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1.
Cancers (Basel) ; 13(21)2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34771481

RESUMO

Gold nanoparticles (AuNPs) were fabricated with biocompatible collagen (Col) and then conjugated with berberine (BB), denoted as Au-Col-BB, to investigate the endocytic mechanisms in Her-2 breast cancer cell line and in bovine aortic endothelial cells (BAEC). Owing to the superior biocompatibility, tunable physicochemical properties, and potential functionalization with biomolecules, AuNPs have been well studied as carriers of biomolecules for diseases and cancer therapeutics. Composites of AuNPs with biopolymer, such as fibronectin or Col, have been revealed to increase cell proliferation, migration, and differentiation. BB is a natural compound with impressive health benefits, such as lowering blood sugar and reducing weight. In addition, BB can inhibit cell proliferation by modulating cell cycle progress and autophagy, and induce cell apoptosis in vivo and in vitro. In the current research, BB was conjugated on the Col-AuNP composite ("Au-Col"). The UV-Visible spectroscopy and infrared spectroscopy confirmed the conjugation of BB on Au-Col. The particle size of the Au-Col-BB conjugate was about 227 nm, determined by dynamic light scattering. Furthermore, Au-Col-BB was less cytotoxic to BAEC vs. Her-2 cell line in terms of MTT assay and cell cycle behavior. Au-Col-BB, compared to Au-Col, showed greater cell uptake capacity and potential cellular transportation by BAEC and Her-2 using the fluorescence-conjugated Au-Col-BB. In addition, the clathrin-mediated endocytosis and cell autophagy seemed to be the favorite endocytic mechanism for the internalization of Au-Col-BB by BAEC and Her-2. Au-Col-BB significantly inhibited cell migration in Her-2, but not in BAEC. Moreover, apoptotic cascade proteins, such as Bax and p21, were expressed in Her-2 after the treatment of Au-Col-BB. The tumor suppression was examined in a model of xenograft mice treated with Au-Col-BB nanovehicles. Results demonstrated that the tumor weight was remarkably reduced by the treatment of Au-Col-BB. Altogether, the promising findings of Au-Col-BB nanocarrier on Her-2 breast cancer cell line suggest that Au-Col-BB may be a good candidate of anticancer drug for the treatment of human breast cancer.

2.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638579

RESUMO

Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin-proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Cevanas/farmacologia , Doença de Parkinson/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , alfa-Sinucleína/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Degeneração Neural/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Substância Negra/metabolismo , Ubiquitina/metabolismo
3.
Phytomedicine ; 80: 153369, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070082

RESUMO

BACKGROUND: Impairment of mitochondrial biogenesis is associated with the pathological progression of Parkinson's disease (PD). Parkin-interacting substrate (PARIS) can be ubiquitinated by parkin and prevents the repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α). PURPOSE: This study investigated whether the neuroprotective mechanism of carnosic acid (CA) from rosemary is mediated via the regulation of PARIS and PGC-1α by parkin. METHODS: The Western blotting and RT-PCR were used to determine protein and mRNA, respectively. To investigate the protein-protein interaction of between PARIS and ubiquitin, the immunoprecipitation assay (IP assay) was utilized. Silencing of endogenous parkin or PGC-1α was performed by using transient transfection of small interfering RNA (siRNA). RESULTS: SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) increased PARIS protein, decreased PGC-1α protein, and reduced protein and mRNA of mitochondrial biogenesis-related genes. CA pretreatment reversed the effects of 6-OHDA. By IP assay, the interaction of PARIS with ubiquitin protein caused by CA was stronger than that caused by 6-OHDA. Moreover, knockdown of parkin attenuated the ability of CA to reverse the 6-OHDA-induced increase in PARIS and decrease in PGC-1α expression. PGC-1α siRNA was used to investigate how CA influenced the effect of 6-OHDA on the modulation of mitochondrial biogenesis and apoptosis. In the presence of PGC-1α siRNA, CA could no longer significantly reverse the reduction of mitochondrial biogenesis or the induction of cleavage of apoptotic-related proteins by 6-OHDA. CONCLUSION: The cytoprotective of CA is related to the enhancement of mitochondrial biogenesis by inhibiting PARIS and inducing PGC-1α by parkin. The activation of PGC-1α-mediated mitochondrial biogenesis by CA prevents the degeneration of dopaminergic neurons, CA may have therapeutic application in PD.


Assuntos
Abietanos/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Repressoras/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Biogênese de Organelas , Oxidopamina/toxicidade , Doença de Parkinson/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , RNA Interferente Pequeno/farmacologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
4.
ACS Appl Mater Interfaces ; 12(40): 44393-44406, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32697572

RESUMO

Controlling the behavior of mesenchymal stem cells (MSCs) through topographic patterns is an effective approach for stem cell studies. We, herein, reported a facile method to create a dopamine (DA) pattern on poly(dimethylsiloxane) (PDMS). The topography of micropatterned DA was produced on PDMS after plasma treatment. The grid-topographic-patterned surface of PDMS-DA (PDMS-DA-P) was measured for adhesion force and Young's modulus by atomic force microscopy. The surface of PDMS-DA-P demonstrated less stiff and more elastic characteristics compared to either nonpatterned PDMS-DA or PDMS. The PDMS-DA-P evidently enhanced the differentiation of MSCs into various tissue cells, including nerve, vessel, bone, and fat. We further designed comprehensive experiments to investigate adhesion, proliferation, and differentiation of MSCs in response to PDMS-DA-P and showed that the DA-patterned surface had good biocompatibility and did not activate macrophages or platelets in vitro and had low foreign body reaction in vivo. Besides, it protected MSCs from apoptosis as well as excessive reactive oxygen species (ROS) generation. Particularly, the patterned surface enhanced the differentiation capacity of MSCs toward neural and endothelial cells. The stromal cell-derived factor-1α/CXantiCR4 pathway may be involved in mediating the self-recruitment and promoting the differentiation of MSCs. These findings support the potential application of PDMS-DA-P in either cell treatment or tissue repair.


Assuntos
Materiais Biocompatíveis/farmacologia , Dimetilpolisiloxanos/farmacologia , Dopamina/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/química , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Dimetilpolisiloxanos/química , Dopamina/química , Humanos , Células-Tronco Mesenquimais/metabolismo , Microscopia de Força Atômica , Estrutura Molecular , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície
5.
Int J Mol Sci ; 21(12)2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32585871

RESUMO

The movement disorder Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Proteínas Quinases/metabolismo , Pterocarpanos/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , alfa-Sinucleína/toxicidade , Adrenérgicos/toxicidade , Animais , Apoptose , Autofagia , Caenorhabditis elegans/crescimento & desenvolvimento , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Neuroblastoma/etiologia , Neuroblastoma/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética
6.
Sci Rep ; 10(1): 2187, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042022

RESUMO

Maintaining the pluripotency of either embryonic stem (ES) cells or induced pluripotent stem (iPS) cells is a fundamental part of stem cell research. In this study, we reported that cordycepin promoted the expression of pluripotency markers in ES and iPS cells. ES cells treated with cordycepin demonstrated their potential for generating embryoid bodies and differentiating into all three germ layers. The expression levels of phospho-Jak2, phospho-Stat3, integrin αV, and integrin ß5 were increased after cordycepin treatment. Furthermore, the protein expression levels of IL-6 family proteins (IL-6, IL-11, LIF, oncostatin M (OSM), ciliary neurotrophic factor (CNTF)), and epidermal growth factor (EGF) were also upregulated after cordycepin treatment, but were restored after co-treatment with a Jak2 inhibitor (AG490). The gene expression levels of Yamanaka factors were upregulated in mouse embryonic fibroblasts (MEFs) after cordycepin treatment. Moreover, the generation efficiencies of iPS cells were elevated after cordycepin treatment. We found that iPS cells generated after cordycepin treatment, not only expressed pluripotency markers, but also showed the ability of differentiating into neuron stem/progenitor cells. Taken together, we demonstrated that cordycepin maintained the pluripotency of stem cells via regulation of extracellular matrix (ECM) and Jak2/Stat3 signaling pathway and improved the generation efficiency of iPSCs.


Assuntos
Desoxiadenosinas/farmacologia , Células-Tronco Pluripotentes/metabolismo , Animais , Diferenciação Celular/genética , Células Cultivadas , Desoxiadenosinas/metabolismo , Corpos Embrioides/metabolismo , Células-Tronco Embrionárias/metabolismo , Fibroblastos/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Integrinas/metabolismo , Janus Quinase 2/metabolismo , Camundongos , Células-Tronco Pluripotentes/efeitos dos fármacos , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
7.
Food Chem Toxicol ; 136: 110942, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31705926

RESUMO

An imbalance in mitochondrial dynamics is strongly associated with Parkinson's disease. The fusion protein optic atrophy 1 (OPA1) is up-regulated through the activation of parkin-mediated IκB kinase γ (IKKγ)/p65 signaling. This study investigated whether the neuroprotection of carnosic acid (CA) from rosemary is involved in mitochondrial dynamics and OPA1 protein induction by parkin/IKKγ/p65 signaling. The neurotoxin 6-hydroxydopamine (6-OHDA) treated with SH-SY5Y cells decreased OPA1 and mitofusin 2 fusion proteins, but increased fission 1 and dynamin related protein 1 (DRP1) fission proteins. By immunofluorescence, 6-OHDA induced the fluorescence of green spots outside the mitochondria, indicating that cytochrome c was released to the cytoplasm. Except for the effects on DRP1 protein, CA pretreatment reversed these effects of 6-OHDA. Additionally, CA treatment increased the ubiquitination of IKKγ, nuclear p65 protein, OPA1-p65 DNA binding activity, and OPA1 protein. However, transfection of parkin small interfering RNA (siRNA) attenuated these effects of CA. Furthermore, transfection of OPA1 siRNA abolished the action of CA to reverse 6-OHDA-increased cytosolic cytochrome c protein, apoptotic-related protein cleavage, and cell death. In conclusion, the mechanism by which CA counteracts the toxicity of 6-OHDA is through modulation of mitochondrial dynamics and upregulation of OPA1 via activation of the parkin/IKKγ/p65 pathway.


Assuntos
Abietanos/farmacologia , GTP Fosfo-Hidrolases/metabolismo , Quinase I-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular Tumoral , Humanos , Quinase I-kappa B/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Neurotoxinas/toxicidade , Oxidopamina/toxicidade , Fator de Transcrição RelA/metabolismo , Ubiquitinação/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
8.
Nutr Res Pract ; 13(4): 286-294, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31388404

RESUMO

BACKGROUND/OBJECTIVES: Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the in vivo conversion of α-linolenic acid. Many enzymes participating in LCPUFA synthesis are regulated by peroxisome proliferator-activated receptor alpha (PPARα). Therefore, it was hypothesized that the tissue accretion of endogenously synthesized DHA could be modified by PPARα. MATERIALS/METHODS: The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among PPARα homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate (PPARα agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA. RESULTS: PPARα ablation reduced the hepatic Acox, Fads1, and Fads2 mRNA levels, as well as the DHA concentration in the liver, but not in the brain cortex. In contrast, PPARα activation increased hepatic Acox, Fads1, Fads2 and Elovl5 mRNA levels, but reduced the DHA concentrations in the liver, retina, and phospholipid of brain cortex, and decreased mRNA and protein levels of the brain-derived neurotrophic factor in brain cortex. CONCLUSIONS: LCPUFA enzyme expression was altered by PPARα. Either PPARα deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance.

9.
Toxins (Basel) ; 11(5)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072027

RESUMO

Aflatoxins are carcinogenic secondary metabolites of fungi that contaminate many staple crops and foods. Aflatoxin contamination is a worldwide problem, especially in developing countries, posing health hazards, e.g., causing aflatoxicosis and hepatocellular carcinoma, and even death. Biological solutions for aflatoxin detoxification are environmentally friendly and a cheaper alternative than chemical methods. The aims of the current study were to investigate: (1) the ability of MSMEG_5998, an aflatoxin-degrading F420H2-dependent reductase from Mycobacterium smegmatis, to degrade aflatoxin B1 (AFB1) and reduce AFB1-caused damage in HepG2 cell culture model; and (2) whether a thioredoxin (Trx) linkage of MSMEG_5998 enhanced the enzyme activity. We show that Trx-linked MSMEG_5998 degraded 63% AFB1 and native MSMEG_5998 degraded 31% after 4 h at 22 °C, indicating that the Trx-linked enzyme had a better AFB1-degrading ability. In a HepG2 cell culture model, Trx-linked MSMEG_5998 reduced DNA damage and p53-mediated apoptosis caused by AFB1 to a greater extent than the native enzyme. These findings suggest that Trx-linked MSMEG_5998 could potentially be developed to protect the liver from AFB1 damage, or as a candidate protein to reduce AFB1-related toxicity in animals.


Assuntos
Aflatoxinas/toxicidade , Mycobacterium smegmatis/enzimologia , Oxirredutases/farmacologia , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Dano ao DNA , Estabilidade Enzimática , Células Hep G2 , Humanos , Proteínas Recombinantes/farmacologia
10.
ACS Appl Bio Mater ; 2(3): 1017-1030, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35021392

RESUMO

A fluorescein isothiocyanate (FITC)-labeled, hyaluronic acid (HA)-coated nanogld (NP-FITC) was developed to carry plasmid or siRNA into mesenchymal stem cells (MSCs). NP-FITC was characterized by scanning electron microscopy (SEM), ultraviolet-visible (UV-vis) spectroscopy, and Fourier transform infrared (FTIR) spectrophotometry. Nontoxicity of NP-FITC in both normal cells and cancer cells was confirmed by the MTT assay. The cellular uptake of NP-FITC at different time points (30 min, 2 h, and 24 h) was verified using an immunofluorescence assay. The delivery efficiency of plasmid was tested on the delivery of superoxide dismutase-1 (SOD-1) plasmid, where the protein expression of SOD-1 was analyzed by Western blots. In addition, the delivery efficiency of siRNA was tested using CXCR4 siRNA. Besides, the siRNA delivery by NP-FITC was employed to elucidate the molecular mechanism associated with the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1). The biological function of MSCs delivered with chemokine (C-X-C motif) receptor 4 (CXCR4) siRNA was examined using ELISA, gelatin zymography, and a migration assay. Finally, we evaluated the tissue distribution of NP-FITC after the direct injection in the retro orbital sinus of mice or after injection of NP-FITC internalized MSCs through the tail vein of mice. The data provided essential information for NP-FITC as a plasmid or siRNA carrier.

11.
Cell Transplant ; 27(3): 456-470, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29756519

RESUMO

Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Doença de Parkinson/terapia , Anidridos Ftálicos/farmacologia , Adipócitos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Cell Transplant ; 27(2): 275-284, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29637814

RESUMO

It is extremely challenging to achieve strong adhesion in soft tissues while minimizing toxicity, tissue damage, and other side effects caused by wound sealing materials. In this study, flexible synthetic hydrogel sealants were prepared based on polyethylene glycol (PEG) materials. PEG is a synthetic material that is nontoxic and inert and, thus, suitable for use in medical products. We evaluated the in vitro biocompatibility tests of the dressings to assess cytotoxicity and irritation, sensitization, pyrogen toxicity, and systemic toxicity following the International Organization for Standardization 10993 standards and the in vivo effects of the hydrogel samples using Coloskin liquid bandages as control samples for potential in wound closure.


Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Polietilenoglicóis/química , Animais , Materiais Biocompatíveis/farmacologia , Masculino , Coelhos , Cicatrização/efeitos dos fármacos
13.
Front Neurol ; 9: 116, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29551991

RESUMO

Background and purpose: The blood-brain barrier (BBB) not only provides a physical obstruction but also recruits and activates neutrophils in cases of infection. Hemorrhagic or ischemic stroke reportedly induces the disruption of the BBB. However, few studies have reported a correlation between the incidence of meningitis in patients with a history of stroke. This study tested the hypothesis that patients with a history of stroke may be more vulnerable to meningitis. Methods: Stroke and age-matched comparison (n = 29,436 and 87,951, respectively) cohorts were recruited from the Taiwan National Health Insurance database (2000-2011). Correlations between the two cohorts were evaluated by Cox proportional hazard regression model, Kaplan-Meier curve, and log-rank tests. Results: The incidence of meningitis was higher in the stroke cohort compared to that in the comparison cohort [hazard ratio (HR), 2.89; 95% confidence interval (CI), 2.23-3.74, p < 0.001]. After adjusting for age, sex, and comorbidities, the estimated HR in the stroke cohort was 2.55-fold higher than that in the comparison cohort (CI, 1.94-3.37; p < 0.001). Notably, patients who had experienced hemorrhagic stroke had a higher incidence rate of meningitis than those with a history of ischemic stroke, except for patients older than 75 years (incidence rates in hemorrhagic/ischemic stroke patients, 3.14/1.48 in patients younger than 45 years, 1.52/0.41 in 45- to 64-year group, 1.15/0.90 in 65- to 74-year group, 0.74/0.93 in patients older than 75 years). Moreover, stroke patients who had undergone head surgery had the highest meningitis risk (adjusted HR, 8.66; 95% CI, 5.55-13.5; p < 0.001) followed by stroke patients who had not undergone head surgery (adjusted HR, 2.11; 95% CI, 1.57-2.82; p < 0.001). Conclusion: Our results indicated that stroke patients have higher risks of meningitis. Compromised BBB integrity in stroke patients may lead to increased vulnerability to infectious pathogens. In summary, our study provided new evidence of the clinical relationship between stroke and meningitis, and our findings suggest the need for precautions to prevent meningitis in stroke patients.

14.
Mol Neurobiol ; 55(2): 1786-1794, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28224479

RESUMO

The mediation of apoptosis-related protein in the TGF-ß signaling pathway (ARTS) and X-liked inhibitor of apoptosis protein (XIAP) by parkin plays a critical role in preventing Parkinson's disease. We studied whether carnosic acid (CA) could prevent 6-hydroxydopamine (6-OHDA)-induced apoptosis by modulating ARTS and XIAP through parkin in SH-SY5Y cells. In cells treated with 6-OHDA, the protein expression of ARTS is increased and XIAP is decreased. Pretreatment of cells with CA reversed these effects. Moreover, CA attenuated the activation of caspase 9 and caspase 7 by 6-OHDA. By immunoprecipitation with ARTS antibody, we found that 6-OHDA increased the protein expression of XIAP. However, pretreatment of cells with CA reduced XIAP protein and increased the ubiquitination of ARTS. Silencing of parkin attenuated the ability of CA to reverse the induction of ARTS and apoptotic-related proteins and the reduction of XIAP and parkin protein by 6-OHDA. Similarly, reversal of 6-OHDA-induced nuclear condensation and apoptotic-related proteins by CA was inhibited in cells with XIAP silencing. In conclusion, CA induces parkin by enhancing the ubiquitination of ARTS, leading to induction of XIAP. This may be a novel strategy for preventing Parkinson's disease.


Assuntos
Abietanos/farmacologia , Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxidopamina/farmacologia , Septinas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Apoptose/fisiologia , Linhagem Celular Tumoral , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação
15.
Food Chem Toxicol ; 103: 194-202, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28288932

RESUMO

Pi class of glutathione S-transferase (GST) is known to suppress c-Jun N-terminal kinase (JNK)-related apoptosis through protein-protein interactions. Moreover, signaling by PKA/cAMP response element binding protein (CREB) is necessary for GSTP up-regulation. This study explored whether carnosic acid (CA) from rosemary prevents 6-hydroxydopamine (6-OHDA)-induced neurotoxicity by inhibition of JNK through GSTP via PKA/CREB signaling. Results indicated that the GSTP protein was increased in SH-SY5Y cells treated with CA for 18 and 24 h. However, CA had no significant effect on alpha or mu class of GST. Treatment of CA increased the induction of p-PKAα, nuclear p-CREB, and CRE-DNA binding activity. These effects of CA were attenuated in cells pretreated with the PKA inhibitor H89. CA pretreatment suppressed 6-OHDA-induced apoptosis by inhibition of JNK phosphorylation, poly(ADP)-ribose polymerase cleavage, and nuclear condensation. Pretreatment with H89 and GSTP siRNA attenuated the ability of CA to reverse 6-OHDA-induced apoptosis. By use of immunoprecipitation with JNK antibody to examine the interaction of GSTP-JNK with CA, we showed that CA pretreatment increased the immunoprecipitation of GSTP after 6-OHDA treatment, which suggests that CA promoted the interaction between GSTP and JNK. CONCLUSION: CA prevents 6-OHDA-induced apoptosis via inhibition of JNK by GSTP through the PKA/CREB pathway.


Assuntos
Abietanos/farmacologia , Apoptose/efeitos dos fármacos , Glutationa S-Transferase pi/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , Oxidopamina/toxicidade , Apoptose/fisiologia , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Glutationa S-Transferase pi/genética , Humanos , Isoquinolinas/farmacologia , MAP Quinase Quinase 4/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia
16.
Cell Transplant ; 26(12): 1903-1918, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29390878

RESUMO

Parkinson's disease (PD) is the second most common degenerative disorder of the central nervous system in the elderly. It is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, as well as by motor dysfunction. Although the causes of PD are not well understood, aggregation of α-synuclein (α-syn) in neurons contributes to this disease. Current therapeutics for PD provides satisfactory symptom relief but not a cure. Treatment strategies include attempts to identify new drugs that will prevent or arrest the progressive course of PD by correcting disease-specific pathogenic process. Betulin is derived from the bark of birch trees and possesses anticancer, antimicrobial, and anti-inflammatory properties. The aim of the present study was to evaluate the potential for betulin to ameliorate PD features in Caenorhabditis elegans ( C. elegans) models. We demonstrated that betulin diminished α-syn accumulation in the transgenic C. elegans model. Betulin also reduced 6-hydroxydopamine-induced dopaminergic neuron degeneration, reduced food-sensing behavioral abnormalities, and reversed life-span decreases in a pharmacological C. elegans model. Moreover, we found that the enhancement of proteasomes activity by promoting rpn1 expression and downregulation of the apoptosis pathway gene, egl-1, may be the molecular mechanism for betulin-mediated protection against PD pathology. Together, these findings support betulin as a possible treatment for PD and encourage further investigations of betulin as an antineurodegenerative agent.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Doença de Parkinson/patologia , Triterpenos
17.
ACS Appl Mater Interfaces ; 8(42): 28982-29000, 2016 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-27714998

RESUMO

The ideal characteristics of surface modification on the vascular graft for clinical application would be with excellent hemocompatibility, endothelialization capacity, and antirestenosis ability. Here, Fourier transform infrared spectroscopy (FTIR), surface enhanced Raman spectroscopy (SERS), atomic force microscopy (AFM), contact angle (θ) measurement, and thermogravimetric analysis (TGA) were used to evaluate the chemical and mechanical properties of collagen-gold nanocomposites (collagen+Au) with 17.4, 43.5, and 174 ppm of Au and suggested that the collagen+Au with 43.5 ppm of Au had better biomechanical properties and thermal stability than pure collagen. Besides, stromal-derived factor-1α (SDF-1α) at 50 ng/mL promoted the migration of mesenchymal stem cells (MSCs) on collagen+Au material through the α5ß3 integrin/endothelial oxide synthase (eNOS)/metalloproteinase (MMP) signaling pathway which can be abolished by the knockdown of vascular endothelial growth factor (VEGF). The potentiality of collagen+Au with MSCs for vascular regeneration was evaluated by our in vivo rat model system. Artery tissues isolated from an implanted collagen+Au-coated catheter with MSCs expressed substantial CD-31 and α-SMA, displayed higher antifibrotic ability, antithrombotic activity, as well as anti-inflammatory response than all other materials. Our results indicated that the implantation of collagen+Au-coated catheters with MSCs could be a promising strategy for vascular regeneration.


Assuntos
Células-Tronco Mesenquimais , Animais , Células Cultivadas , Colágeno , Ouro , Nanocompostos , Ratos , Fator A de Crescimento do Endotélio Vascular
18.
J Biomed Nanotechnol ; 12(4): 732-42, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27301199

RESUMO

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are capable of self-renewal and differentiation into any cell type, thus making them the focus of many clinical application studies. Culturing ESCs on mouse embryonic fibroblast-derived and cell-based feeder layers to maintain pluripotency is a standard laboratory procedure. However, xenogeneic contamination and the large amount of time required for feeder cell preparation are two challenges that encourage the use of a murine-based feeder layer. A novel biomaterial is required to replace the current cell-based feeder system. Toward this goal, we applied a combination of biocompatible polyacrylonitrile (PAN) and electrospinning technology to establish a non-cell-based feeder layer. According to results from stem cell marker staining, scanning electron microscopy, and embryoid body formation tests, optimal ESC stemness and pluripotency were noted in three electrospun groups (2, 4, and 8 minutes), with the longer electrospinning times producing higher feeder-layer densities. KEGG pathway microarray results identified TGF-beta signaling as one of the major deregulatory pathways on electrospun-based feeder layers. Western blot data indicate significant increases in TGF-beta receptor II, phosphorylated Smad3, and Nanog protein levels in the 4- and 8-minute electrospun-based feeder layer groups compared to the non-feeder layer group. Combined, the data suggest that electrospun-based feeder layers are good candidates for maintaining ESC and iPSC pluripotency in clinical applications.


Assuntos
Resinas Acrílicas/química , Técnicas de Cultura Celular por Lotes/métodos , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/fisiologia , Nanofibras/química , Fator de Crescimento Transformador beta/metabolismo , Animais , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Galvanoplastia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Nanofibras/ultraestrutura , Tamanho da Partícula , Transdução de Sinais/fisiologia
19.
Cell Transplant ; 25(5): 899-912, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26787228

RESUMO

Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis, exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.


Assuntos
4-Butirolactona/análogos & derivados , Tecido Adiposo/citologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Transplante de Células-Tronco/métodos , Células-Tronco/efeitos dos fármacos , Acidente Vascular Cerebral/terapia , Tromboembolia/terapia , 4-Butirolactona/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/biossíntese , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Receptores CXCR4/biossíntese , Células-Tronco/metabolismo
20.
Blood ; 127(10): 1336-45, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26679863

RESUMO

L5, the most electronegative and atherogenic subfraction of low-density lipoprotein (LDL), induces platelet activation. We hypothesized that plasma L5 levels are increased in acute ischemic stroke patients and examined whether lectin-like oxidized LDL receptor-1 (LOX-1), the receptor for L5 on endothelial cells and platelets, plays a critical role in stroke. Because amyloid ß (Aß) stimulates platelet aggregation, we studied whether L5 and Aß function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Aß, and platelet LOX-1 expression were significantly higher in acute ischemic stroke patients than in controls without metabolic syndrome (P < .01). In mice subjected to focal cerebral ischemia, L5 treatment resulted in larger infarction volumes than did phosphate-buffered saline treatment. Deficiency or neutralizing of LOX-1 reduced infarct volume up to threefold after focal cerebral ischemia in mice, illustrating the importance of LOX-1 in stroke injury. In human platelets, L5 but not L1 (the least electronegative LDL subfraction) induced Aß release via IκB kinase 2 (IKK2). Furthermore, L5+Aß synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IκBα, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-κB (NF-κB). Injecting L5+Aß shortened tail-bleeding time by 50% (n = 12; P < .05 vs L1-injected mice), which was prevented by the IKK2 inhibitor. Our findings suggest that, through LOX-1, atherogenic L5 potentiates Aß-mediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-κB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.


Assuntos
Isquemia Encefálica/sangue , Lipoproteínas LDL/sangue , Agregação Plaquetária , Acidente Vascular Cerebral/sangue , Peptídeos beta-Amiloides/sangue , Animais , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Feminino , Humanos , Quinase I-kappa B/metabolismo , Arteriosclerose Intracraniana/sangue , Arteriosclerose Intracraniana/patologia , Trombose Intracraniana/sangue , Trombose Intracraniana/patologia , Masculino , Camundongos , Camundongos Knockout , Receptores Depuradores Classe E/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/patologia
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