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1.
J Exp Bot ; 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35436324

RESUMO

Plant sphingolipids are important membrane components and bioactive molecules in development and defense responses. However, the function of sphingolipids in plant defense, especially against herbivores, is not fully understood. Here, we report that Spodoptera exigua feeding affects sphingolipid metabolism in Arabidopsis (Arabidopsis thaliana), resulting in increased levels of sphingoid long-chain bases, ceramides, and hydroxyceramides. Insect-induced ceramide and hydroxyceramide accumulation is dependent on the jasmonate signaling pathway. Loss of the Arabidopsis alkaline ceramidase ACER increases ceramides and decreases long-chain base levels in plants. In this work, we found that loss of ACER enhances plant resistance to S. exigua and responses to mechanical wounding. Moreover, acer-1 mutants exhibited more severe root-growth inhibition and higher anthocyanin accumulation than wild-type plants in response to methyl jasmonate treatment, indicating that loss of ACER increases sensitivity to jasmonate and that ACER functions in jasmonate-mediated root growth and secondary metabolism. Transcript levels of ACER were also negatively regulated by jasmonates, and this process involves the transcription factor MYC2. Thus, our findings reveal that ACER is involved in mediating jasmonate-related plant growth and defense and that jasmonates function in regulating the expression of ACER.

2.
PhytoKeys ; 189: 155-162, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35210913

RESUMO

Silenevanchingshanensis (Caryophyllaceae), a new species from Fanjingshan Mountain in Guizhou (southwest China) is described and illustrated. It is morphologically similar to S.morrisonmontana and S.hupehensis, from which it can be easily distinguished by having pubescent stems usually 10-15 cm long, linear-oblanceolate leaves 3-6 cm × 3-6 mm, often 2-5-flowered cymes, pink or violet petals and narrowly ovoid capsules.

3.
Sci Transl Med ; 14(626): eabf0992, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34985967

RESUMO

High CD8+ T cell infiltration in colorectal cancer (CRC) should suggest a favorable prognosis and a satisfactory response to immunotherapy; however, the vast majority of patients with CRC do not benefit from immunotherapy due to poor T cell infiltration. Therefore, a better understanding of the mechanisms for T cell exclusion from CRC tumors is needed. Tribbles homolog 3 (TRIB3) has been implicated as an oncoprotein, but its role in regulating antitumor immune responses has not been defined. Here, we demonstrated that TRIB3 inhibits CD8+ T cell infiltration in various CRC mouse models. We showed that TRIB3 was acetylated by acetyltransferase P300, which inhibited ubiquitination and subsequent proteasomal degradation of TRIB3. Ectopically expressed TRIB3 inhibited signal transducer and activator of transcription 1 (STAT1) activation and STAT1-mediated CXCL10 transcription by enhancing the epidermal growth factor receptor signaling pathway, causing a reduction in tumor-infiltrating T cells. Genetic ablation of Trib3 or pharmacological acceleration of TRIB3 degradation with a P300 inhibitor increased T cell recruitment and sensitized CRCs to immune checkpoint blockade therapy. These findings identified TRIB3 as a negative modulator of CD8+ T cell infiltration in CRCs, highlighting a potential therapeutic target for treating immunologically "cold" CRCs.


Assuntos
Proteínas de Ciclo Celular , Neoplasias Colorretais , Evasão da Resposta Imune , Proteínas Repressoras , Animais , Linfócitos T CD8-Positivos , Proteínas de Ciclo Celular/metabolismo , Quimiocina CXCL10/metabolismo , Neoplasias Colorretais/patologia , Humanos , Imunoterapia , Camundongos , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
4.
Environ Toxicol ; 37(3): 564-573, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34845814

RESUMO

Overexpression or activation of Yes-associated protein (YAP) is common in cancer cells. Thus, targeting YAP may be a strategy for cancer therapy. Licochalcone A (LicA) is a primary active compound of licorice root and is known to have medicinal effects, such as antioxidant, antibacterial, antiviral, and anticancer effects. However, the anticancer pharmacological mechanism of LicA has not been investigated in cholangiocarcinoma. In this study, we investigated the antiproliferative effect of LicA and the underlying molecular mechanism in HCCC-9810 and RBE human cholangiocarcinoma cells. Our experiments indicated that LicA suppressed the growth of cholangiocarcinoma cells through inactivation of the Hippo pathway. Pescadillo ribosomal biogenesis factor 1 (PES1) was notably upregulated and related to carcinogenesis. We also found that LicA suppressed the expression and nuclear localization of PES1, which was associated with the inhibition of YAP expression and transcriptional activity.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Proliferação de Células , Chalconas , Colangiocarcinoma/tratamento farmacológico , Regulação para Baixo , Humanos , Proteínas de Ligação a RNA , Transdução de Sinais
5.
Ying Yong Sheng Tai Xue Bao ; 32(9): 3377-3384, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34658225

RESUMO

Urban street canyon is one of the most important characteristics and spatial forms of cities. It is one of the most frequently used public spaces in cities, with the most serious automobile exhaust pollution and the largest population density. The unreasonable space configuration and internal composition might decrease self-purification of urban ventilation but increase local air pollutant concentration. Here, we reviewed the impacts of street canyon morphology, street trees, vehicle flow and meteorological factors on the distribution of air pollutants in street canyons. We scrutinized the relevant methods of numerical simulation, wind tunnel experiments, and field monitoring on the distribution and diffusion of air pollutants in street canyons. We recommended that future research should concentrate on the impacts of various parameters on the distribution and diffusion of air pollutants based on the field monitoring data. Meanwhile, further research should develop optimization strategies for street canyon design which is conducive to the dispersion of air pollutants, and put forward scientific support and optimization scheme for the controlling of air pollutants from the perspective of urban planning and pattern optimization.


Assuntos
Poluentes Atmosféricos , Poluentes Atmosféricos/análise , Cidades , Conceitos Meteorológicos , Modelos Teóricos , Emissões de Veículos/análise
7.
Plant Physiol ; 187(3): 1713-1727, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34618068

RESUMO

Sphingolipids are structural components of the lipid bilayer that acts as signaling molecules in many cellular processes, including cell death. Ceramides, key intermediates in sphingolipid metabolism, are phosphorylated by the ceramide kinase ACCELERATED CELL DEATH5 (ACD5). The loss of ACD5 function leads to ceramide accumulation and spontaneous cell death. Here, we report that the jasmonate (JA) pathway is activated in the Arabidopsis (Arabidopsis thaliana) acd5 mutant and that methyl JA treatment accelerates ceramide accumulation and cell death in acd5. Moreover, the double mutants of acd5 with jasmonate resistant1-1 and coronatine insensitive1-2 exhibited delayed cell death, suggesting that the JA pathway is involved in acd5-mediated cell death. Quantitative sphingolipid profiling of plants treated with methyl JA indicated that JAs influence sphingolipid metabolism by increasing the levels of ceramides and hydroxyceramides, but this pathway is dramatically attenuated by mutations affecting JA pathway proteins. Furthermore, we showed that JAs regulate the expression of genes encoding enzymes in ceramide metabolism. Together, our findings show that JAs accelerate cell death in acd5 mutants, possibly by modulating sphingolipid metabolism and increasing ceramide levels.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Morte Celular , Ciclopentanos/farmacologia , Oxilipinas/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Reguladores de Crescimento de Plantas/farmacologia , Esfingolipídeos/metabolismo , Proteínas de Arabidopsis/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
8.
Poult Sci ; 100(10): 101390, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34391965

RESUMO

In this study, 105 broiler chickens were fed with dietary feeds containing different contents of Dichroae Radix extract for 10 consecutive days. Then the residue depletions of its main alkaloids (febrifugine and isofebrifugine) in muscle, kidney and liver samples at different withdrawal times were determined by an ultra-performance liquid chromatography method. Results showed that the 2 alkaloids were mainly at tissue-bound formation. At withdrawal period of 0 d, their concentrations in all samples were high but decreased rapidly after 1 day of cessation (35-91%). After 5 to 7 days of cessation, their residues in muscle and kidney were not detectable, and after at least 10 days of cessation they were not detectable in liver. These results indicated that an appropriate withdrawal time for Dichroae Radix preparation was required if it is licensed as a new drug, and the best target tissue for monitoring its residue was liver.


Assuntos
Galinhas , Resíduos de Drogas , Animais , Resíduos de Drogas/análise , Fígado , Carne/análise , Piperidinas , Quinazolinas
9.
Immunity ; 54(9): 2042-2056.e8, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34407391

RESUMO

Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.


Assuntos
Quimiocina CCL1/metabolismo , Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Fosfoproteínas/metabolismo , Fibrose Pulmonar/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Fibroblastos/patologia , Humanos , Camundongos , Miofibroblastos/patologia , Fibrose Pulmonar/patologia , Transdução de Sinais/fisiologia
10.
Pharmacol Res ; 170: 105728, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34119622

RESUMO

Metabolic reprogramming, characterized by alterations of cellular metabolic patterns, is fundamentally important in supporting the malignant behaviors of cancer cells. It is considered as a promising therapeutic target against cancer. Traditional Chinese medicine (TCM) and its bioactive components have been used in cancer therapy for an extended period, and they are well-known for their multi-target pharmacological functions and fewer side effects. However, the detailed and advanced mechanisms underlying the anticancer activities of TCM remain obscure. In this review, we summarized the critical processes of cancer cell metabolic reprogramming, including glycolysis, mitochondrial oxidative phosphorylation, glutaminolysis, and fatty acid biosynthesis. Moreover, we systemically reviewed the regulatory effects of TCM and its bioactive ingredients on metabolic enzymes and/or signal pathways that may impede cancer progress. A total of 46 kinds of TCMs was reported to exert antitumor effects and/or act as chemosensitizers via regulating metabolic processes of cancer cells, and multiple targets and signaling pathways were revealed to contribute to the metabolic-modulating functions of TCM. In conclusion, TCM has its advantages in ameliorating cancer cell metabolic reprogramming by its poly-pharmacological actions. This review may shed some new light on the explicit recognition of the mechanisms of anticancer actions of TCM, leading to the development of natural antitumor drugs based on reshaping cancer cell metabolism.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Medicina Tradicional Chinesa , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
11.
J Mol Histol ; 52(1): 21-30, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33141360

RESUMO

Despite the efficacy of tamoxifen in preventing disease relapse, a large portion of breast cancer patients show intrinsic or acquired resistance to tamoxifen, leading to treatment failure and unfavorable clinical outcome. MYB proto-oncogene like 2 (MYBL2) is a transcription factor implicated in the initiation and progression of various human cancers. However, its role in tamoxifen resistance in breast cancer remained largely unknown. In the present study, by analyzing public transcriptome dataset, we found that MYBL2 is overexpressed in breast cancer and is associated with the poor prognosis of breast cancer patients. By establishing tamoxifen-resistant breast cancer cell lines, we also provided evidence that MYBL2 overexpression contributes to tamoxifen resistance by up-regulating its downstream transcriptional effectors involved in cell proliferation (PLK1, PRC1), survival (BIRC5) and metastasis (HMMR). In contrast, inhibiting those genes via MYBL2 depletion suppresses cancer progression, restores tamoxifen and eventually reduces the risk of disease recurrence. All these findings revealed a critical role of MYBL2 in promoting tamoxifen resistance and exacerbating the progression of breast cancer, which may serve as a novel therapeutic target to overcome drug resistance and improve the prognosis of breast cancer patients.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Tamoxifeno/farmacologia , Transativadores/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos
12.
J Microbiol Biotechnol ; 31(2): 233-239, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33203817

RESUMO

Cyanobacteriochromes (CBCRs) are phytochrome-related photoreceptor proteins in cyanobacteria and cover a wide spectral range from ultraviolet to far-red. A single GAF domain that they contain can bind bilin(s) autocatalytically via heterologous recombination and then fluoresce, with potential applications as biomarkers and biosensors. Here, we report that a novel red/green CBCR GAF domain, SPI1085g2 from Spirulina subsalsa, covalently binds both phycocyanobilin (PCB) and phycoerythrobilin (PEB). The PCB-binding GAF domain exhibited canonical red/green photoconversion with weak fluorescence emission. However, the PEB-binding GAF domain, SPI1085g2-PEB, exhibited an intense orange fluorescence (λabs.max = 520 nm, λfluor.max = 555 nm), with a fluorescence quantum yield close to 1.0. The fluorescence of SPI1085g2-PEB was selectively and instantaneously quenched by copper ions in a concentration-dependent manner and exhibited reversibility upon treatment with the metal chelator EDTA. This study identified a novel PEB-binding cyanobacteriochrome-based fluorescent protein with the highest quantum yield reported to date and suggests its potential as a biosensor for the rapid detection of copper ions.


Assuntos
Proteínas de Bactérias/química , Cobre/metabolismo , Proteínas Luminescentes/química , Fitocromo/química , Spirulina/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cobre/química , Fluorescência , Luz , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Ficobilinas/química , Ficobilinas/metabolismo , Ficocianina/química , Ficocianina/metabolismo , Ficoeritrina/química , Ficoeritrina/metabolismo , Fitocromo/metabolismo , Domínios Proteicos , Spirulina/química , Spirulina/genética
13.
Appl Microbiol Biotechnol ; 104(23): 10059-10074, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33043389

RESUMO

Several quorum sensing systems occurring in Bacillus subtilis, e.g. Rap-Phr systems, were reported to interact with major regulatory proteins, such as ComA, DegU, and Spo0A, in order to regulate competence, sporulation, and synthesis of secondary metabolites. In this study, we characterized a novel Rap-Phr system, RapA4-PhrA4, in Bacillus velezensis NAU-B3. We found that the rapA4 and phrA4 genes were co-transcribed in NAU-B3. When rapA4 was expressed in the heterologous host Bacillus subtilis OKB105, surfactin production and sporulation were severely inhibited. However, when the phrA4 was co-expressed, the RapA4 activity was inhibited. The transcription of the surfactin synthetase srfA gene and sporulation-related genes were also regulated by the RapA4-PhrA4 system. In vitro results obtained from electrophoretic mobility shift assay (EMSA) proved that RapA4 inhibits ComA binding to the promoter of the srfA operon, and the PhrA4 pentapeptide acts as anti-activator of RapA4. We also found that the F24 residue plays a key role in RapA4 function. This study indicated that the novel RapA4-PhrA4 system regulates the surfactin synthesis and sporulation via interaction with ComA, thereby supporting the bacterium to compete and to survive in a hostile environment. KEY POINTS: •Bacillus velezensis NAU-B3 has a novel Rap-Phr quorum sensing system, which does not occur in model strains Bacillus subtilis 168 and B. velezensis FZB42. •RapA4-PhrA4 regulates surfactin production and sporulation. •RapA4-PhrA4 interacts with the ComA protein from ComP/ComA two-component system.


Assuntos
Regulação Bacteriana da Expressão Gênica , Esporos Bacterianos , Bacillus , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Esporos Bacterianos/metabolismo
14.
Theranostics ; 10(22): 10326-10340, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929351

RESUMO

Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Dislipidemias/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , PPAR gama/metabolismo , Proteínas Repressoras/metabolismo , Receptores X de Retinoides/metabolismo , Adolescente , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
15.
Eur J Mass Spectrom (Chichester) ; 26(5): 332-340, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32741213

RESUMO

Metal complexes have extensive applications in catalysis, however, the efficient evaluation of Lewis acidity of metal complexes is still a challenge. Herein, we report a method by using electrospray ionization mass spectrometry (ESI-MS) to evaluate the Lewis acidity of metal complexes in the presence of a reference Lewis base, in which the value of the Lewis acidity can be quantized by the bond dissociation energy (BDE) of the resultant Lewis acid-base pairs. Using this method, the Lewis acidity of tetradentate Schiff-base metal complexes (designated as salenMX), a class of common metal complexes in the homogeneous catalysis, was studied in detail. For the salenM(III)X complexes (M = Al, Cr, Fe, Co), the Lewis acidity tendency is Al > Cr > Fe > Co due to a strong affinity between the Al complex and the reference Lewis base while a weak affinity concerning on the Co complex. Additionally, the effect of ligand steric and electronic nature on the Lewis acidity was studied by using Co complex. Furthermore, density functional theory (DFT) was employed to calculate the BDE, which consists with the results obtained from ESI-MS. The ESI-MS method provides a convenient and efficient method for evaluating the Lewis acidity of metal complexes.

16.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(7): 790-795, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32669180

RESUMO

This article reported the clinical characteristics and SRD5A2 gene mutation pattern of a child with steroid 5-α reductase type 2 deficiency. The 2-month-old boy showed hypospadias and short penis shortly after birth. DNA was extracted from the peripheral blood of the child and his parents. The endocrine disease-related genes were captured and sequenced by high-throughput sequencing technology, and the family DNA samples were verified by Sanger sequencing. The results showed that c.680G>A(p.R227Q) and c.608G>A(p.G203D) compound heterozygous mutations existed in the SRD5A2 gene of the child. The c.680G>A mutation inherited from his father, which was a known pathogenic mutation. The c.608G>A mutation originated from his mother, which was a novel mutation discovered in this study. These results provide molecular evidence for the etiological diagnosis of the child and genetic counseling for the family, as well as extend the mutation spectrum of SRD5A2 gene.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Proteínas de Membrana/genética , Sequência de Bases , Criança , Feminino , Humanos , Hipospadia , Lactente , Masculino , Mutação
17.
World J Stem Cells ; 12(5): 368-380, 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32547685

RESUMO

BACKGROUND: Intrauterine adhesion (IUA) can cause serious damage to women's reproductive health, yet current treatment methods are difficult to achieve satisfactory results. In our previous studies, we demonstrated that menstrual-derived stromal stem cells (MenSCs), with high proliferative capacity and self-renewal ability, have a powerful therapeutic effect in patients with severe IUA. However, safety assessment of MenSCs transplantation is essential for its further application. AIM: To evaluate the short-, medium-, and long-term biosafety of MenSCs via intrauterine transplantation in a rat model of IUA, with a focus on toxicity and tumorigenicity. METHODS: MenSCs were injected into the sub-serosal layer of the uterus in an IUA rat model, for 3 d, 3 mo, and 6 mo separately, to monitor the corresponding acute, sub-chronic, and chronic effects. Healthy rats of the same age served as negative controls. Toxicity effects were evaluated by body weight, organ weight, histopathology, hematology, and biochemistry tests. Tumorigenicity of MenSCs was investigated in Balb/c-nu mice in vivo and by colony formation assays in vitro. RESULTS: Compared with the same week-old control group, all of the IUA rats receiving MenSC transplantation demonstrated no obvious changes in body weight, main organ weight, or blood cell composition during the acute, sub-chronic, and chronic observation periods. At the same time, serum biochemical tests showed no adverse effects on metabolism or liver and kidney function. After 4 wk of subcutaneous injection of MenSCs in Balb/c-nu nude mice, no tumor formation or cell metastasis was observed. Moreover, there was no tumor colony formation of MenSCs during soft agar culture in vitro. CONCLUSION: There is no acute, sub-chronic, or chronic poisoning, infection, tumorigenesis, or endometriosis in rats with IUA after MenSC transplantation. The above results suggest that intrauterine transplantation of MenSCs is safe for endometrial treatment.

18.
Neural Regen Res ; 15(7): 1350-1359, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31960824

RESUMO

Interleukin 17 (IL-17) and its main producer, T cell receptor γδ cells, have neurotoxic effects in the pathogenesis of intracerebral hemorrhage (ICH), aggravating brain injuries. To investigate the correlation between IL-17 and ICH, we dynamically screened serum IL-17 concentrations using enzyme-linked immunosorbent assay and explored the clinical values of IL-17 in ICH patients. There was a significant negative correlation between serum IL-17 level and neurological recovery status in ICH patients (r = -0.498, P < 0.01). To study the neurotoxic role of IL-17, C57BL/6 mice were used to establish an ICH model by injecting autologous blood into the caudate nucleus. Subsequently, the mice were treated with mouse neural stem cells (NSCs) and/or IL-17 neutralizing antibody for 72 hours. Flow cytometry, brain water content detection, Nissl staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling results indicated that NSC transplantation significantly reduced IL-17 expression in peri-hematoma tissue, but there was no difference in T cell receptor γδ cells. Compared with the ICH group, there were fewer apoptotic bodies and more Nissl bodies in the ICH + NSC group and the ICH + NSC + IL-17 group. To investigate the potential effect of IL-17 on directional differentiation of NSCs, we cultured mouse NSCs (NE-4C) alone or co-cultured them with T cell receptor γδ cells, which were isolated from mouse peripheral blood mononuclear cells, for 7 days. The results of western blot assays revealed that IL-17 secreted by T cell receptor γδ cells reduced the differentiation of NSCs into astrocytes and neurons, while IL-17 neutralization relieved the inhibition of directional differentiation into astrocytes rather than neurons. In conclusion, serum IL-17 levels were elevated in the early stage of ICH and were negatively correlated with outcome in ICH patients. Animal experiments and cytological investigations therefore demonstrated that IL-17 probably has neurotoxic roles in ICH because of its inhibitory effects on the directional differentiation of NSCs. The application of IL-17 neutralizing antibody may promote the directional differentiation of NSCs into astrocytes. This study was approved by the Clinical Research Ethics Committee of Anhui Medical University of China (For human study: Approval No. 20170135) in December 2016. All animal handling and experimentation were reviewed and approved by the Institutional Animal Care and Use Committee of Anhui Medical University (approval No. 20180248) in December 2017.

19.
J Atheroscler Thromb ; 27(6): 545-610, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31597886

RESUMO

AIM: Exosome-derived microRNAs (miRNAs) are potential diagnostic biomarkers. However, little is known about their effectiveness as diagnostic biomarkers of intracranial aneurysms (IAs). This study aimed to explore miRNA levels in plasma exosomes of patients with IA to identify potential biomarkers that predict the development and progress of IA. METHODS: A total of 69 patients with IA and 30 healthy controls (HC) were recruited, among whom 30 had unruptured IA (UA), and 39 had ruptured IA (RA). The miRNA expression profiles of plasma exosomes in 12 IA patients (4 UA and 8 RA) and 4 HC were determined using next-generation sequencing. In addition, significantly differentially expressed miRNAs were further analyzed by Quantitative Real-Time PCR (qRT-PCR) in a validation cohort of 99 subjects. RESULTS: From the sequencing analysis, 181 miRNAs were identified to be differently (p<0.05) expressed. Of these, 9 miRNAs were up-regulated, and 20 were down-regulated in patients with UA compared with HC. Also, 21 were up-regulated, and 10 were down-regulated in patients with RA compared with HC. In addition, compared with UA, 92 miRNAs were up-regulated in RA, whereas 29 were down-regulated. Furthermore, qRT-PCR analysis confirmed that miR-145-5p and miR-29a-3p were up-regulated in IA samples. To distinguish IA patients from controls, the area under the receiver operating characteristic curve was 0.791 for miR-29a-3p, while that of miRNA-145-5p was 0.773 in terms of discriminating whether the aneurysm was ruptured. CONCLUSIONS: Circulating exosomal miRNAs can serve as biomarkers of the development and progression of IA.


Assuntos
Aneurisma Roto , Exossomos/genética , Aneurisma Intracraniano , MicroRNAs/genética , Hemorragia Subaracnóidea , Aneurisma Roto/complicações , Aneurisma Roto/diagnóstico , Aneurisma Roto/epidemiologia , Aneurisma Roto/genética , China/epidemiologia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Aneurisma Intracraniano/diagnóstico , Aneurisma Intracraniano/epidemiologia , Aneurisma Intracraniano/genética , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/epidemiologia
20.
Nat Commun ; 10(1): 5720, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844113

RESUMO

The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/metabolismo , Proteína Forkhead Box O1/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXB1/genética , Animais , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Pessoa de Meia-Idade , Ligação Proteica , Proteólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise Serial de Tecidos , Transcrição Genética , Ensaios Antitumorais Modelo de Xenoenxerto
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