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1.
Adv Mater ; : e1907833, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32270552

RESUMO

Microbe-mediated mineralization is ubiquitous in nature, involving bacteria, fungi, viruses, and algae. These mineralization processes comprise calcification, silicification, and iron mineralization. The mechanisms for mineral formation include extracellular and intracellular biomineralization. The mineral precipitating capability of microbes is often harnessed for green synthesis of metal nanoparticles, which are relatively less toxic compared with those synthesized through physical or chemical methods. Microbe-mediated mineralization has important applications ranging from pollutant removal and nonreactive carriers, to other industrial and biomedical applications. Herein, the different types of microbe-mediated biomineralization that occur in nature, their mechanisms, as well as their applications are elucidated to create a backdrop for future research.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32207559

RESUMO

In the progression of osteoarthritis, pathological calcification in the affected joint is an important feature. The role of these crystallites in the pathogenesis and progression of osteoarthritis is controversial; it remains unclear whether they act as a disease initiator or are present as a result of joint damage. Recent studies reported that the molecular mechanisms regulating physiological calcification of skeletal tissues are similar to those regulating pathological or ectopic calcification of soft tissues. Pathological calcification takes place when the equilibrium is disrupted. Calcium phosphate crystallites are identified in most affected joints and the presence of these crystallites is closely correlated with the extent of joint destruction. These observations suggest that pathological calcification is most likely to be a disease initiator instead of an outcome of osteoarthritis progression. Inhibiting pathological crystallite deposition within joint tissues therefore represents a potential therapeutic target in the management of osteoarthritis.

3.
Sci Transl Med ; 12(526)2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941827

RESUMO

The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting ß-amyloid (Aß) and tau, two key pathological components of AD pathogenesis. Our results show that Aß oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3ß (GSK3ß) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3ß/tau activation in response to nanomolar accumulations of extracellular Aß, which is 50- to 100-fold lower than the amount required to activate GSK3ß by Aß alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aß proteotoxicity, which might have strong implications for the interpretation of Aß clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

4.
Bone ; 133: 115229, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31926929

RESUMO

ß2-adrenergic signal transduction in mesenchymal stem cells (MSCs) induces subchondral bone loss in osteoarthritis (OA) of temporomandibular joints (TMJs). However, whether conditional deletion of ß2-adrenergic receptor (Adrb2) in nestin+ MSCs can alleviate TMJ-OA development remains unknown. In this study, nestin-Cre mice were crossed with Adrb2 flox mice to generate mice lacking Adrb2 expression specifically in the nestin+ MSCs (Adrb2-/-), and TMJ-OA development in such mice was investigated. Adrb2 flox mice (Adrb2+/+) and Adrb2-/- mice were subjected to unilateral anterior crossbite (UAC), while mice in the control group were subjected to sham operation. Adrb2+/+ and Adrb2-/- mice in the control group showed no distinguishable phenotypic changes in body weight and length, mandibular condylar size, and other histomorphological parameters of the condylar subchondral bone. A significant increase in subchondral bone loss and cartilage degradation was observed in Adrb2+/+ UAC mice; the former was characterized by decreased bone mineral density, bone volume fraction, and trabecular plate thickness, and increased trabecular separation, osteoclast number and osteoclast surface, and pro-osteoclastic factor expression; the latter was characterized by decreased cartilage thickness, chondrocyte density, proteoglycan area, and collagen II and aggrecan expression, but increased matrix metalloproteinase and alkaline phosphatase expression and percentage area of calcified cartilage. Adrb2 deletion in nestin+ MSCs largely attenuated UAC-induced increase in condylar subchondral bone loss, cartilage degradation, and aberrant calcification at the osteochondral interface. Thus, Adrb2-expressing MSCs in the condylar subchondral bone play an important role in TMJ-OA progression and may serve as novel therapeutic targets for TMJ-OA.

5.
Spectrochim Acta A Mol Biomol Spectrosc ; 229: 117885, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31813719

RESUMO

It is well known that, the incorporation of halide will improve the optical properties of chalcogenide glasses with a broad transparent range. Here, we investigated the optical properties and structure of Ge-As-Se-I glasses in order to disclose the role of halogen iodine in the formation of chalcogenide glassy network. It was found that, refractive index, zero dispersion wavelength and glass transition temperature Tg decrease with increasing iodine contents, while the cut-off edge (λvis) in the shorter wavelength blue-shifts apparently, and the whole transmission range is expanded widely. The glasses show good chemical stability against moisture. The zero dispersion wavelength of the glasses can be decreased to 4.32 µm by iodine-doping. The evolution of Raman spectra of the glasses indicates that, there is no obvious peak of iodine in Ge-As-Se-I glasses and the dominated glassy network are still the (GeSe) heteropolar bonds.

6.
Opt Lett ; 44(22): 5545-5548, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730104

RESUMO

A novel low-loss selenium-based chalcohalide fiber, with a low zero-dispersion wavelength, was prepared by an innovative preparation process. The composition optimized fiber has a wide transmission range of up to 11.5 µm, a lowest fundamental mode zero-dispersion wavelength of 4.03 µm, and a minimum optical loss of 1.12 dB/m at 6.4 µm, which provides a possibility to replace As2S3 and As2Se3 in a cascade of ZrF4-BaF2-LaF3-AlF3-NaF(ZBLAN)-As2S3-As2Se3 fiber in the practical all-fiberized supercontinuum (SC) source. Meanwhile, the broadest SC spectrum, ∼1.2 to 15.2 µm, was achieved by pumping a 12-cm-long fiber with a femtosecond laser at a deep anomalous-dispersion region. Furthermore, simulations are adopted to interpret the results as well as to demonstrate spectral evolution along the fiber. To the best of our knowledge, this is the broadest SC spectrum reported in any selenium-based chalcogenide fiber.

7.
Oncol Lett ; 18(2): 1365-1371, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423199

RESUMO

Expression of Bmi-1 in gallbladder carcinoma and its clinicopathology and mechanisms of regulation of human gallbladder carcinoma cell proliferation were investigated. Fifty cases of gallbladder carcinoma specimens and 15 normal gallbladder tissues were subjected to immunohistochemical staining to detect the expression of Bmi-1 gene in gallbladder carcinoma and normal gallbladder tissues. Clinicopathological features were compared and analyzed. Bmi1-si RNA and Bmi1-NC vectors were transfected into GBC-SD gallbladder cancer cell lines. Expression of Bmi-1 in GBC-SD-Bmi1-si RNA, GBC-SD-Bmi1-NC and GBC-SD cells was detected by RT-qPCR. Cell proliferation was detected by CCK-8 assay. Flow cytometry was used to detect cell apoptosis. Protein expression was detected by western blot analysis. The positive expression rate of Bmi-1 protein in gallbladder carcinoma tissues was significantly higher than that in normal gallbladder tissues (P<0.05). Expression of Bmi-1 protein in gallbladder carcinoma was correlated with tumor differentiation and stage (P<0.05). Expression level of Bmi-1 in GBC-SD-Bmi1-si RNA was significantly lower than that in GBC-SD-Bmi1-NC and GBC-SD cells. The apoptosis rate of GBC-SD-Bmi1-si RNA cells was significantly higher than that of the two control groups. Compared with the control groups, the expression of anti-apoptotic protein Bcl-2 in GBC-SD-Bmi1-si RNA cells decreased, while the expression of proapoptotic protein Bax and caspase 3 increased, and the expression levels of cyclin D1 and CDK2 decreased. Positive expression rate of Bmi-1 protein in gallbladder carcinoma tissues was significantly higher than that in normal gallbladder tissue. Following inhibition of the expression of Bmi-1 in gallbladder cancer cell line GBC-SD, the growth cycle of cancer cells was prolonged and apoptotic rate increased. The results showed that a decreased expression of cyclin D1 and CDK2 may lead to delayed cell proliferation, decreased expression of anti-apoptotic protein Bcl-2, increased expression of pro-apoptotic protein Bax and caspase 3, leading to increased apoptosis.

8.
Oral Dis ; 25(7): 1759-1768, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357246

RESUMO

OBJECTIVES: To detect whether early growth response 1 (EGR1) in peripheral blood leucocytes (PBLs) indicates temporomandibular joint (TMJ) osteoarthritis (OA) lesions. MATERIALS AND METHODS: Egr1 mRNA expression levels in PBLs were detected in eight malocclusion patients without temporomandibular disorder (TMD) signs and 16 malocclusion patients with clinical TMD signs with (eight) or without (eight) imaging signs of TMJ OA. Twelve 6-week-old rats were randomized to a control group and a unilateral anterior crossbite (UAC) group and were sampled at 4 weeks. The Egr1 mRNA expression levels in PBLs and protein expression levels in different orofacial tissues were measured. RESULTS: Patients with TMD signs with/without TMJ OA diagnosis showed lower Egr1 mRNA expression levels in PBLs than patients without TMD signs. The lower Egr1 mRNA expression was also found in the PBLs of UAC rats, which were induced to exhibit early histo-morphological signs of TMJ OA lesions. In subchondral bone of UAC rats, EGR1 protein expression was decreased, co-localization of EGR1 with osterix or dentin matrix protein-1 was identified, and the number of EGR1 and osterix double-positive cells was reduced (all p < .05). CONCLUSION: Egr1 reduction in PBLs potentially indicates subchondral bone OA lesions at an early stage.


Assuntos
Cartilagem Articular , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Côndilo Mandibular , Osteoartrite , Transtornos da Articulação Temporomandibular/etiologia , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Má Oclusão/complicações , RNA Mensageiro , Distribuição Aleatória , Ratos , Articulação Temporomandibular , Transtornos da Articulação Temporomandibular/metabolismo , Tomografia Computadorizada por Raios X , Fatores de Transcrição/análise
10.
Dev Biol ; 452(1): 1-7, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042497

RESUMO

Cardiomyocytes undergo dramatic changes during the fetal to neonatal transition stage to adapt to the new environment. The molecular and genetic mechanisms regulating these changes remain elusive. In this study, we showed Sema6D as a novel signaling molecule regulating perinatal cardiomyocyte proliferation and maturation. SEMA6D is a member of the Semaphorin family of signaling molecules. To reveal its function during cardiogenesis, we specifically inactivated Sema6D in embryonic cardiomyocytes using a conditional gene deletion approach. All mutant animals showed hypoplastic myocardial walls in neonatal hearts due to reduced cell proliferation. We further revealed that expression of MYCN and its downstream cell cycle regulators is impaired in late fetal hearts in which Sema6D is deleted, suggesting that SEMA6D acts through MYCN to regulate cardiomyocyte proliferation. In early postnatal mutant hearts, expression of adult forms of sarcomeric proteins is increased, while expression of embryonic forms is decreased. These data collectively suggest that SEMA6D is required to maintain late fetal/early neonatal cardiomyocytes at a proliferative and less mature status. Deletion of Sema6D in cardiomyocytes led to reduced proliferation and accelerated maturation. We further examined the consequence of these defects through echocardiographic analysis. Embryonic heart deletion of Sema6D significantly impaired the cardiac contraction of male adult hearts, while having a minor effect on female mutant hearts, suggesting that the effect of Sema6D-deletion in adult hearts is sex dependent.


Assuntos
Proliferação de Células , Embrião de Mamíferos/embriologia , Coração/embriologia , Miócitos Cardíacos/metabolismo , Organogênese , Semaforinas/metabolismo , Animais , Ecocardiografia , Embrião de Mamíferos/citologia , Deleção de Genes , Coração/diagnóstico por imagem , Masculino , Camundongos , Camundongos Transgênicos , Contração Miocárdica , Miócitos Cardíacos/citologia , Semaforinas/genética , Desenvolvimento Sexual
11.
Exp Ther Med ; 17(5): 3935-3942, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31007736

RESUMO

Liver fibrosis is the most common pathological outcome and the most severe complication of chronic liver diseases. Accumulating evidence suggests that miRNAs are involved in cell proliferation, differentiation, apoptosis, as well as the occurrence and development of various diseases. In this study, we found that the expression of let-7a was markedly decreased in the liver tissue samples and blood samples from patients with liver fibrosis compared with healthy volunteers. Furthermore, let-7a was downregulated in the liver tissues and blood samples in mouse models of liver fibrosis. Further analysis indicated that let-7a suppresses the activation level of hepatic stellate cells (HSCs). In addition, overexpression of let-7a reduced cell viability and promoted apoptosis of HSCs. Western blot analysis showed that let-7a might inhibit HSCs through TGFß/SMAD signaling pathway. The present study provides a potential accurate target and vital evidence to better understand the underlying pathogenesis for early diagnosis and treatment of liver fibrosis.

12.
Opt Express ; 27(3): 2036-2043, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30732248

RESUMO

We have prepared a well-structured tellurium chalcogenide (ChG) fiber with a specialized double cladding structure by an improved extrusion method, and experimentally demonstrated an ultra-flat mid-infrared (MIR) supercontinuum (SC) generation in such a fiber. The step-index fiber had an optical loss of <1 dB/m in a range from 7.4 to 9.7 µm with a minimum loss of 0.69 dB/m at 7.87 µm. Simulation showed that an all-normal dispersion profile can be realized in this double cladding tellurium fiber. An ultra-flat MIR SC spectrum (~3.2-12.1µm at -10 dB, ~2-14 µm at -30 dB) was generated from a 22-cm long fiber pumped with a femtosecond laser at 5 µm (~150 fs, 1 kHz). Then the degree of coherence was calculated out based on a simulation, showing that a high coherent MIR SC (from 2.9 to 13.1 µm) can be generated in this double-cladding tellurium fiber.

13.
Stem Cells ; 37(4): 453-462, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30629778

RESUMO

Tumorigenic and non-neoplastic tissue injury occurs via the ischemic microenvironment defined by low oxygen, pH, and nutrients due to blood supply malfunction. Ischemic conditions exist within regions of pseudopalisading necrosis, a pathological hallmark of glioblastoma (GBM), the most common primary malignant brain tumor in adults. To recapitulate the physiologic microenvironment found in GBM tumors and tissue injury, we developed an in vitro ischemic model and identified chromodomain helicase DNA-binding protein 7 (CHD7) as a novel ischemia-regulated gene. Point mutations in the CHD7 gene are causal in CHARGE syndrome (a developmental disorder causing coloboma, heart defects, atresia choanae, retardation of growth, and genital and ear anomalies) and interrupt the epigenetic functions of CHD7 in regulating neural stem cell maintenance and development. Using our ischemic system, we observed microenvironment-mediated decreases in CHD7 expression in brain tumor-initiating cells and neural stem cells. Validating our approach, CHD7 was suppressed in the perinecrotic niche of GBM patient and xenograft sections, and an interrogation of patient gene expression datasets determined correlations of low CHD7 with increasing glioma grade and worse patient outcomes. Segregation of GBM by molecular subtype revealed a novel observation that CHD7 expression is elevated in proneural versus mesenchymal GBM. Genetic targeting of CHD7 and subsequent gene ontology analysis of RNA sequencing data indicated angiogenesis as a primary biological function affected by CHD7 expression changes. We validated this finding in tube-formation assays and vessel formation in orthotopic GBM models. Together, our data provide further understanding of molecular responses to ischemia and a novel function of CHD7 in regulating angiogenesis in both neoplastic and non-neoplastic systems. Stem Cells 2019;37:453-462.

14.
Minerva Med ; 110(2): 107-114, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30371044

RESUMO

BACKGROUND: Foam cells are characteristic pathologic cells of atherosclerosis (AS), they are lipid-loaded macrophages present on atherosclerotic lesions. A large number of studies has shown that the pathogenesis of AS is the result of interactions between the lipid metabolism disorders and chronic inflammatory responses in the body. Albiflorin can inhibit the inflammatory response and it has shown a therapeutic effect on certain inflammatory diseases. METHODS: In this study, a human acute monocytic leukemia cell line (THP-1)-derived foam cell model was established via oxidized low-density lipoprotein (ox-LDL) to observe the effects of albiflorin on the AS-characteristic foam cells. RESULTS: Our results showed that, after the treatment with ox-LDL, macrophages induced by propylene glycol methyl ether acetate (PMA), presented large amounts of lipid deposition in their cytoplasm, indicating that the THP-1-derived foam cell model was successfully established. On the other hand, the same cells pretreated with albiflorin presented significantly reduced amounts of lipid deposition, and their contents of total cholesterol and triglyceride were also clearly lower. Besides, the expression levels of low-density lipoprotein receptor-1 (LOX-1) and nuclear factor-κB (NF-κB) were significantly decreased, and the expression levels of downstream factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also obviously decreased in the cells treated with albiflorin but not in the negative control cells. Moreover, after treatment of macrophages with different concentrations of ox-LDL, the expression levels of LOX-1 and NF-κB were up-regulated in an ox-LDL concentration-dependent manner, and so were the expression levels of IL-6 and TNF-α. And, it was found after treatment with LOX-1 neutralizing antibody or NF-κB inhibitor (during the foam cell formation induction via ox-LDL) that the lipid deposition in the cytoplasm of the cells was reduced, as in the cells treated with albiflorin. CONCLUSIONS: Taken together, our findings suggest that albiflorin decreases lipid deposition in the cytoplasm and blocks the foaming process by regulating the LOX-1/NF-κB signaling pathway.


Assuntos
Aterosclerose/patologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células Espumosas/efeitos dos fármacos , Leucemia Monocítica Aguda/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Linhagem Celular Tumoral , Colesterol/metabolismo , Citoplasma/metabolismo , Células Espumosas/citologia , Células Espumosas/metabolismo , Humanos , Interleucina-6/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , NF-kappa B/metabolismo , Propilenoglicóis , Receptores Depuradores Classe E/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
15.
J Cell Biochem ; 120(3): 3038-3045, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30474257

RESUMO

OBJECTIVE: The current study aimed to explore the role and the molecular mechanism of Shen'ge powder in cardiomyocyte hypertrophy in chronic heart failure (CHF). METHODS: Sprague-Dawley rats were selected for the study and divided randomly into four groups: control, model, Shen'ge powder, and fasudil group. An inverted microscope was used to determine the diameter of cardiomyocytes in each group. The survival and apoptotic rate of cardiomyocytes in each group was determined by the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. The messenger RNA levels and protein expression of RhoA, Rho-associated coiled-coil forming protein kinase (ROCK), myosin light-chain phosphatase (MLCP), and myosin light-chain kinase (MLCK) were determined by quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. RESULTS: CHF increased the diameter and apoptotic rate of cardiomyocytes and decreased the survival rate of cardiomyocytes. The levels of RhoA, ROCK, and MLCK were increased significantly in CHF model rats, and the level of MLCP was decreased. After treating with Shen'ge powder, the expression of RhoA, ROCK, and MLCK decreased dramatically and the expression of MLCP increased. CONCLUSION: Shen'ge powder could reduce cardiomyocyte hypertrophy in CHF by regulating the Rho/ROCK signaling pathway.

16.
Chin J Nat Med ; 16(11): 838-845, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30502765

RESUMO

Postmenopausal women, who have reduced circulating estrogen levels, are more prone to develop obesity and related metabolic diseases than premenopausal women. The absence of safe and effective treatments for postmenopausal obesity has changed the focus to natural products as alternative remedies. Total salvianolic acids (TSA) are the major water-soluble ingredients of Danshen. Salvianolic acid (SA) is the major constituent of the TSA. Salvianolic acids, including TSA and SA, are widely used in traditional Chinese medicine. In the present study, ovariectomized rats and LO2 cells were used to study the effects of salvianolic acids on body weight gain and hepatic steatosis. Salvianolic acids reduced ovariectomy (OVX)-induced body weight gain, attenuated the expressions of hepatic lipogenic genes, such as sterol regulatory element binding protein (SREBP)1, fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD)1, and decreased the liver triglyceride (TG) and total cholesterol (TC). For the molecular mechanisms, OVX and high glucose-induced phosphorylation of signal transducer and activator of transcription (STAT)-3 was inhibited by salvianolic acids treatment. In LO2 cells, inhibition of STAT-3 by siRNA attenuated the increased expression of SREBP1 and TG induced by high glucose. Salvianolic acids reduced the upregulation of SREBP1 and TG induced by high glucose in LO2 cells. In conclusion, these findings illustrated that salvianolic acids markedly alleviated the lipid metabolism disorders and protected against the postmenopausal obesity. The underlying mechanism was probably associated with the regulation of STAT-3 signaling.


Assuntos
Alcenos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Polifenóis/administração & dosagem , Pós-Menopausa/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Feminino , Humanos , Fígado/metabolismo , Obesidade/genética , Obesidade/metabolismo , Ovariectomia , Pós-Menopausa/genética , Pós-Menopausa/metabolismo , Ratos , Fator de Transcrição STAT3/genética , Salvia miltiorrhiza/química , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
17.
Adv Sci (Weinh) ; 5(10): 1800873, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30356983

RESUMO

Biomineralization in vertebrates is initiated via amorphous calcium phosphate (ACP) precursors. These precursors infiltrate the extracellular collagen matrix where they undergo phase transformation into intrafibrillar carbonated apatite. Although it is well established that ACP precursors are released from intracellular vesicles through exocytosis, an unsolved enigma in this cell-mediated mineralization process is how ACP precursors, initially produced in the mitochondria, are translocated to the intracellular vesicles. The present study proposes that mitophagy provides the mechanism for transfer of ACP precursors from the dysfunctioned mitochondria to autophagosomes, which, upon fusion with lysosomes, become autolysosomes where the mitochondrial ACP precursors coalesce to form larger intravesicular granules, prior to their release into the extracellular matrix. Apart from endowing the mitochondria with the function of ACP delivery through mitophagy, the present results indicate that mitophagy, triggered upon intramitochondrial ACP accumulation in osteogenic lineage-committed mesenchymal stem cells, participates in the biomineralization process through the BMP/Smad signaling pathway.

18.
Cell Death Dis ; 9(11): 1070, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341283

RESUMO

Multidrug resistance (MDR) accounts for poor prognosis in gastric cancer (GC). MicroRNAs (miRNAs) are critical regulators of MDR via modulation of the target genes. The present study revealed that miR-495-3p could act via a target gene, GRP78, to regulate the process of autophagy and inhibit MDR. Based on the in vitro and in vivo gain-of-function or loss-of-function experiments, overexpression of miR-495-3p was sufficient to reverse the MDR to four chemotherapeutics in vitro and inhibit the tumor growth in vivo. Moreover, GRP78 was positively associated with the occurrence of autophagy. Thus, reducing the expression of GRP78 by siRNA resulted in autophagy-suppressive activity similar to that of miR-495-3p on mammalian target of rapamycin (mTOR) and its substrates activation and autophagy inhibition, while restoring GRP78 attenuated the anti-autophagy effects caused by miR-495-3p. Clinically, either miR-495-3p downregulation or GRP78 upregulation was associated with malignant phenotypes in patients with GC. In conclusion, these findings demonstrate that miR-495-3p is an important regulator of autophagy balance and MDR by modulating the GRP78/mTOR axis. In addition, miR-495-3p and GRP78 could be used as prognostic factors for overall survival in GC, which implicates miR-495-3p as a therapeutic target in cancer.


Assuntos
Adenocarcinoma/metabolismo , Autofagia , Resistência a Múltiplos Medicamentos , Proteínas de Choque Térmico/metabolismo , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno/genética , Transfecção
19.
PLoS Genet ; 14(7): e1007491, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29975682

RESUMO

mTOR is a highly conserved serine/threonine protein kinase that is critical for diverse cellular processes in both developmental and physiological settings. mTOR interacts with a set of molecules including Raptor and Rictor to form two distinct functional complexes, namely the mTORC1 and mTORC2. Here, we used novel genetic models to investigate functions of the mTOR pathway for cranial neural crest cells (NCCs), which are a temporary type of cells arising from the ectoderm layer and migrate to the pharyngeal arches participating craniofacial development. mTOR deletion elicited a proliferation deficit and excessive apoptosis of post-migratory NCCs, leading to growth arrest of the facial primordia along with midline orofacial clefts. Furthermore, NCC differentiation was impaired. Thus, NCC derivatives, such as skeletons, vasculatures and neural tissues were either rudimentary or malformed. We further demonstrate that disruption of mTOR caused P53 hyperactivity and cell cycle arrest in cranial NCCs, and lowering P53 activity by one copy reduction attenuated the severity of craniofacial phenotype in NCC-mTOR knockout mice. Remarkably, NCC-Rptor disruption caused a spectrum of defects mirroring that of the NCC-mTOR deletion, whereas NCC-Rictor disruption only caused a mild craniofacial phenotype compared to the mTOR and Rptor conditional knockout models. Altogether, our data demonstrate that mTOR functions mediated by mTORC1 are indispensable for multiple processes of NCC development including proliferation, survival, and differentiation during craniofacial morphogenesis and organogenesis, and P53 hyperactivity in part accounts for the defective craniofacial development in NCC-mTOR knockout mice.


Assuntos
Anormalidades Craniofaciais/genética , Crista Neural/embriologia , Transdução de Sinais/fisiologia , Crânio/embriologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/fisiologia , Diferenciação Celular , Movimento Celular , Proliferação de Células , Anormalidades Craniofaciais/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Morfogênese/fisiologia , Crista Neural/citologia , Crista Neural/metabolismo , Organogênese/fisiologia , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/metabolismo
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