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Oxya chinensis sinuosa (OC) is a well-known edible insect. Several researches on the health benefits of OC consumption have been performed to date; however, their effect on eye health remains largely unknown. This study aimed to assess the protective effects of OC extracts on the oxidative stress on the retinal pigment epithelium (RPE) cells. Oxidative damage has been identified as one of the key regulatory factors in age-related macular degeneration. H2O2-induced reactive oxygen species (ROS) production, a well-known oxidative stress factor, can cause cell death in retinal pigment epithelia cells. In this study, we found that three OC extracts effectively prevented H2O2-induced ROS production and subsequent death of ARPE-19 cells in a dose-dependent manner. In addition, the OC extracts inhibited the phosphorylation of mitogen-activated protein kinases including p38, JNK, and ERK. The OC extracts restored IκBα degradation induced by H2O2, indicating that OC extracts suppressed the activation of nuclear factor-κB. Furthermore, the three OC extracts were shown to have antioxidant effects by up-regulating the intracellular expression of key antioxidant proteins such as SOD, NQO, and HO-1. Here we demonstrated the antioxidant and anti-apoptotic effects of the OC extracts on ARPE-19, indicating their potential role in improving eye health. These results suggest that three OC extracts plays a critical role in oxidative stress-induced cell death protects in ARPE-19 cells.
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[This corrects the article DOI: 10.5851/kosfa.2024.e15.].
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Short sleep duration has been reported to increase the risk of diabetes. However, the influence of sleep duration on glycemic control in diabetic patients has not been clarified. In this study we evaluated the association between sleep duration and glycemic control in diabetic patients. We analyzed the data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2010. Sleep duration was classified into five groups: <6, 6, 7, 8, and ≥9 h/day. Fasting blood glucose and HbA1c showed a U-shaped trend according to sleep duration. Sleep duration of 7 h/day had the lowest HbA1c (7.26%) among the subjects (P=0.026). In the older age group (≥65 yr), a sleep duration of 6 h/day was associated with the lowest HbA1c (7.26%). The adjusted odds ratio (OR) with a 95% confidence interval (CI) of worse glycemic control (HbA1c ≥7.0%) in group of sleep duration of ≥9 h/day was 1.48 (1.04-2.13) compared with the group of 7 h/day. This relationship disappeared after adjusting duration of diabetes (OR, 1.38; 95% CI, 0.93-2.03). Our results suggest that sleep duration and glycemic control in diabetic patients has U-shaped relationship which was mainly affected by duration of diabetes.
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Glicemia/análise , Diabetes Mellitus Tipo 2/diagnóstico , Hemoglobinas Glicadas/análise , Sono/fisiologia , Fatores Etários , Idoso , Povo Asiático , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , República da Coreia , Fatores de RiscoRESUMO
In the present study, we aimed to examine the inhibition of genomic DNA from Lactiplantibacillus plantarum (LpDNA) on Porphyromonas gingivalis lipopolysaccharide (PgLPS)-induced inflammatory responses in RAW264.7 cells. Pretreatment with LpDNA for 15 h significantly inhibited PgLPS-induced mRNA expression and protein secretion of interleukin (IL)-1ß, IL-6, and monocyte chemoattractant protein-1. LpDNA pretreatment also reduced the mRNA expression of Toll-like receptor (TLR)2 and TLR4. Furthermore, LpDNA inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and the activation of nuclear factor-κB (NF-κB) induced by PgLPS. Taken together, these findings demonstrate that LpDNA attenuates PgLPS-induced inflammatory responses by regulating MAPKs and NF-κB signaling pathways through the suppression of TLR2 and TLR4 expression.
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This study aimed to assess whether genomic DNA (gDNA) extracted from Pediococcus acidilactici inhibits Porphyromonas gingivalis lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells. Pretreatment with gDNA of P. acidilactici K10 or P. acidilactici HW01 for 15 h effectively inhibited P. gingivalis LPS-induced mRNA expression of interleukin (IL)-1ß, IL-6, and monocyte chemoattractant protein (MCP)-1. Although both gDNAs did not dose-dependently inhibit P. gingivalis LPS-induced mRNA expression of IL-6 and MCP-1, they inhibited IL-1ß mRNA expression in a dose-dependent manner. Moreover, pretreatment with both gDNAs inhibited the secretion of IL-1ß, IL-6, and MCP-1. When RAW 264.7 cells were stimulated with P. gingivalis LPS alone, the phosphorylation of mitogen-activated protein kinases (MAPKs) was increased. However, the phosphorylation of MAPKs was reduced in the presence of gDNAs. Furthermore, both gDNAs restored IκBα degradation induced by P. gingivalis LPS, indicating that both gDNAs suppressed the activation of nuclear factor-κB (NF-κB). In summary, P. acidilactici gDNA could inhibit P. gingivalis LPS-induced inflammatory responses through the suppression of MAPKs and NF-κB, suggesting that P. acidilactici gDNA could be effective in preventing periodontitis.
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BACKGROUND: Hypothermia in severely burned patients is associated with a significant increase in morbidity and mortality. The use of an oesophageal heat exchanger tube (EHT) can improve perioperative body temperatures in severely burned patients. The aim of this study was to investigate the intraoperative warming effect of oesophageal heat transfer in severe burn patients. METHODS: Single-centre retrospective study performed at the Burns Centre of the University Hospital Zurich. Between January 2020 and May 2021 perioperative temperature management with EHT was explored in burned patients with a total body surface area (TBSA) larger than 30%. Data from patients, who received perioperative temperature management by EHT, were compared to data from the same patients during interventions performed under standard temperature management matching for length and type of intervention. RESULTS: A total of 30 interventions (15 with and 15 without EHT) in 10 patients were analysed. Patient were 38 [26-48] years of age, presented with severe burns covering a median of 50 [42-64] % TBSA and were characterized by an ABSI of 10 [8-12] points. When receiving EHT management patients experienced warming at 0.07 °C per minute (4.2 °C/h) compared to a temperature loss of - 0.03 °C per minute (1.8 °C/h) when only receiving standard temperature management (p < 0.0001). No adverse or serious adverse events were reported. CONCLUSION: The use of an oesophageal heat transfer device was effective and safe in providing perioperative warming to severely burned patients when compared to a standard temperature management protocol. By employing an EHT as primary temperature management device perioperative hypothermia in severely burned patients can possibly be averted, potentially leading to reduced hypothermia-associated complications.
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Queimaduras , Hipotermia Induzida , Hipotermia , Humanos , Temperatura Corporal , Temperatura , Estudos Retrospectivos , Queimaduras/terapiaRESUMO
The aim of the study was to investigate the effect of bacteriocin-like inhibitory substance (BLIS) from Enterococcus faecium DB1 on cariogenic Streptococcus mutans biofilm. Crystal violet staining, fluorescence, and scanning electron microscopy analyses demonstrated that the BLIS from Enterococcus faecium DB1 (DB1 BLIS) inhibited S. mutans biofilm. When DB1 BLIS was co-incubated with S. mutans, biofilm formation by S. mutans was significantly reduced (p<0.05). DB1 BLIS also destroyed the preformed biofilm of S. mutans. In addition, DB1 BLIS decreased the viability of S. mutans biofilm cells during the development of biofilm formation and in the preformed biofilm. DB1 BLIS significantly decreased the growth of S. mutans planktonic cells. Furthermore, S. mutans biofilm on the surface of saliva-coated hydroxyapatite discs was reduced by DB1 BLIS. Taken together, DB1 BLIS might be useful as a preventive and therapeutic agent against dental caries caused by S. mutans.
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Aging, and other disease-related muscle disorders are serious health problems. Dexamethasone (DEX), a synthetic glucocorticoid, can trigger skeletal muscle atrophy. This study examined the effects of mealworm (Tenebrio molitor larva) ethanol extract (TME) on C2C12 myoblast differentiation and DEX-induced myotube atrophy. TME induced myotube formation compared to the differentiation medium (DM) group. TME also significantly increased the mRNA expression of muscle creatine kinase (CKm) and myogenic regulatory factors (MRFs), such as myogenin (MyoG), myogenic factor (Myf)5, and MRF4 (Myf6). TME dramatically increased the muscle-specific protein, MyoG, compared to the control, whereas the expression of myogenic differentiation 1 (MyoD) remained unchanged. It also activated the mammalian target of rapamycin (mTOR) signaling pathway. In the DEX-induced muscle atrophy C2C12 model, TME reduced the gene expression of atrogin-1, muscle RING finger protein-1 (MuRF-1), and myostatin, which are involved in protein degradation in skeletal muscles. Furthermore, TME elevated the phosphorylation of forkhead box O3 (FoxO3α) and protein kinase B (Akt). These findings suggest that TME can enhance myotube hypertrophy by regulating the mTOR signaling pathway, and can rescue DEX-induced muscle atrophy by alleviating atrophic muscle markers mediated by Akt activation. Thus, TME can be a potential therapeutic agent for treating muscle weakness and atrophy.
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Probiotics in livestock feed supplements are considered to be an alternative to antibiotics. However, effector molecules responsible for the beneficial roles of probiotics in pigs are in general not well known. Thus, this study demonstrated that a well-known virulence factor, flagellin of Salmonella typhimurium, significantly induced IL-8 production in porcine peripheral blood mononuclear cells, whereas lipoteichoic acid (LTA), a major cell wall component of Gram-positive bacteria Lactobacillus plantarum, L. casei, and L. rhamnosus GG, effectively inhibited flagellin-induced IL-8 production at mRNA and protein levels. However, the lipoproteins of L. plantarum, L. casei, and L. rhamnosus GG did not suppress flagellin-induced IL-8 production. While D-alanine-deficient L. plantarum LTA inhibited flagellin-induced IL-8 production, L. plantarum LTA deficient in both D-alanine and acyl chains failed to inhibit it; this suggests that the acyl moieties of L. plantarum LTA are essential for inhibiting flagellin-induced IL-8 production. Taken together, L. plantarum LTA plays an important role in improving anti-inflammatory responses of porcine peripheral blood mononuclear cells.
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Flagelina/toxicidade , Interleucina-8/biossíntese , Lactobacillus plantarum/química , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Salmonella typhimurium , Ácidos Teicoicos/farmacologia , Animais , Flagelina/química , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Lipopolissacarídeos/química , Salmonella typhimurium/química , Salmonella typhimurium/patogenicidade , Suínos , Ácidos Teicoicos/químicaRESUMO
Pseudomonas aeruginosa is a potential source of food contamination that leads to food spoilage and infections as a result of the generation of biofilm and virulence factors. In the present study, we demonstrate that bacteriocin produced by Pediococcus acidilactici HW01 (HW01 bacteriocin) effectively inhibited the biofilm formation of Ps. aeruginosa (66.41, 45.77, and 21.73% of biofilm formation at 0.5, 1, and 2 mg/mL of HW01 bacteriocin, respectively) as well as the production of virulence factors. By means of a microtiter plate method and scanning electron microscopy, HW01 bacteriocin inhibited biofilm formation by Ps. aeruginosa in a dose-dependent manner. Although the viability of biofilm cells of Ps. aeruginosa was reduced in the presence of HW01 bacteriocin, the viability of planktonic cells of Ps. aeruginosa was not affected by HW01 bacteriocin (2.0 × 109 CFU/mL vs. 2.4 × 109 CFU/mL in the absence and the presence of HW01 bacteriocin, respectively). Additionally, HW01 bacteriocin decreased the twitching motility of Ps. aeruginosa as well as the production of virulence factors, such as pyocyanin, protease, and rhamnolipid. Furthermore, HW01 bacteriocin significantly inhibited Ps. aeruginosa biofilm formation on the surface of stainless steel (57% reduction at 24 h and 83% reduction at 72 h). These results indicate that HW01 bacteriocin is an effective antagonist of Ps. aeruginosa as a result of its ability to inhibit biofilm formation and the production of virulence factors.
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Antibacterianos/farmacologia , Bacteriocinas/farmacologia , Biofilmes/efeitos dos fármacos , Pediococcus acidilactici/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Fatores de Virulência/metabolismo , Proteínas de Bactérias/metabolismoRESUMO
BACKGROUND/AIMS: Probiotics are expected to modify the composition of gut microbiota. We aimed to investigate the changes in the composition and diversity of gut microbiota by the administration of probiotics in healthy individuals. METHODS: Twelve healthy volunteers with age range of 30-42 years provided baseline fecal samples. Subsequently, they took commercially available probiotic capsules (a mixture for Bifidobacterium, Lactobacillus, and Enterococcus) for 4 weeks. Fecal samples were collected at 4 weeks of administration and 2 weeks after the stop of administration. Fecal microbiota was analyzed via 16S ribosomal RNA gene sequencing. RESULTS: The mean Shannon index was not significantly altered by the 4-week administration of probiotics (4.365 vs 4.556, P ï¼ 0.05). The proportion of Bacteroidetes, Actinobacteria, Firmicutes , and Proteobacteria was not significantly changed by the 4-week administration of probiotics. At the genus level, the proportions of Lactobacillus (2.138% vs 2.773%, P = 0.028) and Enterococcus (0.022% vs 2.758%, P = 0.004) significantly increased 4 weeks after the administration of probiotics, but reduced 2 weeks after the stop of administration (2.773% vs 3.292%, P = 0.064 and 2.758% vs 0.001%, P = 0.001). CONCLUSIONS: The diversity of fecal microbiota is not significantly affected by 4 weeks of probiotics administration. The proportion of fecal microbiota at the genus level is significantly altered by the administration of probiotics. However, this effect does not seem to last long, probably because of homeostasis or dietary influence.
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PURPOSE: Allergic rhinitis (AR) is a common and increasing disease in which Dermatophagoides (D.) farinae is one of the most common causative allergens. The aims of this study were to confirm the presence of locally produced antibodies to D. farinae in nasal secretions between nasal provocation test (NPT)-positive and -negative groups of AR patients, to evaluate their relationships with the levels of inflammatory mediators, and to determine adaptive and innate immune responses in nasal mucosa. METHODS: Sixty AR patients sensitive to house dust mites confirmed by skin prick test or serum specific IgE to D. farinae underwent NPT for D. farinae. Nasal packs were placed in both nasal cavities of the patients for 5 minutes to obtain nasal secretions after NPT. The levels of total IgE, specific IgE to D. farinae, eosinophil cationic protein (ECP), and tryptase in nasal secretions were detected by using ImmunoCAP. The levels of specific IgE, IgA, and secretory IgA antibodies to D. farinae in nasal secretions were measured by using ELISA. The levels of IL-8, VEGF, IL-25, and IL-33 were also measured by using ELISA. RESULTS: High levels of total IgE, specific IgE, specific IgA, and secretory IgA to D. farinae, as well as inflammatory mediators, such as ECP, IL-8, VEGF and tryptase, were detected in nasal secretions, although the differences were not statistically significant between the NPT-positive and NPT-negative groups. Levels of all immunoglobulins measured in this study significantly correlated with ECP, IL-8, and VEGF (P<0.05), but not with tryptase (P>0.05). IL-33 and IL-25 were also detected, and IL-25 level significantly correlated with IL-8 (r=0.625, P<0.001). CONCLUSIONS: These findings confirmed the presence of locally produced specific antibodies, including D. farinae-specific IgE and IgA, in nasal secretions collected from D. farinae-sensitive AR patients in both the NPT-positive and NPT-negative groups, and close correlations were noted between antibodies and nasal inflammatory mediators, including such as ECP, IL-8 and VEGF, indicating that locally produced antibodies may be involved in the nasal inflammation of AR.
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BACKGROUND: Recent studies have shown that men with diabetes have lower testosterone levels than healthy men. However, studies on the correlation between testosterone and diabetes are rare in Korea. We examined the relationship between testosterone deficiency and markers related to diabetes in adult Korean men. METHODS: A total 464 men with diabetes who visited an outpatient clinic at Ajou University Hospital and had serum total testosterone and serum insulin levels measured between January 2000 and September 2013 were selected. Blood samples were collected after the subjects had fasted overnight. We divided the participants into testosterone deficient and normal groups. Testosterone deficiency was defined as having a serum total testosterone level <3.5 ng/mL. RESULTS: Of 464 subjects, 34.9% had a testosterone deficiency. The mean levels of fasting plasma glucose (P=0.007) and glycated hemoglobin (HbA1c; P=0.038) were significantly higher in the testosterone deficiency group than in the normal group. To clarify the relationship between serum total testosterone level and fasting plasma glucose or HbA1c values, Pearson's correlation test was performed. Fasting plasma glucose levels (r=-0.142, P=0.002) and HbA1c values (r=-0.097, P=0.040) showed a significant negative correlation with serum testosterone levels in men with diabetes. CONCLUSION: Major markers of diabetes that are associated with testosterone deficiency are fasting plasma glucose and HbA1c values. Poor glycemic control appears to be associated with testosterone deficiency in Korean men with diabetes.
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Argonaute2 (Ago2) is a well-known factor that has intrinsic endonuclease activity and is a part of the fundamental gene regulatory machinery. Recently, we showed that nuclear Ago2 regulates voltage-gated potassium (Kv) channels and that Ago2/Kv1.3 has crucial functions in the self-renewal and cell de-aging processes in adipose tissue-derived stromal cells (ATSCs). In the nucleus, Ago2 bound to the promoter regions of calcium-activated potassium channel 3, potassium channel subfamily K member 1 (KCNK1), and voltage-gated potassium channel 2, and the expression of these genes was significantly upregulated at the level of transcription. We detected an active K+ channel that plays a critical role in Ago2-mediated ATSC self-renewal through the control of membrane potential during cell self-renewal and differentiation. Among the several regulatory subunits of voltage-dependent K+ (Kv) channels, Kv1.3 and Kv1.5 have been shown to impact tissue differentiation and cell growth in cultured ATSCs following their direct binding to the regulatory region of the Kv channel gene. In ATSCs, interference with Ago2 or K+ channel gene expression or treatment with tetraethylammonium significantly downregulated stemness gene expression, induced cell cycle arrest, and inhibited the ability of cells to transdifferentiate into neurons or ß-cells via Oct4 knockdown. Blockage of the K+ channel significantly induced protein kinase C (PKC) α, ß, and δ phosphorylation and negatively affected Ago2 and Oct4 expression. This K+ channel blockage also resulted in the upregulation of p53 and p21 expression and the inactivation of mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase 1/2 (ERK 1/2), AKT, ß-catenin, and STAT3. Our results suggest that the nuclear Ago2 regulation of the K+ channel or stemness-related gene expression plays a critical role in adult stem cell self-renewal and differentiation.
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Gordura Abdominal/citologia , Células-Tronco Adultas/metabolismo , Proteínas Argonautas/metabolismo , Núcleo Celular/metabolismo , Canais de Potássio/metabolismo , Transporte Ativo do Núcleo Celular , Células-Tronco Adultas/fisiologia , Proteínas Argonautas/genética , Células Cultivadas , Senescência Celular , Metilação de DNA , Ativação Enzimática , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Fator 3 de Transcrição de Octâmero/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/genética , Regiões Promotoras Genéticas , Proteína Quinase C-delta/metabolismo , Interferência de RNA , Transdução de Sinais , Tetraetilamônio/farmacologia , Transcrição GênicaRESUMO
In the present study, we show that Rex-1 mRNA and protein are found at high levels in both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioma cell subpopulations and malignant glioblastoma multiforme (GBM) tissue. We used a combination therapy of small interfering RNA (siRNA) against Rex-1 (siRex-1) and BCNU to target GBM cells. Rex-1 siRNA/BCNU treatment resulted in growth inhibition and a diminished S phase. The treatment efficiently induced P38/JNK and Akt/PI3K/GSK3ß signaling and led to apoptosis both in vitro and in vivo. We also show that Rex-1/ABCG2 (ATP binding cassette transporter G2)-coexpressing subpopulations were chemoresistant; however, BCNU was not a substrate for ABCG2. siRex-1 treatment led to cell death in GBM subpopulations by promoting apoptosis. Moreover, siRex-1/BCNU combination therapy targeted both the major population and cancer stem cell-like subpopulations. Our findings are important for the development of clinical applications to treat GBM.
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Apoptose , Carmustina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Glioma/tratamento farmacológico , Glioma/metabolismo , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , RNA Interferente Pequeno/genética , Animais , Antineoplásicos/uso terapêutico , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Metilação de DNA , Feminino , Glioma/genética , Humanos , Técnicas Imunoenzimáticas , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais CultivadasRESUMO
Argonaute 2 (Ago2) has a leading function in miRNA-induced RNA silencing, a conserved gene regulatory mechanism in cells and organisms. miRNAs are critical for stem cell self-renewal, development, and other functions. Here, we report that nuclear Ago2, by binding to a specific region of functional genes, directly controls adipose tissue-derived stem cell (ATSC) survival in response to a critical dose of reactive oxygen species (ROS)-mediated oxidative cell damage or senescence. The role of nuclear Ago2 has not been previously reported. Here, we show that human ATSCs in which Ago2 was downregulated underwent apoptosis. Silencing of Ago2 in ATSCs significantly induces upregulation of miR10b and miR23b expression. These miRNAs directly interfere with ROS-scavenging gene expression, such as TXNL1 and GPX3. Upregulation of miR10b and miR23b is sufficient to induce ATSC cell apoptosis via p38 MAPK phosphorylation and caspase 3 activation. In addition, Ago2 overexpression or interference by miR10b and miR23b expression in ATSCs partially rescued H(2) O(2) /ROS-mediated apoptotic cell death by upregulating the expression of TXNL2, JUNK, caspase-3, and cytochrome C. Nuclear Ago2-mediated miR10b and miR23b downregulation also allows cells to escape senescence, which results in telomerase reverse transcriptase, stemness overexpression, and improved self-renewal and differentiation through Wnt5a/ß-catenin activation. Argonaute 2 expression is critical for stem cells to escape senescence by downregulating miR10b and miR23b. The Ago2-binding gene selenoprotein N1 (SEPN1) was also effectively involved in ATSC survival and self-renewal through ROS-mediated p38 MAPK inactivation.
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Tecido Adiposo/citologia , Núcleo Celular/metabolismo , Sobrevivência Celular/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Receptores Imunológicos/metabolismo , Selenoproteínas/metabolismo , Células-Tronco/fisiologia , Apoptose/fisiologia , Proteínas Argonautas , Sequência de Bases , Proliferação de Células , Células Cultivadas , Fator de Iniciação 2 em Eucariotos/genética , Técnicas de Silenciamento de Genes , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Glicoproteínas de Membrana/genética , Dados de Sequência Molecular , Proteínas Musculares/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores Imunológicos/genética , Selenoproteínas/genética , Células-Tronco/citologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Vascular endothelial growth factor (VEGF) is an angiogenic protein that has effects on damaged neurons. We investigated VEGF function and found that it effectively induces the transition of skin-derived epithelial progenitor cells (EPCs) to more primitive stem cells. This change was accompanied by the epigenetic reprogramming of many genes. Among these genes are several stem-cell-associated transcription factors, such as Rex1, Oct4, Nanog, and Sox2. The VEGF-induced reprogramming of EPCs occurred through the FLK1 receptor and Janus kinase (JAK)/signal transducer- and activator of transcription 3 (STAT3) phosphorylation. When we engrafted VEGF-sensitized EPCs into sites of brain trauma, both engrafted VEGF/EPCs and endogenous cells showed functionally active neurogenesis and potent immunomodulatory function. These results indicate that VEGF actively induces the reprogramming of EPCs to become more primitive stem cells that display active cell growth, neurogenesis, migration, and survival behaviors, which may lead to a novel therapeutic strategy for central nervous system disorders.
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Células Epiteliais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/citologia , Camundongos , Transdução de Sinais/fisiologia , Pele/citologia , Pele/metabolismo , Células-Tronco/citologiaRESUMO
BACKGROUND: To clarify the role of the POU domain transcription factor Oct4 in Adipose Tissue Stromal Cells (ATSCs), we investigated the regulation of Oct4 expression and other embryonic genes in fully differentiated cells, in addition to identifying expression at the gene and protein levels. The ATSCs and several immature cells were routinely expressing Oct4 protein before and after differentiating into specific lineages. METHODOLOGY/PRINCIPAL FINDINGS AND CONCLUSIONS: Here, we demonstrated the role of Oct4 in ATSCs on cell proliferation and differentiation. Exogenous Oct4 improves adult ATSCs cell proliferation and differentiation potencies through epigenetic reprogramming of stemness genes such as Oct4, Nanog, Sox2, and Rex1. Oct4 directly or indirectly induces ATSCs reprogramming along with the activation of JAK/STAT3 and ERK1/2. Exogenic Oct4 introduced a transdifferentiation priority into the neural lineage than mesodermal lineage. Global gene expression analysis results showed that Oct4 regulated target genes which could be characterized as differentially regulated genes such as pluripotency markers NANOG, SOX2, and KLF4 and markers of undifferentiated stem cells FOXD1, CDC2, and EPHB1. The negatively regulated genes included FAS, TNFR, COL6A1, JAM2, FOXQ1, FOXO1, NESTIN, SMAD3, SLIT3, DKK1, WNT5A, BMP1, and GLIS3 which are implicated in differentiation processes as well as a number of novel genes. Finally we have demonstrated the therapeutic utility of Oct4/ATSCs were introduced into the mouse traumatic brain, engrafted cells was more effectively induces regeneration activity with high therapeutic modality than that of control ATSCs. Engrafted Oct4/ATSCs efficiently migrated and transdifferentiated into action potential carrying, functionally neurons in the hippocampus and promoting the amelioration of lesion cavities.