Ratos Sprague-Dawley
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