Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 101
Filtrar
1.
Neurochem Res ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34993705

RESUMO

To explore the mechanism regarding the regulation of spinal cord ischemia (SCI) in rats by mild hypothermia. A SCI rat model was established through aorta occlusion, and in some cases, the rats were intervened with mild hypothermia, after which motor function, microglia activation, and M1/M2 polarization in rats were measured. Also, the expression of inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and neuronal apoptosis were examined. Lipopolysaccharide (LPS)-induced M1 microglia and IL-4-induced M2 microglia were intrathecally injected into rats to evaluate the effect of microglial polarization on SCI. In in vitro experiments, primary microglial cells were treated under hypothermic condition, in which M1/M2 polarization and microglia apoptosis, the levels of iNOS, CD86, CD206, Arg-1 and inflammatory cytokines were assessed. Western blot analysis detected the activation of the TLR4/NF-κB pathway to investigate the role of this pathway in M1/M2 polarization. SCI treatment impaired motor function, induced higher M1 microglia proportion, and increased the levels of pro-inflammatory cytokines in rats, and mild hypothermic treatment attenuated these trends. Moreover, injection of M1 microglia increased M1 microglia proportion and increased the levels of pro-inflammatory cytokines, while injection of M2 microglia induced the reverse results, i.e. decreased M1 microglia proportion and reduced pro-inflammatory cytokine levels. In LPS-induced microglial cells, mild hypothermia treatment increased M2 microglia proportion and decreased pro-inflammatory cytokine levels, relative to normothermia. Mild hypothermia inactivated the TLR4/NF-κB pathway in LPS-treated microglia. TLR4 overexpression reversed the function of mild hypothermia in LPS-stimulated microglia, and under normal condition, TLR4/NF-κB pathway suppressed microglial M2 polarization. Mild hypothermia inhibits TLR4/NF-κB pathway and promotes microglial M2 polarization, thus attenuating SCI-induced injury and inflammation.

2.
Front Pharmacol ; 12: 773660, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776985

RESUMO

Bone regeneration in osteoporosis and fragility fractures which are highly associated with age remains a great challenge in the orthopedic field, even though the bone is subjected to a continuous process of remodeling which persists throughout lifelong. Regulation of osteoblast and osteoclast differentiation is recognized as effective therapeutic targets to accelerate bone regeneration in osteopenic conditions. Anthocyanins (ACNs), a class of naturally occurring compounds obtained from colored plants, have received increasing attention recently because of their well-documented biological effects, such as antioxidant, anti-inflammation, and anti-apoptosis in chronic diseases, like osteoporosis. Here, we summarized the detailed research progress on ACNs on bone regeneration and their molecular mechanisms on promoting osteoblast differentiation as well as inhibiting osteoclast formation and differentiation to explore their promising therapeutic application in repressing bone loss and helping fragility fracture healing. Better understanding the role and mechanisms of ACNs on bone regeneration is helpful for the prevention or treatment of osteoporosis and also for the exploration of new bone regenerative medicine.

3.
Am J Transl Res ; 13(9): 10908-10921, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650772

RESUMO

BACKGROUND: Osteoarthritis (OA) is common in the elderly. Baicalin (BA) is a flavonoid monomer extracted from Scutellaria baicalensis Georgi, which has been reported to have anti-inflammatory, anti-deformation and anti-bacterial effects. METHODS: Cultures of micromass and 3D alginate beads, Alcian blue and Safranin O (SO)/fast green staining were used to investigate chondrocyte viability and extracellular matrix (ECM) synthesis in chondrocytes of all groups. The expression of SOX9, Smad3, Aggrecan (ACAN), type II collagen (Col2α), matrix metallopetidase 9 (MMP9), MMP13 and ADAMTS5 in chondrocytes of all groups were detected by western blot or qRT-PCR. RESULTS: The present study demonstrates that BA neutralized the IL-1ß-induced downregulation of chondrocyte viability and ECM secretion, including ACAN and Col2α. The downregulation of SOX9, and the upregulation of MMP9, MMP13 and ADAMTS5 induced by IL-1ß were reversed by BA treatment. Moreover, BA increased the nuclear translocation of Smad3 and SOX9 in chondrocytes cultured by micromass and 3D alginate beads. Interestingly, Smad3 inhibitor SIS3 reversed the promoting effect of BA on chondrocyte viability, ECM secretion, SOX9 and Smad3 nuclear translocation, and the inhibiting effect of BA on MMP9 and ADAMTS5 expressions. BA treatment also attenuated the decrease of Smad3 phosphorylation, SOX9 expression and the damage of cartilage integrity in mice which were induced by destabilization of the medial meniscus (DMM). CONCLUSION: BA promotes chondrocyte viability and the cell matrix synthesis through TGF-ß/Smad3 pathway in IL-1ß-treated chondrocytes and DMM treated mice. BA is a potential therapeutic target for OA.

4.
J Orthop Surg Res ; 16(1): 644, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34717682

RESUMO

BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is one of the most common fragile fractures, and percutaneous vertebroplasty provides considerable long-term benefits. At the same time, there are many reports of postoperative complications, among which fracture after percutaneous vertebroplasty is one of the complications after vertebroplasty (PVP). Although there are many reports on the risk factors of secondary fracture after PVP at home and abroad, there is no systematic analysis on the related factors of secondary fracture after PVP. METHODS: The databases, such as CNKI, Wan Fang Database and PubMed, were searched for documents on secondary fractures after percutaneous vertebroplasty published at home and abroad from January 2011 to March 2021. After strictly evaluating the quality of the included studies and extracting data, a meta-analysis was conducted by using Revman 5.3 software. RESULTS: A total of 9 articles were included, involving a total of 1882 patients, 340 of them diagnosed as secondary fractures after percutaneous vertebroplasty. CONCLUSION: The additional history of fracture, age, bone mineral density (BMD), bone cement leakage, intravertebral fracture clefts and Cobb Angle might be risk factors related to secondary fractures after percutaneous vertebroplasty for osteoporotic vertebral compression fractures. The height of vertebral anterior and body mass index (BMI) were not correlated.

5.
Front Cell Dev Biol ; 9: 682719, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336835

RESUMO

Objective: Fibrocartilage transition zone (FC) is difficult to regenerate after surgical re-attachment of tendon to bone. Here, we investigated whether type II collagen-sponges (CII-sponges) facilitated tendon stem/progenitor cells (TSPCs) to adopt chondrogenic phenotypes and further observed if this material could increase the FC areas in bone-tendon junction (BTJ) injury model. Methods: CII-sponges were made as we previously described. The appearance and pore structure of CII-sponges were photographed by camera and microscopies. The viability, proliferation, and differentiation of TSPCs were examined by LIVE/DEAD assay, alamarBlue, and PKH67 in vitro tracking. Subsequently, TSPCs were seeded in CII-sponges, Matrigel or monolayer, and induced under chondrogenic medium for 7 or 14 days before being harvested for qPCR or being transplanted into nude mice to examine the chondrogenesis of TSPCs. Lastly, partial patellectomy (PP) was applied to establish the BTJ injury model. CII-sponges were interposed between the patellar fragment and tendon, and histological examination was used to assess the FC regeneration at BTJ after surgery at 8 weeks. Results: CII-sponges were like sponges with interconnected pores. TSPCs could adhere, proliferate, and differentiate in this CII-sponge up to 14 days at least. Both qPCR and immunostaining data showed that compared with TSPCs cultured in monolayer or Matrigel, cells in CII-sponges group adopted more chondrogenic phenotypes with an overall increase of chondrocyte-related genes and proteins. Furthermore, in PP injured model, much more new formed cartilage-like tissues could be observed in CII-sponges group, evidenced by a large amount of positive proteoglycan expression and typical oval or round chondrocytes in this area. Conclusion: Our study showed that CII-sponges facilitated the TSPCs to differentiate toward chondrocytes and increased the area of FCs, which suggests that CII-sponges are meaningful for the reconstruction of FC at bone tendon junction. However, the link between the two phenomena requires further research and validation.

6.
J Clin Anesth ; 73: 110308, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33930679

RESUMO

STUDY OBJECTIVE: To evaluate the efficacy of perioperative dexmedetomidine (DEX) administration for preventing delirium in adults after non-cardiac surgery. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). INTERVENTIONS: Perioperative administration of DEX to prevent delirium in adults following non-cardiac surgery. MEASUREMENTS: The incidence of postoperative delirium (POD). METHODS: The databases of PubMed, Embase and Cochrane Central Register were searched from inception to Mar 4, 2021 for all available RCTs that assessed DEX for POD in adults after non-cardiac surgery. Risk ratio (RR) with a 95% confidence interval (CI) was calculated for dichotomous data. Standardized mean difference (SMD) was calculated for continuous data. Risk of bias was assessed using the second version of the Cochrane risk-of-bias tool for RCTs (RoB 2.0), and the level of certainty for main outcomes were assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. MAIN RESULTS: Thirteen studies, including the meta-analysis with a total of 4015 patients (DEX group: 2050 patients; placebo group: 1965 patients), showed that DEX significantly reduced the incidence of POD in adults after non-cardiac surgery compared with control group (RR: 0.60; 95%CI: 0.46 to 0.77, P = 0.0001, I2 = 55%, GRADE = moderate). Meanwhile, there was a statistical difference by the subgroup analysis between the mean age ≥ 65 years group and the mean age<65 years group. There were no statistical differences in length of hospital stay following surgery (SMD: -0.36; 95%CI: -0.80 to 0.07, P = 0.1, I2 = 97%, GRADE = low) and all-cause mortality rate (RR:0.57; 95%CI: 0.25 to 1.28, P < 0.17, I2 = 0%, GRADE = moderate) compared with placebo group. However, Meta-analysis showed that DEX administration significantly resulted in intraoperative bradycardia when compared with placebo group (RR: 1.39; 95%CI: 1.14 to 1.69, P = 0.0009, I2 = 0%, GRADE = high), and as well as intraoperative hypotension (RR: 1.25; 95%CI: 1.11 to 1.42, P = 0.0004, I2 = 0%, GRADE = high). CONCLUSION: This systematic review and meta-analysis suggests that perioperative administration of DEX could significantly reduce the incidence of POD in patients elder than 65 years following non-cardiac surgery. However, there was no definite evidence that perioperative DEX could reduce the incidence of POD in patients younger than 65 years of age after non-cardiac surgery. In addition, perioperative DEX administration was associated with an elevated risk of bradycardia and hypotension.


Assuntos
Delírio , Dexmedetomidina , Hipotensão , Adulto , Idoso , Bradicardia , Delírio/epidemiologia , Delírio/prevenção & controle , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle
7.
Biomark Res ; 9(1): 16, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663617

RESUMO

Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a multifunctional protein participated in diverse cellular processes, including chromosome remodeling, cell differentiation and development. CHD1L is a regulator of chromosomal integrity maintenance, DNA repair and transcriptional regulation through its bindings to DNA. By regulating kinds of complex networks, CHD1L has been identified as a potent anti-apoptotic and pro-proliferative factor. CHD1L is also an oncoprotein since its overexpression leads to dysregulation of related downstream targets in various cancers. The latest advances in the functional molecular basis of CHD1L in normal cells will be described in this review. As the same time, we will describe the current understanding of CHD1L in terms of structure, characteristics, function and the molecular mechanisms underlying CHD1L in tumorigenesis. We inference that the role of CHD1L which involve in multiple cellular processes and oncogenesis is well worth further studying in basic biology and clinical relevance.

8.
Front Pharmacol ; 12: 768708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35002708

RESUMO

Amentoflavone is an active phenolic compound isolated from Selaginella tamariscina over 40 years. Amentoflavone has been extensively recorded as a molecule which displays multifunctional biological activities. Especially, amentoflavone involves in anti-cancer activity by mediating various signaling pathways such as extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (NF-κB) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and emerges anti-SARS-CoV-2 effect via binding towards the main protease (Mpro/3CLpro), spike protein receptor binding domain (RBD) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. Therefore, amentoflavone is considered to be a promising therapeutic agent for clinical research. Considering the multifunction of amentoflavone, the current review comprehensively discuss the chemistry, the progress in its diverse biological activities, including anti-inflammatory, anti-oxidation, anti-microorganism, metabolism regulation, neuroprotection, radioprotection, musculoskeletal protection and antidepressant, specially the fascinating role against various types of cancers. In addition, the bioavailability and drug delivery of amentoflavone, the molecular mechanisms underlying the activities of amentoflavone, the molecular docking simulation of amentoflavone through in silico approach and anti-SARS-CoV-2 effect of amentoflavone are discussed.

9.
Biosci Rep ; 40(11)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33155655

RESUMO

Articular cartilage injury or defect is a common disease and is mainly characterized by cartilage degradation because of chondrocyte inflammation. By now, there are no effective drugs and methods to protect articular cartilage from degradation. Icariin (ICA) is a typical flavonoid compound extracted from Epimedii Folium with anti-inflammatory and bone-protective effects. Our previous studies demonstrate that ICA up-regulates HIF-1α expression and glycolysis in chondrocytes and maintains chondrocyte phenotype. As another member of HIFs family, HIF-2α always plays a key role in inflammation. The effect of ICA on HIF-2α is unclear by now. In the present study, we confirmed the findings in our previous study that ICA promoted not only chondrocyte vitality and extracellular matrix (ECM) synthesis, but also the anti-inflammatory effect of ICA. In bone defect mice, ICA inhibited the expressions of NF-κB and HIF-2α. In TNF-α-treated ADTC5 chondrocytes, ICA neutralized the activation of IKK (IKK phosphorylation), the phosphorylation of IkB and NF-κB and the expression of HIF-2α. Furthermore, ICA inhibited the nucleus transfer of NF-κB and the expressions of MMP9 and ADAMTS5, two key targets of NF-κB/HIF-2α signal pathway. Taken together, the present study demonstrated that ICA may increase the vitality of chondrocytes by suppressing the inflammatory injury through the inhibition on NF-κB/HIF-2α signaling pathway. ICA is one effective candidate drug for the treatment of articular cartilage injury.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Flavonoides/farmacologia , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Osteoartrite/patologia , Fosforilação , Transdução de Sinais
10.
Cancer Metab ; 8: 23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101674

RESUMO

Background: Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 mut ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG). Methods: We have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity. Results: We report the adaptability of IDH1 mut cells' metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. Conclusions: Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 mut gliomas.

11.
Oncol Lett ; 20(5): 168, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32934735

RESUMO

Ovarian cancer is the seventh most common cancer and the second most common cause of cancer-associated mortality among gynecological malignancies worldwide. The combination of antimitotic agents, such as taxanes, and the DNA-damaging agents, such as platinum compounds, is the standard treatment for ovarian cancer. However, due to chemoresistance, development of novel therapeutic strategies for the treatment of ovarian cancer remains critical. Amentoflavone (AMF) is a biflavonoid derived from the extracts of Selaginella tamariscina, which has been used as a Chinese herb for thousands of years. A previous study demonstrated that AMF inhibits angiogenesis of endothelial cells and induces apoptosis in hypertrophic scar fibroblasts. In order to check the influence of AMF on cell proliferation, the effects of AMF on cell cycle and DNA damage were measured by cell viability, flow cytometry, immunofluorescence and western blotting assays in SKOV3 cells, an ovarian cell line. In the present study, treatment with AMF inhibited ovarian cell proliferation, increased P21 expression, decreased CDK1/2 expression, interrupted the balance of microtubule dynamics and arrested cells at the G2 phase. Furthermore, treatment with AMF increased the expression levels of phospho-Histone H2AX (γ-H2AX; a variant of histone 2A, that belongs to the histone 2A family member X) and the DNA repair protein RAD51 homolog 1 (Rad51), indicating the occurrence of DNA damage since γ-H2AX and Rad51 are both key markers of DNA damage. Consistent with previous findings, the results of the present study suggest that AMF is a potential therapeutic agent for the treatment of ovarian cancer. In addition, the effects of AMF on cell cycle arrest and DNA damage induction may be the molecular mechanisms by which AMF might exert its potential therapeutic benefits in ovarian cancer.

12.
Sci Rep ; 10(1): 14238, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859971

RESUMO

Speckle-tracking imaging has the advantages of simple setup and high-sensitivity to slowly varying phase gradients. Subset size choice is regarded as a trade-off problem for speckle-tracking X-ray imaging where one needs to balance the spatial resolution and accuracy, where the subset was defined as the region of interest of windowing choice for digital image correlation algorithm. An adaptive subset size choice method based on a Fourier transform for effectively detecting sample phase information without foreknowledge of the sample structure is presented in this study. The speckle-tracking phase-contrast and the form of dark-field imaging based on this method have the advantages of (i) high resolution and time saving compared to large subset choice and (ii) partially improvement the influence from experimental noises, background fluctuations, and false signals compared to small subset choice at the same time. This method has proven to be particularly robust in the experimental condition of poor signal-to-noise ratio. The proposed method may be expanded to all speckle-based imaging methods and other imaging techniques based on the subset or window matching.

13.
Cell Prolif ; 53(7): e12813, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32515860

RESUMO

OBJECTIVES: Accumulating studies have investigated the PM2.5-induced pulmonary toxicity, while gaps still remain in understanding its toxic mechanism. Due to its high specific surface area and adsorption capacity similar to nanoparticles, PM2.5 acts as a significant carrier of metals in air and then leads to altered toxic effects. In this study, we aimed to use CBs and Ni as model materials to investigate the autophagy changes and pulmonary toxic effects at 30 days following intratracheal instillation of CBs-Ni mixture. MATERIALS AND METHODS: Groups of mice were instilled with 100 µL normal saline (NS), 20 µg CBs, and 4 µg Ni or CBs-Ni mixture, respectively. At 7 and 30 days post-instillation, all the mice were weighed and then sacrificed. The evaluation system was composed of the following: (a) autophagy and lysosomal function assessment, (b) trace element biodistribution observation in lungs, (c) pulmonary lavage biomedical analysis, (d) lung histopathological evaluation, (e) coefficient analysis of major organs and (f) CBs-Ni interaction and cell proliferation assessment. RESULTS: We found that after CBs-Ni co-exposure, no obvious autophagy and lysosomal dysfunction or pulmonary toxicity was detected, along with complete clearance of Ni from lung tissues as well as recovery of biochemical indexes to normal range. CONCLUSIONS: We conclude that the damaged autophagy and lysosomal function, as well as physiological function, was repaired at 30 days after exposure of CBs-Ni. Our findings provide a new idea for scientific assessment of the impact of fine particles on environment and human health, and useful information for the comprehensive treatment of air pollution.


Assuntos
Autofagia/efeitos dos fármacos , Carbono/efeitos adversos , Pneumopatias/induzido quimicamente , Pulmão/efeitos dos fármacos , Metais/efeitos adversos , Animais , Linhagem Celular , Pulmão/metabolismo , Pneumopatias/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Células RAW 264.7 , Distribuição Tecidual
14.
J Orthop Translat ; 22: 101-108, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32440505

RESUMO

Background: Bone-tendon junction (BTJ) is a unique structure connecting tendon and bone through a fibrocartilage zone. Owing to its unique structure, the regeneration of BTJ remains a challenge. Here, we study the fibrochondrogenic differentiation of human tendon-derived stem/progenitor cells (TSPCs) both in vitro and in vivo. Methods: TSPCs were isolated from human patellar tendon tissues and investigated for their multidifferentiation potential. TSPCs were cultured in chondrogenic medium with transforming growth factor beta 3 (TGF-ß3) and BMP-2 in vitro â€‹and examined for the expression of fibrochondrogenic marker genes by quantitative real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. TSPCs pretreated were also seeded in collage II sponge and then transplanted in immunocompromised nude mice to examine if the fibrochondrogenic characteristics were conserved in vivo. Results: We found that TSPCs were differentiated towards fibrochondrogenic lineage, accompanied by the expression of collagen I, collagen II, SRY-box transcription factor 9 (Sox 9), and tenascin C. Furthermore, after TSPCs were seeded in collagen II sponge and transplanted in immunocompromised nude mice, they expressed fibrochondrogenic genes, including proteoglycan, collagen I, and collagen II. Conclusion: Taken together, this study showed that TSPCs are capable of differentiating towards fibrocartilage-like cells, and the fibrochondrogenic characteristics were conserved even in vivo, and thus might have the potential application for fibrocartilage regeneration in BTJ repair. The translational potential of this article: TSPCs are able to differentiate into fibrocartilage-like cells and thus might well be one potential cell source for fibrocartilage regeneration in a damaged BTJ repair.

15.
Int J Biol Sci ; 16(9): 1640-1647, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226308

RESUMO

Limited genetic factors were uncovered for the development of congenital anomalies of the kidney and urinary tract (CAKUT). We previously reported that a Holliday junction resolvase Gen1 was essential for early metanephric development in mice. This comprehensive follow-up study focused on the roles of Gen1 in late metanephric development. We found that Gen1 mutation impaired the late development of both kidney and urinary tract. In vivo and ex-vivo kidney primordia culture confirmed decreased ureteric bud branching in Gen1 mutants, which consequently caused hypoplasia. We also observed abnormal urinary tract development. Programmed apoptosis at the end of nephric duct disappeared in Gen1 mutants, which caused abnormal ureter-bladder connections, leading to vesicoureteral reflux (VUR) or ureterovesical junction obstruction (UVJO). Mechanistically, RNA-seq analysis proved that Gen1 mutation impaired the expression of multiple regulatory genes for the metanephric development, including Six2. Taken together, our study provides more insight into the roles of Gen1 in the development of the kidney and urinary tract, which may have potential clinical significance in the treatment and/or prevention of CAKUT.


Assuntos
Resolvases de Junção Holliday/fisiologia , Rim/anormalidades , Sistema Urinário/anormalidades , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Animais , Regulação da Expressão Gênica , Resolvases de Junção Holliday/metabolismo , Rim/metabolismo , Camundongos , Mutação
16.
Cancers (Basel) ; 12(4)2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32224866

RESUMO

Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in lower grade gliomas. The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming. However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness. In the present study, by using unbiased transcriptomic profiling, we showed that IDH1 mutations result in substantial changes in the gene sets that govern cellular motility, chemotaxis, and invasion. Mechanistically, rapamycin-insensitive companion of mammalian target of rapamycin (Rictor)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling plays an essential role in the motility and proliferation of IDH1-mutated cells by prompting cytoskeleton reorganization, lamellipodia formation, and enhanced endocytosis. Targeting the Rictor/Rac1 pathway suppresses IDH1-mutated cells by limiting endocytosis and cell proliferation. Overall, our findings indicate a novel metabolic reprogramming mechanism of IDH1-mutated cells by exploiting metabolites from the extracellular milieu. Targeting the Rictor/Rac1 pathway could be an alternative therapeutic strategy for IDH1-mutated malignancies.

17.
Colloids Surf B Biointerfaces ; 189: 110837, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32058250

RESUMO

Epithelial ovarian cancer is still the leading cause of death in gynecology due to its resistance to platinum-based first-line chemotherapeutic drugs. The utilization of mitochondria-targeted drugs has become an important direction in anti-tumor drug research and development. In this work, cisplatin (DDP)-loaded ZIF-90 with mitochondrial-targeting was synthesized at room temperature with a high drug loading (11.7 %, calculated based on Pt content). The ZIF-90@DDP showed high cellular uptake and less toxicity in both non- and DDP-resistant ovarian cancer cells with effective pH- and ATP-responsive drug release. Both mitochondria-targeting and responsive drug release could increase the drug concentration in mitochondria of drug-resistant cancer cells to reverse such resistance. Conclusively, the mitochondria-targeting ZIF-90@DDP with high drug loading could trigger responsive drug release in mitochondria of epithelial ovarian cancer cells, inhibit DPP-resistant epithelial ovarian cancer cells, and reverse drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Zeolitas/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Imidazóis/síntese química , Imidazóis/química , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de Superfície , Células Tumorais Cultivadas , Zeolitas/síntese química , Zeolitas/química
18.
Nanoscale ; 12(3): 1801-1810, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31898712

RESUMO

Black titanium dioxide (TiO2) nanoparticles have attracted great attention due to their application in photothermal therapy (PTT). However, single-mode phototherapy has the risk of recurrence, and the high-dose laser usually imposed to improve the PTT performance can bring a potential threat to security. Here, polydopamine (PDA)-coated black TiO2 (b-P25@PDA) nanoparticles with a core-shell structure were synthesized for enhanced PTT; then, synergistic phototherapy nanoprobes (b-P25@PDA-Ce6 (Mn)) were constructed by coupling chlorin e6 (Ce6) and chelating Mn2+ for simultaneous photodynamic therapy (PDT)/PTT and magnetic resonance (MR) imaging, in which a low-dose laser was used and imaging-guided phototherapy with high efficiency and high safety was achieved. The prepared nanoprobes showed high photothermal conversion efficiency (32.12%), high reactive oxygen generation and excellent MR imaging. In the 4T1 tumor-bearing nude mouse model, the tumors completely disappeared under the combination of PDT/PTT with a low-dose laser but were only partially inhibited by single PDT and single PTT. The current work developed a multifunctional black TiO2-based nanoprobe for enhanced synergistic PDT/PTT and MR imaging, which will be important for the safe and efficient visualized theranostics of cancers.


Assuntos
Meios de Contraste , Indóis , Imageamento por Ressonância Magnética , Neoplasias Mamárias Animais , Manganês , Nanopartículas , Fototerapia , Polímeros , Porfirinas , Titânio , Animais , Linhagem Celular Tumoral , Clorofilídeos , Meios de Contraste/química , Meios de Contraste/farmacologia , Feminino , Indóis/química , Indóis/farmacologia , Neoplasias Mamárias Animais/diagnóstico por imagem , Neoplasias Mamárias Animais/tratamento farmacológico , Manganês/química , Manganês/farmacologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Polímeros/química , Polímeros/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Titânio/química , Titânio/farmacologia
19.
Neuro Oncol ; 22(4): 480-492, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31665443

RESUMO

BACKGROUND: Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. Isocitrate dehydrogenase (IDH)-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses toward secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood. METHODS: We employed model systems for IDH1 mutant (IDH1mut) gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome, and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic, we analyzed data from The Cancer Genome Atlas. RESULTS: We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially lactate dehydrogenase A (LDHA), and have increased mRNA and metabolite levels compared with the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP)-high molecular subtype in patients and is associated with the worst outcome. CONCLUSION: We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Metilação de DNA , Glioma/genética , Guanina , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , Fenótipo
20.
Cancer Biol Ther ; 21(3): 213-222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31651209

RESUMO

Enhancer of zeste homolog 2 (EZH2) is an important member of the epigenetic regulatory factor polycomb group proteins (PcG) and is abnormally expressed in a wide variety of tumors, including osteosarcoma. Scientists consider EZH2 as an attractive target for the treatment of osteosarcoma and have found many potential EZH inhibitors, such as GlaxoSmithKline 343 (GSK343). It has been reported that GSK343 can be used as an inhibitor in different types of cancer. This study demonstrated that GSK343 not only induced apoptosis by increasing cleaved Casp-3 and poly ADP-ribose polymerase (PARP) expression, but also induced autophagic cell death by inhibiting p62 expression. Apoptosis and autophagic cell death induced by GSK343 were confirmed by the high expression of cleaved caspase-3, LC3-II and transmission electron microscopy. GSK343 inhibited the expression of EZH2 and c-Myc. Additionally, GSK343 inhibited the expression of FUSE binding protein 1 (FBP1), which was identified by its regulatory effects on c-Myc expression. Since c-Myc is a common target of EZH2 and FBP1, and GSK343 inhibited the expression of these proliferation-promoting proteins, a mutual regulatory mechanism between EZH2 and FBP1 was proposed. The knockdown of EZH2 suppressed the expression of FBP1; similarly, the knockdown of FBP1 suppressed the expression of EZH2. These results suggest the mutual regulatory association between EZH2 and FBP1. The knockdown of either EZH2 or FBP1 accelerated the sensitivity of osteosarcoma cells to GSK343. Based on these results, this study clarified that GSK343, an EZH2 inhibitor, may have potential for use in the treatment of osteosarcoma. The underlying mechanisms of the effects of GSK343 are partly mediated by its inhibitory activity against c-Myc and its regulators (EZH2 and FBP1).


Assuntos
Apoptose , Neoplasias Ósseas/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Indazóis/farmacologia , Osteossarcoma/patologia , Piridonas/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfatase/antagonistas & inibidores , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...