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1.
ACS Nano ; 18(12): 8718-8732, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38465955

RESUMO

Although stem cell therapy is proved to be a promising strategy for bone repair and regeneration, transplanted allogeneic stem cells generally suffer from unfavorable apoptosis instead of differentiation into osteocytes. How the apoptotic stem cells promote bone regeneration still needs to be uncovered. In this work, we found that apoptotic extracellular vesicles released by allogeneic stem cells are critical mediators for promoting bone regeneration. Based on the results of in vivo experiments, a mechanism of apoptotic stem cells determined autologous stem cell recruitment and enhance osteogenesis was proposed. The nanoscaled apoptotic extracellular vesicles released from transplanted stem cells were endocytosed by vascular endothelial cells and preferentially distribute at endoplasmic reticular region. The oxidized phosphatidylcholine enriched in the vesicles activated the endoplasmic reticulum stress and triggered the reflective elevation of adhesion molecules, which induced the recruitment of autologous stem cells located in the blood vessels, transported them into the defect region, and promoted osteogenesis and bone repair. These findings not only reveal the mechanism of stem cell therapy of bone defects but also provide a cue for investigation of the biological process of stem cell therapy for other diseases and develop stem cell therapeutic strategies.


Assuntos
Células Progenitoras Endoteliais , Vesículas Extracelulares , Transplante de Células-Tronco Hematopoéticas , Osteogênese , Vesículas Extracelulares/metabolismo , Diferenciação Celular
2.
Biol Res ; 57(1): 3, 2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38217055

RESUMO

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.


Assuntos
Exossomos , Neomicina , Neomicina/toxicidade , Neomicina/metabolismo , Exossomos/metabolismo , Células Ciliadas Auditivas , Autofagia/fisiologia
3.
Adv Sci (Weinh) ; 11(13): e2306884, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38247172

RESUMO

Sepsis poses a significant challenge in clinical management. Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a Staphylococcus aureus-induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage-released apoEVs, which bound iron-containing proteins and neutralized α-toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti-inflammatory agents (microRNA-146a). These engineered apoEVs can capture iron and neutralize α-toxin with their natural membrane while also regulating inflammation by releasing microRNA-146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes-driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron-loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.


Assuntos
Vesículas Extracelulares , MicroRNAs , Sepse , Humanos , Ferro/metabolismo , Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Sepse/terapia , MicroRNAs/metabolismo , Eritrócitos
4.
Biol. Res ; 57: 3-3, 2024. ilus, graf, tab
Artigo em Inglês | LILACS | ID: biblio-1550058

RESUMO

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.


Assuntos
Neomicina/metabolismo , Neomicina/toxicidade , Exossomos/metabolismo , Autofagia/fisiologia , Células Ciliadas Auditivas
5.
Anal Sci ; 39(12): 2059-2065, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37704924

RESUMO

The enzyme-linked immunosorbent assay (ELISA) offers several advantages, including simple operation, high throughput, and low cost, making it an ideal immunoassay method for efficient screening of disease-related biomarkers in clinical samples. However, the traditional colorimetric ELISA has relatively low sensitivity, which promotes the continuous emergence of various novel signal amplification technologies. In this work, we fused the AFP-specific nanobody (A1) with the streptavidin-binding peptide (SBP) to develop a fusion protein (A1-SBP) as biorecognition element in a colorimetric ELISA for detecting AFP. Besides, to further improve the sensitivity of the traditional colorimetric ELISA, the streptavidin-conjugated polymerized horseradish peroxidase (SA-PolyHRP) were selected as a detection probe for signal amplification. The proposed signal enhancement strategy demonstrated a limit of detection (LOD) of 0.597 ng/mL for the SA-polyHRP-based ELISA, which is 7.67-fold lower than that of the traditional SA-HRP-based ELISA without additional steps. Furthermore, the proposed SA-polyHRP-based ELISA showed a good correlation with the detection of clinical samples using the Roche E601 chemiluminescence immunoassay analyzer. Therefore, the proposed signal enhancement strategy is an attractive approach for improving the sensitivity of immunoassay without requiring additional steps.


Assuntos
alfa-Fetoproteínas , Estreptavidina , alfa-Fetoproteínas/análise , Imunoensaio/métodos , Ensaio de Imunoadsorção Enzimática , Peroxidase do Rábano Silvestre/metabolismo
6.
Nat Metab ; 5(1): 111-128, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36658400

RESUMO

Immediate restriction of iron initiated by the host is a critical process to protect against bacterial infections and has been described in the liver and spleen, but it remains unclear whether this response also entails a humoral mechanism that would enable systemic sequestering of iron upon infection. Here we show that upon bacterial invasion, host macrophages immediately release extracellular vesicles (EVs) that capture circulating iron-containing proteins. Mechanistically, in a sepsis model in female mice, Salmonella enterica subsp. enterica serovar Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol-requiring enzyme 1α signaling, triggering lysosomal dysfunction and thereby promoting the release of EVs, which bear multiple receptors required for iron uptake. By binding to circulating iron-containing proteins, these EVs prevent bacteria from iron acquisition, which inhibits their growth and ultimately protects against infection and related tissue damage. Our findings reveal a humoral mechanism that can promptly regulate systemic iron metabolism during bacterial infection.


Assuntos
Vesículas Extracelulares , Salmonelose Animal , Feminino , Animais , Camundongos , Salmonelose Animal/metabolismo , Salmonelose Animal/microbiologia , Salmonella typhimurium/metabolismo , Ferro/metabolismo , Antibacterianos , Vesículas Extracelulares/metabolismo
7.
Int J Oral Sci ; 15(1): 7, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36646698

RESUMO

Severe muscle injury is hard to heal and always results in a poor prognosis. Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine, however, whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown. Herein, we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells (MSCs-ApoEVs) to treat cardiotoxin induced tibialis anterior (TA) injury and found that MSCs-ApoEVs promoted muscles regeneration and increased the proportion of multinucleated cells. Besides that, we also found that apoptosis was synchronized during myoblasts fusion and MSCs-ApoEVs promoted the apoptosis ratio as well as the fusion index of myoblasts. Furthermore, we revealed that MSCs-ApoEVs increased the relative level of creatine during myoblasts fusion, which was released via activated Pannexin 1 channel. Moreover, we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived ApoEVs (Myo-ApoEVs) instead of apoptotic myoblasts, and creatine was the pivotal metabolite involved in myoblasts fusion. Collectively, our findings firstly revealed that MSCs-ApoEVs can promote muscle regeneration and elucidated that the new function of ApoEVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel, which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.


Assuntos
Conexinas , Creatina , Vesículas Extracelulares , Mioblastos , Creatina/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Regeneração , Conexinas/metabolismo
8.
Adv Sci (Weinh) ; 9(21): e2105650, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35603963

RESUMO

Inflammation plays a crucial role in triggering regeneration, while inadequate or chronic inflammation hinders the regenerative process, resulting in refractory wounds. Inspired by the ideal regeneration mode in lower vertebrates and the human oral mucosa, realigning dysregulated inflammation to a heightened and acute response provides a promising option for refractory wound therapy. Neutrophils play important roles in inflammation initiation and resolution. Here, a hybrid biomaterial is used to stimulate transiently heightened inflammatory responses by precise tempospatial regulation of neutrophil recruitment and apoptosis. The hybrid biomaterial (Gel@fMLP/SiO2 -FasL) is constructed by loading of formyl-met-leu-phe (fMLP) and FasL-conjugated silica nanoparticles (SiO2 -FasL) into a pH-responsive hydrogel matrix. This composition enables burst release of fMLP to rapidly recruit neutrophils for heightened inflammation initiation. After neutrophils act to produce acids, the pH-responsive hydrogel degrades to expose SiO2 -FasL, which induces activated neutrophils apoptosis via FasL-Fas signaling triggering timely inflammation resolution. Apoptotic neutrophils are subsequently cleared by macrophages, and this efferocytosis activates key signalings to promote macrophage anti-inflammatory phenotypic transformation to drive regeneration. Ultimately, Gel@fMLP/SiO2 -FasL successfully promotes tissue regeneration by manipulating inflammation in critical-sized calvarial bone defects and diabetic cutaneous wound models. This work provides a new strategy for refractory wound therapy via inducing transiently heightened inflammatory responses.


Assuntos
Materiais Biocompatíveis , Dióxido de Silício , Animais , Humanos , Hidrogéis , Inflamação , Cicatrização
9.
Small Methods ; 6(3): e2100763, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35312228

RESUMO

Innervation and extracellular vesicle secretion co-exist in the local tissue microenvironment for message transfer, but whether they are interconnected to regulate organ homeostasis remains unknown. Sympatho-adrenergic activation is implicated in stress-induced depression and leads to bone loss, but the mechanisms and therapeutics are incompletely elucidated. Here, it is revealed that sympathetic neurostress through the ß1/2 -adrenergic receptor (ß1/2-AR) signaling triggers the transcription response of a microRNA, miR-21, in osteoblasts, which is transferred to osteoclast progenitors via exosomes for dictating osteoclastogenesis. After confirming that miR-21 deficiency retards the ß1/2-AR agonist isoproterenol (ISO)-induced osteopenia, it is shown that the pharmacological inhibition of exosome release by two clinically-relevant drugs, dimethyl amiloride and omeprazole, suppresses osteoblastic miR-21 transfer and ameliorates bone loss under both ISO and chronic variable stress (CVS)-induced depression conditions. A targeted delivery approach to specifically silence osteoblastic miR-21 is further applied, which is effective in rescuing the bone remodeling balance and ameliorating ISO- and CVS-induced osteopenias. These results decipher a previously unrecognized paradigm that neural cues drive exosomal microRNA communication to regulate organ homeostasis and help to establish feasible strategies to counteract bone loss under psychological stresses.


Assuntos
Doenças Ósseas Metabólicas , Exossomos , MicroRNAs , Osso e Ossos , Exossomos/genética , Homeostase , Humanos , MicroRNAs/genética
10.
Environ Toxicol ; 36(4): 550-561, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33236829

RESUMO

ZnO nanoparticles (NPs) are among the most manufactured nanoparticles in the consumer products, industries, and researches. An increasing body of evidence indicated that ZnO NPs show toxicological effects in vivo. Sex differences in the toxicity of ZnO NPs are not clear, thus the aim of this study was to investigate the effects of ZnO NPs on the female and male reproductive organs (uterus, ovary and testes). ZnO NPs were orally administered to female and male mice at dosages level of 0 and 100 mg/kg body weight. The biological material was sampled 3 days after tube feeding. The results demonstrated that Zinc contents were accumulated in the reproductive organs of treated mice. Furthermore, ZnO NPs administration induced significant decrease in the testes weight, an imbalance of hematological and serum biochemical parameters in male mice. The histopathological examinations showed that structural disorder and the appearance of cell apoptosis and death in the ZnO NPs-exposed mice. Additionally, the RT-qPCR data indicated ZnO NPs can activate mitochondrial-mediated signaling pathway and induce caspase depend damage that ultimately injured the uterus. In the ovary, ZnO NPs induce cell apoptosis in Shh pathway activated ovary cells, and affect the synthesis of steroidogenesis. In the testes, ZnO NPs effectively changed the expression level of genes related to oxidant stress, detox/metabolic process, and apoptosis. It was found that ZnO NPs caused more serious reproductive toxicity in the male mice than female mice. Overall, these findings indicated that ZnO NPs could induce exposure-related risks to reproductive health, especially in those who are at the occupational level.


Assuntos
Expressão Gênica/efeitos dos fármacos , Nanopartículas/toxicidade , Ovário/efeitos dos fármacos , Testículo/efeitos dos fármacos , Útero/efeitos dos fármacos , Óxido de Zinco/toxicidade , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Bioacumulação , Biomarcadores/sangue , Caspases/genética , Feminino , Masculino , Camundongos , Nanopartículas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Transdução de Sinais , Testículo/metabolismo , Testículo/patologia , Útero/metabolismo , Útero/patologia , Zinco , Óxido de Zinco/metabolismo
11.
Ther Adv Musculoskelet Dis ; 12: 1759720X20953331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029202

RESUMO

AIMS: Osteoporosis is underdiagnosed because of the lack of a convenient diagnostic method. Circulating microRNAs (miRNAs) emerge as novel biomarkers for disease diagnosis. Here, we conducted a case-control study that included a total of 448 serum samples collected from 182 healthy participants, 132 osteopenia participants, and 134 osteoporosis patients. METHODS: Circulating miRNAs dysregulated during osteoporosis were screened and analyzed in three randomly determined sub-cohorts: the discovery cohort identified 22 candidate miRNAs; the training cohort tested the candidate miRNAs and constructed Index 1, comprising five miRNAs by logistic regression, and Index 2, comprising four miRNAs, was developed by linear combination. RESULTS: Both indices were tested in the validation cohort and showed statistically significant results in distinguishing osteoporosis patients from healthy and osteopenic patients. Moreover, Index 1 also showed improved performance over traditional bone turnover biomarkers type I pro-collagen (tPINP) and type I collagen (ß-CTx). CONCLUSION: In conclusion, circulating miRNAs are potential biomarkers for osteoporosis. The diagnostic panel of circulating miRNAs could be a complementary method for dual-energy X-ray absorptiometry (DXA) in mass screening and routine examination to enhance the osteoporosis detection rate.

12.
Nanomaterials (Basel) ; 9(2)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769773

RESUMO

The toxicity, especially the transgenerational toxicity of quantum dots (QDs) in vivo, is still scarcely understood in spite of great promising applications of QDs in biomedicine. In this study, the maternal status, pregnancy outcome, and fetus development of parental generation (P0) to offspring in three generations (F3) were investigated after Kunming mice perinatal (GD 13-PND 5) exposure to Cd containing QDs (CdSe/ZnS QDs) and CdCl2. The results show CdSe/ZnS QDs induced placenta injuries in P0 and diminished placenta diameters in F1 and F2. Bodyweight growth decreased in the CdSe/ZnS QDs treatment group in the F1 and F2 generation. Additionally, CdSe/ZnS QDs significantly altered the expression of key genes in the Shh signal pathway. Overall, this study exhibited that the CdSe/ZnS QDs exposure during perinatal period impaired placenta growth in the first two generations, but not on the third generation. The toxicological actions of the CdSe/ZnS QDs might be through the effects on the Shh signal pathway.

13.
IET Nanobiotechnol ; 12(5): 562-568, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30095413

RESUMO

Various surface modifications of iron oxide magnetic nanoparticles (IOMNs) can improve their stability and long-term retention time in vivo, expanding applications of biomedical fields. However, whether the long-term retention of IOMNs coated with different surface modifications has toxic effects remains poorly understood. Here, the toxicity of IOMNs modified with polyethylene glycol (PEG), bovine serum albumin (BSA), and carboxyl group (COOH), forming PEG-IOMNs, BSA-IOMNs, and COOH-IOMNs, respectively, were evaluated in the rats. The high accumulation of PEG-IOMNs and COOH-IOMNs both in the liver and lung, and the high accumulation BSA-IOMNs in blood after 24 day recovery were observed by elemental content analysis. Except individual neutrophils in the local portal area, PEG-IOMNs can also induce cytoplasmic vacuolisation in partial liver cells by histopathological examination. Furthermore, the results of RT-qPCR showed that PEG-IOMNs, BSA-IOMNs, and COOH-IOMNs can change the transcript levels of most genes related to iron homeostasis, mitochondria apoptosis, inflammatory response, but <2-fold alteration. COOH-IOMNs seemed to induce normal cell apoptosis more easily than BSA-IOMNs and PEG-IOMNs. In conclusion, BSA-IOMNs had longer-term retention time in blood. IOMNs coated with PEG and BSA can still induce side effects on the liver.


Assuntos
Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/toxicidade , Animais , Apoptose/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Distribuição Tecidual
14.
Nanoscale ; 10(24): 11564-11577, 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29892752

RESUMO

The in vivo toxicity of QDs in animals has been broadly studied; however, their reproductive toxicity towards lactating rodents is currently unknown. This study therefore aims to assess the potential toxicity against dams and offspring after postnatal QD exposure at two doses (5 and 1 nmol per rat) and unravel whether QDs can translocate to pups via breastfeeding. The dose-dependent systemic toxicity of QDs in dams was observed by examining the body weight, hematology, biochemistry, histopathological changes, and sex hormone levels. It was found that the QDs primarily accumulated in the liver and spleen of dams at 1 day post injection (dpi), but the highest concentrations were found in the kidneys at 18 dpi. A few QDs were detected in breast milk and stomach and intestine of pups; this suggested that the QDs were transmitted to breast milk via blood circulation and then transferred to pups via breastfeeding. High-dose QDs induced severe growth inhibition and a 71.08% offspring mortality, while pups showed growth restriction within 90 dpi in the low-dose group. Moreover, the hematology, biochemistry, and histology results showed limited chronic toxicity against offspring in the long term. This study provides a theoretical foundation for the exposure assessment of nanomaterials in lactating animals and for the advancement of QDs in the biomedical field.


Assuntos
Lactação , Exposição Materna/efeitos adversos , Pontos Quânticos/toxicidade , Animais , Peso Corporal , Feminino , Masculino , Leite/química , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Testes de Toxicidade
15.
Stem Cell Res Ther ; 9(1): 88, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615126

RESUMO

BACKGROUND: Skeletal muscle plays an important role in the body's physiology but there are still no effective treatments for volumetric muscle loss (VML) resulting from severe traumatic injury or tumor excision. Recent studies show that a tissue engineering strategy using a compound containing mesenchymal stem cells (MSCs) and decellularized extracellular matrix (ECM) scaffold generates significant regenerative effects on VML injury, but the underlying mechanisms are not fully understood. METHODS: The characteristics of human umbilical cord MSCs, including multiplication capacity and multidifferentiation ability, were determined. We constructed a compound containing MSCs and decellularized ECM scaffold which was used for tissue regeneration in a VML model. RESULTS: We found that MSCs and decellularized ECM scaffold generated synergistic effects on promoting skeletal muscle tissue regeneration. Interestingly, both MSCs and decellularized ECM scaffold could promote macrophage polarization toward the M2 phenotype and suppress macrophage polarization toward the M1 phenotype, which is widely regarded as an important promoting factor in tissue regeneration. More importantly, MSCs and decellularized ECM scaffold generate synergistic promoting effects on macrophage polarization toward the M2 phenotype, not just an additive effect. CONCLUSIONS: Our findings uncover a previously unknown mechanism that MSCs and decellularized ECM scaffold promote tissue regeneration via collaboratively regulating macrophage polarization.


Assuntos
Diferenciação Celular , Matriz Extracelular/metabolismo , Macrófagos/citologia , Células-Tronco Mesenquimais/citologia , Músculo Esquelético/fisiologia , Regeneração , Animais , Células Cultivadas , Humanos , Macrófagos/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Ratos , Ratos Sprague-Dawley
16.
FASEB J ; 32(4): 1982-1992, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29203591

RESUMO

Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , MicroRNAs/genética , Osteoporose/imunologia , Animais , Apoptose , Células Cultivadas , Colite Ulcerativa/terapia , Proteína Ligante Fas/metabolismo , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Linfócitos T/imunologia , Receptor fas/metabolismo
17.
Sci Rep ; 7(1): 3303, 2017 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-28607366

RESUMO

Nanoparticles (NPs) size, surface functionalization, and concentration were claimed to contribute to distribution and toxicity outcomes of NPs in vivo. However, intrinsic chemical compositions of NPs caused inconsistent biodistribution and toxic profiles which attracted little attention. In this study, silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were used to determine the biodistribution, toxickinetic, and genotoxicity variances in murine animals. The results demonstrated AgNPs and AuNPs were primarily deposited in the mononuclear phagocyte system (MPS) such as the liver and spleen. In particular, AuNPs seemed to be prominently stored in the liver, whereas AgNPs preferentially accumulated in more organs such as the heart, lung, kidney, etc. Also, the circulation in the blood and fecal excretions showed higher AgNPs contents in comparison with the AuNPs. Measurements of the mouse body and organ mass, hematology and biochemistry evaluation, and histopathological examinations indicated slight toxic difference between the AgNPs and AuNPs over a period of two months. RT-qPCR data revealed that AgNPs induced greater changes in gene expression with relevance to oxidative stress, apoptosis, and ion transport. Our observations proved that the NPs chemical composition played a critical role in their in vivo biodistribution and toxicity.


Assuntos
Ouro/administração & dosagem , Ouro/toxicidade , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/toxicidade , Prata/administração & dosagem , Prata/toxicidade , Administração Intravenosa , Animais , Peso Corporal/efeitos dos fármacos , Perfilação da Expressão Gênica , Processamento de Imagem Assistida por Computador , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Especificidade de Órgãos , Distribuição Tecidual/efeitos dos fármacos
18.
Environ Pollut ; 218: 863-869, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27524254

RESUMO

Ultra-fine-ZnO showed low toxicity in complex water matrix containing multiple components such as PBS buffer and the toxic mechanism of ultra-fine-ZnO has not been clearly elucidated. In present study, enhanced antibacterial activity of 200 nm diameter ultra-fine-ZnO in PBS buffer against Bacillus cereus and Escherichia coli were observed in the presence of several organic acids in comparison with ultra-fine-ZnO in PBS buffer alone. These findings indicated that the toxic effects of the ultra-fine-ZnO was dependent on the concentration of released Zn2+ which was affected by organic acids. The production of reactive oxygen species (ROS) did not responsible to the toxic mechanism of ultra-fine-ZnO which was tested using the antioxidant N-Acetylcysteine (NAC). Indeed, ultra-fine-ZnO induced bacteria cell membrane leakages and cell morphology damages that eventually led to cell death, which were confirmed using propidium monoazide (PMA) in combination with PCR and scanning electron microscopy (SEM). All data gathered herein suggested that released Zn2+ played a major role in the microbial toxicity of ultra-fine-ZnO.


Assuntos
Antibacterianos/farmacologia , Bacillus cereus/efeitos dos fármacos , Ácidos Carboxílicos/química , Escherichia coli O157/efeitos dos fármacos , Fosfatos/química , Óxido de Zinco/farmacologia , Antibacterianos/química , Azidas/química , Bacillus cereus/metabolismo , Bacillus cereus/ultraestrutura , Soluções Tampão , Relação Dose-Resposta a Droga , Escherichia coli O157/metabolismo , Escherichia coli O157/ultraestrutura , Viabilidade Microbiana/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Propídio/análogos & derivados , Propídio/química , Espécies Reativas de Oxigênio/metabolismo , Solubilidade , Soluções , Óxido de Zinco/química
19.
J Hazard Mater ; 318: 61-69, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27399148

RESUMO

In this study, the effects of cadmium containing QDs (such as CdSe/ZnS and CdSe QDs) and bulk CdCl2 in pregnant mice, their fetuses, and the pregnancy outcomes were investigated. It was shown that although the QDs and bulk CdCl2 were effectively blocked by the placental barrier, the damage on the placenta caused by CdSe QDs still led to fetus malformation, while the mice in CdSe/ZnS QDs treatment group exhibited slightly hampered growth but showed no significant abnormalities. Moreover, the Cd contents in the placenta and the uterus of CdSe QDs and CdSe/ZnS QDs treatment groups showed significantly higher than the CdCl2 treated group which indicated that the nanoscale size of the QDs allowed relative ease of entry into the gestation tissues. In addition, the CdSe QDs more effectively altered the expression levels of susceptive genes related to cell apoptosis, dysplasia, metal transport, cryptorrhea, and oxidative stress, etc. These findings suggested that the nanoscale size of the QDs were probably more important than the free Cd in inducing toxicity. Furthermore, the results indicated that the outer surface shell coating played a protective role in the adverse effects of QDs on late pregnancy mice.


Assuntos
Compostos de Cádmio/toxicidade , Prenhez/efeitos dos fármacos , Pontos Quânticos/análise , Pontos Quânticos/toxicidade , Animais , Compostos de Cádmio/química , Compostos de Cádmio/farmacocinética , Feminino , Feto/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios Esteroides Gonadais/metabolismo , Crescimento/efeitos dos fármacos , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Tamanho da Partícula , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Resultado da Gravidez , Útero/química , Útero/metabolismo
20.
J Hazard Mater ; 317: 119-126, 2016 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-27262279

RESUMO

ZnO nanoparticles (NPs) have been assessed to show adverse effects on the liver, but the molecular mechanisms and the role of nanoparticle properties in these adverse reactions have not been sufficiently studied. In this study, the toxicity of various sizes of ZnO particles (bulk, 90nm, and 30nm) that were ingested orally over a period of 3days were evaluated in mice. The blood biochemistry, hematological analyses, and histopathological evaluation showed that there was apparent toxicity caused by smaller ZnO NPs (30nm) in liver. The smallest ZnO NPs showed highest accumulation in the mice liver. The RT-qPCR data indicated that 30nm ZnO NPs can induce significant endoplasmic reticulum (ER) stress responses. The ER stress marker of PERK, eIF2α, ATF4, Chop, JNK, caspase-12, caspase-9, GRP94, and Bax at the mRNA levels were higher expression in 30nm ZnO NP than that in bulk or 90nm ZnO. These findings implied that the smaller ZnO NPs (30nm) activated ER stress responses that signified severe apoptosis in murine liver.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas/toxicidade , Óxido de Zinco/toxicidade , Administração Oral , Animais , Biomarcadores/sangue , Estresse do Retículo Endoplasmático/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos , Nanopartículas/análise , Tamanho da Partícula , Óxido de Zinco/análise
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