RESUMO
The neuropeptide oxytocin (OXT) is well recognized for eliciting anxiolytic effects and promoting social reward. However, emerging evidence shows that OXT increases aversive events. These seemingly inconsistent results may be attributable to the broad OXT receptor (OXTr) expression in the central nervous system. This study selectively activated septal neurons expressing OXTr using chemogenetics. We found that chemogenetic activation of septal OXTr neurons induced anxiety- but not depressive-like behavior. In addition, septal OXTr neurons projected dense fibers to the horizontal diagonal band of Broca (HDB), and selective stimulation of those HDB projections also elicited anxiety-like behaviors. We also found that septal OXTr neurons express the vesicular GABA transporter (vGAT) protein and optogenetic stimulation of septal OXTr projections to the HDB inactivated HDB neurons. Our data collectively reveal that septal OXTr neurons increase anxiety by projecting inhibitory GABAergic inputs to the HDB.
Assuntos
Ocitocina , Receptores de Ocitocina , Ansiedade , Neurônios/metabolismo , Ocitocina/metabolismo , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Comportamento SocialRESUMO
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with low survival rate, so new therapies are urgently needed. Histone deacetylases (HDACs) play a critical role in tumorigenesis, and HDACs inhibition is a potential therapeutic target in ESSC. In our study, we evaluated the effect and molecular mechanism of MS-275 (an inhibitor of HDACs) on ESCC cells. We found that HDAC1 and HDAC2 were overexpressed in ESCC tissues and related with clinical pathological features of patients with ESCC. MS-275 markedly reduced HDAC1 and HDAC2 expression, whereas increased the level of AcH3 and AcH2B. MS-275 suppressed proliferation and clonogenicity of ESCC cells in a concentration-dependent manner. In addition, MS-275 induced apoptosis, arrested cell cycle, and inhibited migration, epithelial-mesenchymal transition, and sphere-forming ability of ESCC cells in vitro. Moreover, p-Akt1 and p-mTOR were downregulated by MS-275. Finally, MS-275 significantly inhibited tumor growth in vivo. Taken together, HDAC1 and HDAC2 are associated with the progression of ESCC, and MS-275 hinders the progression and stemness of ESCC cells by suppressing the PI3K/Akt/mTOR pathway. Our findings show that MS-275 inhibits ESCC cells growth in vitro and in vivo, which is a potential drug for the ESCC therapy.
Assuntos
Benzamidas/farmacologia , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Movimento Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Experimentais , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
Mesenchymal stem cells (MSCs) are unique precursor cells characterized by active self-renewal and differentiation potential. These cells offer the advantages of ease of isolation and limited ethical issues as a resource and represent a promising cell therapy for neurodegenerative diseases. However, replicative senescence during cell culture as well as low efficiency of cell migration and differentiation after transplantation are major obstacles. In our previous study, we found that FOXQ1 binds directly to the SIRT1 promoter to regulate cellular senescence and also promotes cell proliferation and migration in many tumor cell lines. Currently, little is known about the effects of FOXQ1 on normal somatic cells. Therefore, we examine the effects of FOXQ1 on senescence and migration of MSCs. Lentiviral vector-mediated overexpression of FOXQ1 in human umbilical cord mesenchymal stem cells (hUC-MSCs) resulted in enhanced cell proliferation and viability. Furthermore, the expression of proteins and markers positively associated with senescence (p16, p21, p53) was reduced, whereas expression of proteins negatively associated with senescence (SIRT1, PCNA) was promoted. Following transplantation of hUC-MSCs overexpressing FOXQ1 in an animal model of Alzheimer's disease (APPV717I transgenic mice) resulted in amelioration of the effects of Alzheimer's disease (AD) on cognitive function and pathological senescence accompanied the increased numbers of hUC-MSCs in the AD brain. In conclusion, FOXQ1 overexpression promotes anti-senescence and migration of hUC-MSCs in vitro and in vivo. These findings also suggest that this strategy may contribute to optimization of the efficiency of stem cell therapy.
Assuntos
Movimento Celular/genética , Senescência Celular/genética , Fatores de Transcrição Forkhead/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/citologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Células HEK293 , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Camundongos TransgênicosRESUMO
The incidence of cognitive impairment is rising globally, but there is no effective therapy. Recent studies showed that fucoidan (Fuc), a sulfated polysaccharide enriched in brown algae, is widely used due to its anti-inflammatory, antioxidant, and prebiotic effects. However, the effects and mechanisms of Fuc on lipopolysaccharide (LPS)-induced neuronal cell damage and cognitive impairment in mice need to be explored further. In the present study, we found that Fuc treatment protected HT22 cells from LPS-induced damage by inhibiting the activation of NLRP3 inflammasomes. Fuc exerted neuroprotective effects in mice with LPS-induced cognitive impairment by ameliorating neuroinflammation, promoting neurogenesis, and reducing blood-brain barrier and intestinal barrier permeability. Mechanistically, Fuc supplement significantly restructured the gut microbiota composition, which may be related to glucose and fructose metabolism. In conclusion, Fuc ameliorated LPS-induced neuronal cell damage and cognitive impairment in mice, suggesting that Fuc may be a medicinal and food homologous functional agent to improve cognitive function.
Assuntos
Disfunção Cognitiva , Phaeophyceae , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológicoRESUMO
Stem cell therapy is promising for neural repair in devastating traumatic brain injury (TBI). However, the low survival and differentiation rates of transplanted stem cells are main obstacles to efficient stem cell therapy in TBI. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are key factors that regulate the survival, recruitment, and differentiation of stem cells. Herein, we synthesized a sodium alginate (SA)/collagen type I (Col)/SDF-1 hydrogel and investigated whether the SA/Col/SDF-1 hydrogel loaded with bone marrow-derived mesenchymal stem cells (BMSCs) had therapeutic effects on a TBI model. Our results showed that the SA/Col/SDF-1 scaffold could stably release SDF-1 and provide biocompatible and biodegradable microenvironment for the survival, migration, and neuronal differentiation of BMSCs in vitro. In a rat model of TBI, the SA/Col/SDF-1 hydrogel loaded with BMSCs significantly ameliorated motor and cognition dysfunction and relieved anxiety and depressive-like behaviors. In addition, the BMSCs/SA/Col/SDF-1 scaffold reduced brain lesions and neuronal cell death and mitigated neuroinflammation. Further studies demonstrated that the BMSCs/SA/Col/SDF-1 hydrogel promoted the migration of BMSCs in the lesions and partly enhanced neurogenesis by activating the SDF-1/CXCR4-mediated FAK/PI3K/AKT pathway. Taken together, our results indicate that the SA/Col/SDF-1 scaffold loaded with BMSCs exerts neuroreparative effects in a TBI rat model, and thus, it may serve as an alternative neural regeneration scaffold for brain injury repair. STATEMENT OF SIGNIFICANCE: Hydrogel facilitates the biological behaviors of transplanted stem cells for tissue regeneration. In this study, we synthesized sodium alginate (SA)/collagen type I (Col)/ scaffold to simultaneously deliver stromal cell derived factor-1 (SDF-1) and bone marrow mesenchymal stem cells (BMSCs) in a rat model of traumatic brain injury (TBI). We found that the SA/Col/SDF-1 hydrogel could continuously release SDF-1 and was conducive to the survival, migration and neuronal differentiation of BMSCs in vitro. In addition, the SA/Col/SDF-1 hydrogel loaded with BMSCs significantly ameliorated neurological deficits, mitigated neuroinflammation, promoted the recruitment of BMSCs and enhanced neurogenesis in TBI partly by activating the SDF-1/CXCR4-mediated FAK/PI3K/AKT pathway. Our results may serve as an alternative neural regeneration strategy for brain injury.
Assuntos
Lesões Encefálicas Traumáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Alicerces Teciduais , Alginatos/farmacologia , Animais , Lesões Encefálicas Traumáticas/terapia , Quimiocina CXCL12 , Colágeno , Ratos , Receptores CXCR4 , Recuperação de Função Fisiológica , Transdução de SinaisRESUMO
The inflammatory microenvironment in a lesion is not conducive to the survival of stem cells. Improving the inflammatory microenvironment may be an alternative strategy to enhance the efficacy of stem cells. We evaluated the therapeutic effect and molecular mechanism of mitsugumin53 (MG53) on lipopolysaccharide (LPS)-induced damage in human umbilical cord mesenchymal stem cells (hUC-MSCs) and in C57/BL6 mice. MG53 significantly promoted the proliferation and migration of hUC-MSCs, protected hUC-MSCs against LPS-induced apoptosis and mitochondrial dysfunction, and reversed LPS-induced inflammatory cytokine release. Furthermore, MG53 combined with hUC-MSCs transplantation improved LPS-induced memory impairment and activated neurogenesis by promoting the migration of hUC-MSCs and enhancing ßIII-tubulin and doublecortin (DCX) expression. MG53 protein combined with hUC-MSCs improved the M1/M2 phenotype polarization of microglia accompanied by lower inducible nitric oxide synthase (iNOS) expression and higher arginase 1 (ARG1) expression. MG53 significantly suppressed the expression of tumor necrosis factor α (TNF-α), Toll-like receptor 4 (TLR4), nucleotide oligomerization domain-like receptor protein 3 (NLRP3), cleaved-caspase-1, and interleukin (IL)-1ß to alleviate LPS-induced neuroinflammation on hUC-MSCs and C57/BL6 mice. In conclusion, our results indicated that MG53 could protect hUC-MSCs against LPS-induced inflammatory damage and facilitate their efficacy in LPS-treated C57/BL6 mice partly by inhibiting the NLRP3/caspase-1/IL-1ß axis.
Assuntos
Transplante de Células-Tronco Mesenquimais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Encéfalo , Caspase 1 , Proteína Duplacortina , Proteínas de Membrana , Camundongos , Cordão UmbilicalRESUMO
Chimeric RNAs are transcripts composed of RNA fragments from different genes and are traditionally well-known cancer-causing genetic events. Recent studies show chimeric RNAs being present in multiple non-neoplastic tissues and cells, suggesting that at least some may have roles in normal physiology. However, chimeric RNAs and their implications in brain development and neural differentiation have not been formally studied. Here, we firstly characterized the landscape of chimeric RNAs in human infant brain tissues and identified 599 chimeric RNAs. Through a series of filtering, 22 were selected and tested in a neural differentiation process starting from stem cells. Ten were validated experimentally. One of these ten chimeric RNAs, DUS4L-BCAP29, dramatically increased when human umbilical mesenchymal stem cells were induced for neural differentiation. Consistently, we found that overexpressed DUS4L-BCAP29 effectively promoted neural differentiation. Our results support the important role(s) chimeric RNAs play in neural differentiation, and are consistent with the new notion that chimeric RNAs also exist in normal physiology, and likely serve biological purposes.
Assuntos
Encéfalo/citologia , Diferenciação Celular/genética , Fusão Gênica/genética , Humanos , Lactente , Proteínas de Membrana/genética , RNA Mensageiro/genéticaRESUMO
Neuroinflammation plays important roles in the pathogenesis and development of neurodegenerative disorders. Lipopolysaccharide (LPS) induces neuroinflammation and causes neurotoxicity, which results in cell damage or memory impairment in different cells and animals. In the present study, we investigated the neuroprotective effects of MG53, a member of the TRIM family proteins, against LPS-induced neuroinflammation and neurotoxicity in vitro and in vivo. MG53 significantly protected HT22 cells against LPS-induced cell apoptosis and cell cycle arrest by inhibiting TNF-α, IL-6 and IL-1ß expression. In addition, MG53 ameliorated LPS-induced memory impairment and neuronal cell death in mice. Interestingly, MG53 significantly promoted newborn cell survival, improved neurogenesis, and mitigated neuroinflammation evidenced by lower production of IL-1ß and IL-6, less activation of microglia in the hippocampus of LPS treated mice. Further studies demonstrated that MG53 significantly inhibited TLR4 expression and nuclear factor-κB (NF-κB) phosphorylation in LPS treated HT22 cells and mice. Taken together, our results suggested that MG53 attenuated LPS-induced neurotoxicity and neuroinflammation partly by inhibiting TLR4/NF-κB pathway in vitro and in vivo.
Assuntos
Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas com Motivo Tripartido/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismoRESUMO
[This corrects the article DOI: 10.3389/fncel.2018.00498.].
RESUMO
BACKGROUND: Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. METHODS: In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. RESULTS: We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3ß signaling. CONCLUSION: MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.
Assuntos
Lesões Encefálicas Traumáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Estresse Oxidativo , Transdução de Sinais , Proteínas com Motivo Tripartido/metabolismo , Cordão Umbilical , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/terapia , Sobrevivência Celular , Modelos Animais de Doenças , Xenoenxertos , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Cordão Umbilical/metabolismo , Cordão Umbilical/patologiaRESUMO
Accumulating evidence suggests that oxidative stress induced by beta-amyloid (Aß) is implicated in the pathlogical progression of Alzheimer's disease (AD). 3H-1,2-dithiole-3-thione (D3T), the simplest compound of the sulfur-containing dithiolethiones, has been proved to be a strongly active antioxidant factor by regulation of the nuclear factor E2-related factor 2 (Nrf2). Previous study reported that D3T confers protection to AD cell model in vitro, however, the neuroprotective effect of D3T in the AD mammalian model is unknown. In the present study, we aimed to evaluate the therapeutic potential of D3T in the Tg2576 AD mouse model and investigate the mechanisms underlying its beneficial effects. We showed that intraperitoneal administration of D3T significantly alleviated cognitive deficits in AD mice and dramatically decreased insoluble Aß level and oxidative stress. Further mechanistic studies revealed that D3T significantly promoted hippocampal neurogenesis, and up-regulated levels of silent information regulator 1 (Sirt1), Nrf2 and heme oxygenase-1 (HO-1). Moreover, the positive effect of D3T on behavioral performance of AD mice was markedly attenuated by inhibition of the Sirt1/Nrf2 pathway by the antagonist EX527. In summary, our studies on a mouse AD model indicate that D3T could serve as a potential therapeutic agent for this devastating disease.
Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Tionas/farmacologia , Tiofenos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tionas/administração & dosagem , Tionas/metabolismo , Tiofenos/administração & dosagem , Tiofenos/metabolismoRESUMO
Stem cell transplantation is a promising therapy for traumatic brain injury (TBI), but low efficiency of survival and differentiation of transplanted stem cells limits its clinical application. Histone deacetylase 1 (HDAC1) plays important roles in self-renewal of stem cells as well as the recovery of brain disorders. However, little is known about the effects of HDAC1 on the survival and efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in vivo. In this study, our results showed that HDAC1 silence promoted hUC-MSCs engraftment in the hippocampus and increased the neuroprotective effects of hUC-MSCs in TBI mouse model, which was accompanied by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus. Further mechanistic studies revealed that the expressions of phosphorylated PTEN (p-PTEN), phosphorylated Akt (p-Akt), and phosphorylated GSK-3ß (p-GSK-3ß) were upregulated. Intriguingly, the neuroprotective effects of hUC-MSCs with HDAC1 silence on behavioral performance of TBI mice was markedly attenuated by LY294002, an inhibitor of the PI3K/AKT pathway. Taken together, our findings suggest that hUC-MSCs transplantation with HDAC1 silence may provide a potential strategy for treating TBI in the future.
RESUMO
Mesenchymal stem cell transplantation is a promising therapeutic approach for Alzheimer's disease (AD). However, poor engraftment and limited survival rates are major obstacles for its clinical application. Resveratrol, an activator of silent information regulator 2, homolog 1 (SIRT1), regulates cell destiny and is beneficial for neurodegenerative disorders. The present study is designed to explore whether resveratrol regulates the fate of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and whether hUC-MSCs combined with resveratrol would be efficacious in the treatment of neurodegeneration in a mouse model of AD through SIRT1 signaling. Herein, we report that resveratrol facilitates hUC-MSCs engraftment in the hippocampus of AD mice and resveratrol enhances the therapeutic effects of hUC-MSCs in this model as demonstrated by improved learning and memory in the Morris water maze, enhanced neurogenesis and alleviated neural apoptosis in the hippocampus of the AD mice. Moreover, hUC-MSCs and resveratrol jointly regulate expression of hippocampal SIRT1, PCNA, p53, ac-p53, p21, and p16. These data strongly suggests that hUC-MSCs transplantation combined with resveratrol may be an effective therapy for AD.
Assuntos
Doença de Alzheimer/terapia , Diferenciação Celular/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Estilbenos/farmacologia , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Humanos , Memória/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Resveratrol , Cordão Umbilical/citologiaRESUMO
Recently, we reported that ß-carotene exhibited anticancer activity against human esophageal squamous cell carcinoma cells in vitro. In the present study, we examined a novel therapeutic strategy by combining ß-carotene with 5-fluorouracil (5-FU) in human esophageal cancer in vitro and in vivo, and elucidated the underlying mechanisms. We found that the combination of 5-FU and ß-carotene displayed greater growth inhibitory effects than did either compound alone in esophageal squamous cell carcinoma (ESCC) cells. In addition, the combination of 5-FU and ß-carotene displayed greater tumor growth inhibition in an Eca109 xenograft mouse model than did a single agent with low systemic toxicity. ß-Carotene enhanced 5-FU-induced apoptosis. TUNEL staining revealed that the rate of TUNEL-positive cells was markedly increased in tumor tissues after treatment with 5-FU and ß-carotene. Western blotting and immunohistochemistry revealed the down-regulation of Bcl-2 and PCNA and the up-regulation of Bax and caspase-3 in tumor tissues. Further studies demonstrated that the combined administration of 5-FU and ß-carotene significantly down-regulated the protein levels of Cav-1, p-AKT, p-NF-κB, p-mTOR and p-p70S6K in Eca109 cells more effectively than did 5-FU alone. These data suggested that the combined therapy of 5-FU and ß-carotene exerted synergistic antitumor effects in vivo and in vitro and could constitute a novel therapeutic treatment for ESCC.