RESUMEN
This study was conducted to evaluate the potential anti-inflammatory and immune-enhancement properties of lipids derived from Aptocyclus ventricosus eggs on RAW264.7 cells. Firstly, we determined the fatty acid compositions of A. ventricosus lipids by performing gas chromatography analysis. The results showed that A. ventricosus lipids contained saturated fatty acids (24.37%), monounsaturated fatty acids (20.90%), and polyunsaturated fatty acids (54.73%). They also contained notably high levels of DHA (25.91%) and EPA (22.05%) among the total fatty acids. Our results for the immune-associated biomarkers showed that A. ventricosus lipids had immune-enhancing effects on RAW264.7 cells. At the maximum dose of 300 µg/mL, A. ventricosus lipids generated NO (119.53%) and showed greater phagocytosis (63.69%) ability as compared with untreated cells. A. ventricosus lipids also upregulated the expression of iNOS, IL-1ß, IL-6, and TNF-α genes and effectively upregulated the phosphorylation of MAPK (JNK, p38, and ERK) and NF-κB p65, indicating that these lipids could activate the MAPK and NF-κB pathways to stimulate macrophages in the immune system. Besides their immune-enhancing abilities, A. ventricosus lipids significantly inhibited LPS-induced RAW264.7 inflammatory responses via the NF-κB and MAPK pathways. The results indicated that these lipids significantly reduced LPS-induced NO production, showing a decrease from 86.95% to 38.89%. Additionally, these lipids downregulated the expression of genes associated with the immune response and strongly suppressed the CD86 molecule on the cell surface, which reduced from 39.25% to 33.80%. Collectively, these findings imply that lipids extracted from A. ventricosus eggs might have biological immunoregulatory effects. Thus, they might be considered promising immunomodulatory drugs and functional foods.
Asunto(s)
FN-kappa B , Transducción de Señal , Animales , Ratones , Células RAW 264.7 , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Lípidos , Macrófagos/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Huevos , Fagocitosis/efectos de los fármacos , Ácidos Grasos/farmacología , Óxido Nítrico/metabolismo , Citocinas/metabolismoRESUMEN
The importance of evaluating the cardiotoxicity potential of common chemicals as well as new drugs is increasing as a result of the development of animal alternative test methods using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Bisphenol A (BPA), which is used as a main material in plastics, is known as an endocrine-disrupting chemical, and recently reported to cause cardiotoxicity through inhibition of ion channels in CMs even with acute exposure. Accordingly, the need for the development of alternatives to BPA has been highlighted, and structural analogues including bisphenol AF, C, E, F, and S have been developed. However, cardiotoxicity data for analogues of bisphenol are not well known. In this study, in order to evaluate the cardiotoxicity potential of analogues, including BPA, a survival test of hiPSC-CMs and a dual-cardiotoxicity evaluation based on a multi-electrode array were performed. Acute exposure to all bisphenol analogues did not affect survival rate, but spike amplitude, beat period, and field potential duration were decreased in a dose-dependent manner in most of the bisphenols except bisphenol S. In addition, bisphenols, except for bisphenol S, reduced the contractile force of hiPSC-CMs and resulted in beating arrest at high doses. Taken together, it can be suggested that the developed bisphenol analogues could cause cardiotoxicity even with acute exposure, and it is considered that the application of the MEA-based dual-cardiotoxicity evaluation method can be an effective help in the development of safe alternatives.
Asunto(s)
Compuestos de Bencidrilo , Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Animales , Humanos , Cardiotoxicidad/etiología , Células Madre Pluripotentes Inducidas/fisiología , Fenoles/toxicidadRESUMEN
BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Biosimilares Farmacéuticos/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Administración Intravenosa , Adolescente , Adulto , Anciano , Proteína C-Reactiva/efectos de los fármacos , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Sustitución de Medicamentos , Heces/química , Femenino , Humanos , Infliximab/administración & dosificación , Infliximab/sangre , Inyecciones Subcutáneas , Complejo de Antígeno L1 de Leucocito/efectos de los fármacos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: A radiocephalic arteriovenous fistula (RCAVF) is associated with better long-term patency and fewer complications. However, RCAVF have lower maturation rate for hemodialysis compared with upper AVF or arteriovenous graft. We performed this study to determine the effect of the radiocephalic (RC) anastomotic length on the AVF maturation. METHODS: We reviewed the patients who underwent RCAVF creation with a side-to-end manner from March 2015 to December 2018. AVF maturation was defined as successful hemodialysis (HD) in at least two consecutive sessions. We compared the possible factors including the RC anastomotic length between the initial HD success group and initial HD failure group. RESULTS: A total of 114 patients underwent RCAVF creation: 72 males and 42 females (63.2% and 36.8%, respectively). The mean preoperative arteriotomy length of the AVF was 14.1 mm (range 11.0-16.0 mm). Out of 114 patients, initial HD was executed successfully in 83 patients (72.8%). Among the 31 patients with initial HD failure (27.2%) balloon angioplasty was successfully performed in 17 patients, failed in 4 patients, and not performed in 10 patients. The secondary success rate after balloon angioplasty was 87.7%. After factor analysis, pre-emptive AVF (P = 0.01), vein diameter (P < 0.001), and flow rate (P < 0.001) were revealed significant factors for initial HD success, but not RC anastomotic length of AVF (P = 0.55). CONCLUSION: The length of the radiocephalic anastomosis does not affect the RCAVF maturation rate statistically. However, lengthening of arteriotomy on the radial artery may increase the initial success rate of HD.
Asunto(s)
Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Anastomosis Quirúrgica , Derivación Arteriovenosa Quirúrgica/efectos adversos , Femenino , Humanos , Masculino , Arteria Radial/diagnóstico por imagen , Arteria Radial/cirugía , Diálisis Renal , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Extremidad Superior/irrigación sanguínea , Grado de Desobstrucción VascularRESUMEN
Arsenic is a human carcinogen. Data on urinary arsenic species analyses of Koreans are limited. This study evaluated the arsenic exposure level, contributing factors, and health effects in Korean adults. Dietary intake information and urine samples were obtained from 2044 participants. Arsenic exposure was assessed based on urinary concentrations of arsenic species, such as inorganic arsenic, As(III) and As(V), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and arsenobetaine (AsB), using high-performance liquid chromatography with inductively coupled plasma mass spectrometry, followed by determination of biomarkers, malondialdehyde and c-peptide. The geometric mean concentrations were 30.9 µg/L for the sum of inorganic arsenic and their metabolites, and 84.7 µg/L for the total sum of arsenic measured. Urinary concentrations of arsenic species were influenced by age, inhabitant area (inland or coastal), and seafood intake, which was positively correlated with inorganic arsenic, DMA, and AsB. Rice intake was positively correlated with inorganic arsenic and its metabolites but not with AsB. Additionally, malondialdehyde and c-peptide levels were significantly associated with urinary concentrations of various arsenic species. Seafood and rice are major sources of organic/inorganic arsenic exposure in Korean adults; however, it is necessary to evaluate whether their overconsumption could have a potentially detrimental effect on human health.
Asunto(s)
Arsénico , Oryza , Adulto , Arsénico/análisis , Ácido Cacodílico , Cromatografía Líquida de Alta Presión , Humanos , Oryza/química , República de CoreaRESUMEN
A recent in vitro cardiovascular safety pharmacology test uses cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) to overcome the limitations of the classical test systems, such as species differences and local channel analysis. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a new proarrhythmia screening paradigm proposed by a CiPA steering expert group, which essentially requires iPSCs derived cardiomyocyte-based electrophysiological evaluation technology. Moreover, the measurement of the contractile force is also emerging as an important parameter to recapitulate non-proarrhythmic cardiotoxicity. Therefore, we constructed an multielectrode assay (MEA) evaluation method that can measure the electrophysiological changes with 6 reference drugs in hiPSC-derived cardiomyocytes. Subsequently, it was confirmed that the electrophysiological were changed in accordance with the mechanism of action of the drugs. Furthermore, based on the multi-probe impedance, we confirmed the decrease in contractile force due to treatment with drugs, and developed a platform to evaluate cardiotoxicity according to drugs along with field potential changes. Our excitation-contraction coupling cardiotoxicity assessment is considered to be more supportive in cardiac safety studies on pharmacologic sensitivity by complementing each assessment parameter.
Asunto(s)
Cardiotoxicidad/etiología , Células Madre Pluripotentes Inducidas/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Pruebas de Toxicidad/métodos , Bloqueadores de los Canales de Calcio/toxicidad , Cardiotoxicidad/patología , Células Cultivadas , Electrodos , Humanos , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/citología , Nifedipino/toxicidad , Quinidina/toxicidad , Pruebas de Toxicidad/instrumentaciónRESUMEN
OBJECTIVE: To assess non-inferiority of s.c. to i.v. CT-P13 in RA. METHODS: Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46-54) then PFS (W56-64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: -0.6). RESULTS: Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS. CONCLUSION: CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Biosimilares Farmacéuticos/uso terapéutico , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antirreumáticos/efectos adversos , Antirreumáticos/farmacocinética , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , Método Doble Ciego , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with lucanthone and TRAIL significantly induced apoptosis in human renal carcinoma (Caki and ACHN), prostate carcinoma (PC3), and lung carcinoma (A549) cells. However, combined treatment did not induce apoptosis in normal mouse kidney cells (TCMK-1) and normal human skin fibroblast (HSF). Lucanthone downregulated protein expression of deubiquitinase DUB3, and a decreased expression level of DUB3 markedly led to enhance TRAIL-induced apoptosis. Ectopic expression of DUB3 inhibited combined treatment with lucanthone and TRAIL-induced apoptosis. Moreover, lucanthone increased expression level of DR5 mRNA via downregulation of miR-216a-5p. Transfection of miR-216a-5p mimics suppressed the lucanthone-induced DR5 upregulation. Taken together, these results provide the first evidence that lucanthone enhances TRAIL-induced apoptosis through DR5 upregulation by downregulation of miR-216a-5p and DUB3-dependent Mcl-1 downregulation in human renal carcinoma cells.
Asunto(s)
Endopeptidasas/metabolismo , Lucantona/farmacología , MicroARNs/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Neoplasias/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Células A549 , Animales , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Células PC-3 , Regulación hacia ArribaRESUMEN
Farrerol (FA) is a flavanone isolated from the Chinese herbal medicine "Man-shan-hong" (Rhododendron dauricum L.). In the present study, FA decreased the viability of SKOV3 cells in a dose- and time-dependent manner, and it induced G2/M cell cycle arrest and cell apoptosis. Cell cycle distribution analysis via flow cytometry showed that FA decreased G1 populations and increased G2/M populations in SKOV3 cells. Additionally, Western blotting confirmed an increase in the expression level of proteins involved in the cell cycle, e.g., CDK and cyclins. FA-induced apoptosis in SKOV3 cells was also investigated using a TUNEL assay, and increased expression levels of proapoptotic factors, including Caspase-3 and poly ADP ribose polymerase (PARP), through the Extracellular signal-regulated kinase (ERK)/MAPK pathway were investigated. Proinflammatory cytokines (e.g., IL-6, TNF-α, and IL-1) have been identified as a driver of the pathological mechanisms underlying involuntary weight loss and impaired physical function, i.e., cachexia, during cancer; in the present study, we showed that farrerol attenuates TNF-α-induced lipolysis and increases adipogenic differentiation in 3T3-L1 cells. Thus, farrerol could potentially be used as an anticancer agent or anticachetic drug.
Asunto(s)
Cromonas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Lipólisis/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/farmacología , Apoptosis , Ciclo Celular , Proliferación Celular , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Vitrification is the most promising technology for successful cryopreservation of living organisms without ice crystal formation. However, high concentrations (up to ~ 6-8 M) of cryoprotective agents (CPAs) used in stem cell induce osmotic and metabolic injuries. Moreover, the application of conventional slow-freezing methods to cultures of 3-D organoids of stem cells in various studies, is limited by their size. RESULTS: In this study, we evaluated the effect of high concentrations of CPAs including cytotoxicity and characterized human mesenchymal stem cell (MSC) at single cell level. The cell viability, cellular damage, and apoptotic mechanisms as well as the proliferation capacity and multipotency of cells subjected to vitrification were similar to those in the slow-freezing group. Furthermore, we identified the possibility of vitrification of size-controlled 3-D spheroids for cryopreservation of organoid with high survivability. CONCLUSIONS: Our results demonstrate successful vitrification of both single cell and spheroid using high concentration of CPAs in vitro without cytotoxicity.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Criopreservación/métodos , Crioprotectores/química , Células Madre/citología , Vitrificación , Proliferación Celular , Supervivencia Celular , Congelación , Humanos , Células Madre Mesenquimatosas , Especies Reactivas de OxígenoRESUMEN
Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell-based therapies of ischemic disease. However, there are some hurdles in their clinical application such as poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor-derived Wharton's jelly (WJ)-derived MSCs and 8 factors among 55 angiogenesis-related factors were secreted at considerable levels. Two distinct WJ-MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor-derived WJ-MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin-8, monocyte chemoattractant protein-1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ-MSCs, but also bone marrow-derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77-88.
Asunto(s)
Células Madre Mesenquimatosas/metabolismo , Neovascularización Fisiológica/genética , Comunicación Paracrina/genética , Animales , Diferenciación Celular , Humanos , Masculino , RatonesRESUMEN
The derivation of human embryonic stem cells (hESCs) by somatic cell nuclear transfer (SCNT) has prompted a re-emerging interest in using such cells for therapeutic cloning. Despite recent advancements in derivation protocols, the functional potential of CHA-NT4 derived cells is yet to be elucidated. For this reason, this study sought to differentiate CHA-NT4 cells toward an endothelial lineage in order to evaluate in vitro and in vivo functionality. To initial differentiation, embryoid body formation of CHA-NT4 was mediated by concave microwell system which was optimized for hESC-endothelial cell (EC) differentiation. The isolated CD31+ cells exhibited hallmark endothelial characteristics in terms of morphology, tubule formation, and ac-LDL uptake. Furthermore, CHA-NT4-derived EC (human nuclear transfer [hNT]-ESC-EC) transplantation in hind limb ischemic mice rescued the hind limb and restored blood perfusion. These findings suggest that hNT-ESC-EC are functionally equivalent to hESC-ECs, warranting further study of CHA-NT4 derivatives in comparison to other well established pluripotent stem cell lines. This revival of human SCNT-ESC research may lead to interesting insights into cellular behavior in relation to donor profile, mitochondrial DNA, and oocyte quality. Stem Cells 2019;37:623-630.
Asunto(s)
Diferenciación Celular/genética , Células Endoteliales/trasplante , Células Madre Embrionarias Humanas/trasplante , Células Madre Pluripotentes Inducidas/trasplante , Animales , Miembro Posterior/patología , Miembro Posterior/trasplante , Humanos , Isquemia/terapia , Ratones , Técnicas de Transferencia NuclearRESUMEN
Present-day lifestyles associated with high calorie-fat intake and accumulation, as well as energy imbalance, have led to the development of obesity and its comorbidities, which have emerged as some of the major health issues globally. To combat the disease, many studies have reported the anti-obesity effects of natural compounds in foods, with some advantages over chemical treatments. Carotenoids, such as xanthophyll derived from seaweeds, have attracted the attention of researchers due to their notable biological activities, which are associated mainly with their antioxidant properties. Their involvement in oxidative stress modulation, the regulation of major transcription factors and enzymes, and their antagonistic effects on various obesity parameters have been examined in both in vitro and in vivo studies. The present review is a collation of published research over the last decade on the antioxidant properties of seaweed xanthophyll carotenoids, with a focus on fucoxanthin and astaxanthin and their mechanisms of action in obesity prevention and treatment.
Asunto(s)
Obesidad/tratamiento farmacológico , Algas Marinas/química , Xantófilas/uso terapéutico , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Obesidad/metabolismo , Manejo de la Obesidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Xantófilas/química , Xantófilas/farmacologíaRESUMEN
Background and objectives: Sargassum miyabei Yendo, belonging to the family Sargassaceae, has been reported to have various biological effects such as anti-tyrosinase activity and anti-inflammation. However, the anti-obesity effect of Sargassum miyabei Yendo has not yet been reported. Materials and Methods: The effects of Sargassum miyabei Yendo extract (SME) on 3T3-L1 adipocytes were screened by3-(4,5)-dimethylthiazo-2-yl-2,5-diphenyltetrazolium bromide (MTT), Oil red O staining, western blot, and Real-time reverse transcription polymerase chain reaction analyses. Results: Here, we show that SME had potent 2,2'-azinobis-3-ehtlbezothiazoline-6-sulfonic acid radical decolorization (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) antioxidant activity with half maximal inhibitory concentration (IC50) value of 0.2868 ± 0.011 mg/mL and 0.2941 ± 0.014 mg/mL, respectively. In addition, SME significantly suppressed lipid accumulation and differentiation of 3T3-L1 preadipocytes, as shown by Oil Red O staining results. SME attenuated the expression of adipogenic- and lipogenic-related genes such as peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT-enhancer-binding protein alpha (C/EBPα), CCAAT-enhancer-binding protein delta (C/EBPδ), adiponectin, adipose triglyceride lipase (ATGL), fatty acid synthase (FAS), hormone-sensitive lipase (HSL), and lipoprotein lipase (LPL). Conclusions: These findings suggest that SME may have therapeutic implications for developing a new anti-obesity agent.
Asunto(s)
Adipocitos/efectos de los fármacos , PPAR gamma , Phaeophyceae , Sargassum , Células 3T3-L1 , Animales , Antioxidantes , Diferenciación Celular , Ratones , PPAR gamma/genéticaRESUMEN
Herein, we report the synthesis of an unsymmetrical diruthenium bridging unit containing a multidentate oxamate ligand and the subsequent formation of a rectangular supramolecule. The reaction of oxamate 1, 2-((4-bromo-2,6-dimethylphenyl)amino)-2-oxo-acetic acid, and [(p-cymene)RuCl2]2 affords a novel unsymmetrical diruthenium acceptor clip 2, where two ruthenium metal centers are ligated with either [O,O] or [N,O]. The molecular clip 2 and bipyridine donor self-assemble to form two-dimensional rectangular supramolecule 3. Self-assembly can produce seven possible isomers depending on the position of the substituted bromoaryl groups. However, 1H NMR spectroscopic investigation indicated only two different isomers in the reaction mixture. A single isomer is isolated via crystallization, and X-ray crystallography confirms that the product is a C1 symmetric two-dimensional rectangular supramolecule, in which two bromoaryl groups are located in the farthest position from each other. Theoretical calculations suggest that the self-assembly of supramolecule 3 occurred via 1:1 adducts of the diruthenium molecular clip and bipyridine as an intermediate to predominantly form a single isomer.
RESUMEN
Obesity is a condition associated with the accumulation of excess fat in the body, energy imbalance, lipogenesis, etc., which increases adipose tissue mass through adipogenesis and poses a health risk. Its prevalence has become an economic burden to the health care system and the world at large. One of the alternatives to tackling obesity involves the use of bioactive compounds. We critically examined the effects of Hibiscus sabdariffa extract (HSE) on various parameters associated with the development of obesity such as; the effect of HSE on body weight, the effect of HSE on lipid accumulation, cholesterol metabolism and plasma parameters, the inhibitory effect of HSE on pancreatic lipase, and the effect of HSE on adipocyte differentiation/adipogenesis. This review has gathered reports on the various anti-obesity effects of H. sabdariffa bioactive compounds in cell and animal models, as well as in humans. Available toxicology information on the consumption of H. sabdariffa revealed that its toxicity is dose-dependent and may cause an adverse effect when administered over a long period of time. Reports have shown that H. sabdariffa derived bioactive compounds are potent in the treatment of obesity with an evident reduction in body weight, inhibition of lipid accumulation and suppression of adipogenesis through the PPARγ pathway and other transcriptional factors.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Hibiscus/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Fármacos Antiobesidad/uso terapéutico , Productos Biológicos/uso terapéutico , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Extractos Vegetales/uso terapéuticoRESUMEN
Mesenchymal stromal/stem cells (MSCs) have been promising source for regenerative cell therapy in ischemic diseases. To improve efficacy of MSC therapy, various priming methods have been developed, and hypoxic priming has been reported to enhance therapeutic efficacy of MSCs by increasing secretion level of growth factors and cytokines. Recently, it has been reported that bone marrow MSCs primed with hypoxic condition show an increase of autophagy. Here, we addressed whether proangiogenic activity increased by hypoxic condition is associated with autophagy. Wharton's jelly derived MSCs primed with hypoxia showed increase of autophagy with increased hypoxia inducible factor-1α level, and conditioned medium (CM) derived from these cells showed increased levels of migration and tube formation of human umbilical vein endothelial cells (HUVECs) compared to non-primed MSCs-derived CM. Pretreatment with autophagy inhibitor 3-methyladenine or chloroquine prior to exposure of hypoxia resulted in reduction of migration and tube formation of HUVECs. CM obtained under hypoxic condition from MSCs in which autophagy activity was inhibited by ATG5 and ATG7 siRNA treatment also showed decrease of migration and tube formation of HUVECs. Accordingly, secretion levels of angiogenin and VEGF that were markedly increased upon hypoxia exposure was decreased by ATG5/7 knockdown. Therefore, it may be suggested that autophagy plays an important role in hypoxia-driven enhancement of paracrine effect of MSCs.
Asunto(s)
Autofagia , Células Madre Mesenquimatosas/patología , Neovascularización Fisiológica , Proteínas Relacionadas con la Autofagia/metabolismo , Hipoxia de la Célula , Técnicas de Silenciamiento del Gen , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , ARN Interferente Pequeño/metabolismo , Ribonucleasa Pancreática/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismo , Gelatina de Wharton/citologíaRESUMEN
Salinomycin, a monocarboxylic ionophore in Streptomyces albus, has been studied as an anti-cancer agent. However, we wondered whether salinomycin has another effect such as an anti-oxidant and hepatic protectant, because some chemical drugs treating human diseases were sometimes related with their toxic effects. Therefore, this study was conducted to examine the effects of salinomycin against oxidative stress and mitochondrial impairment in vivo and in vitro as well as the cellular mechanisms of action. In hepatocyte, salinomycin inhibited arachidonic acid (AA)â¯+â¯iron-induced apoptosis, mitochondrial dysfunction and ROS production. As a molecular mechanism, salinomycin induced autophagy through AMP-activated protein kinase (AMPK) activation, as assessed by the accumulation of acidic vesicle organelles, p62 and LC3-II. Moreover, these protective effects were blocked by AMPK inhibition, which indicates the importance of AMPK in the process of salinomycin's effects. In mice, oral administration of salinomycin protected against carbon tetrachloride (CCl4)-induced oxidative stress and liver injury, and also activated AMPK as well as autophagy-related proteins in the liver. Collectively, salinomycin had the ability to protect hepatocytes against AA+iron-induced reactive oxygen species production and mitochondrial dysfunction, as well as CCl4-induced liver injury. Although this beneficial effect was demonstrated under severe oxidative stress, this study showed that salinomycin protected the liver against the oxidative stress and liver damage through AMPK and autophagy, and suggest that salinomycin has a possibility to treat a broad range of diseases.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/efectos de los fármacos , Hepatopatías/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Piranos/farmacología , Animales , Apoptosis/efectos de los fármacos , Ácido Araquidónico/farmacología , Tetracloruro de Carbono/farmacología , Línea Celular Tumoral , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hepatopatías/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Herein, we report the formation of multinuclear Ir4, Ir6, and Ir12 supramolecular complexes via the bridge-driven self-assembly of tetrazolyl ligands. The synthesis of dimeric half-sandwich Ir units was made by the reaction of half-sandwich Ir units and tetrazolyl ligands in a molar ratio of 1:2. The use of different ligands containing multiple tetrazolyl units resulted in the formation of different Ir supramolecular architectures. The reaction of [Cp*IrCl2]2, AgOTf, and 1,2- or 1,3-ditetrazolyl benzene in a molar ratio of 1:3:1 resulted in the formation of rectangular tetranuclear or truncated trigonal pyramidal hexanuclear Ir complexes, respectively. On the other hand, the reaction of [Cp*IrCl2]2, AgOTf, and 1,3,5-tritetrazolyl benzene in a molar ratio of 6:18:4 produced a supramolecular dodecanuclear iridium complex. The molecular structure of the complex resembled a truncated tetrahedral structure with a large inner cavity, as determined by X-ray crystallography.
RESUMEN
A 20-membered N2O2S2-macrocycle (L1) and a 40-membered N4O4S4-macrocycle (L2) were employed as a [1:1] and a [2:2] cyclization product, respectively, for the preparation of diverse types of supramolecular complexes including a cascade complex. Six complexes (1-6) of the smaller macrocycle L1 including discrete to continuous forms, mono- to heteronuclear, and endo- to exo- and endo/exocoordination were prepared and their coordination modes were discussed systemically. First, the reaction of L1 with CuI in the presence of trifluoroacetic acid afforded an exocyclic 1-D coordination polymer {[(µ4-Cu4I4)(HL1)2](CF3COO)2} n (1). Meanwhile, the reaction of L1 with Cu(ClO4)2·6H2O afforded a typical endocyclic mononuclear complex [CuII(L1)](ClO4)2·H2O (2). In the reactions of L1 with CdX2 (X = Br and I), isostructural sandwich-type complexes [Cd(L1)2Br2] (3) and [Cd(L1)2I2] (4) were isolated. The treatment of L1 with Hg(ClO4)2 also afforded a sandwich-type complex [Hg(L1)2](ClO4)2 (5). One-pot reaction of L1 with a mixture of HgI2 and CdI2 afforded a dumbbell-type heteronuclear complex {[Cd(L1)]2(µ-Hg2I6)}[Hg2I6] (6), in which the Cd(II) ion occupies the macrocyclic cavity. Further, such two endocyclic Cd(II) complex units are bridged by a square-type (µ-Hg2I6)2- cluster remaining another same cluster separately. The comparative NMR data exhibited a higher affinity of Cd(II) over Hg(II) toward L1, in the parallel to the situation occurred in the solid state. Meanwhile, complexations of the extra-large macrocycle L2 is more challenging to afford some interesting dimercury(II) coordination products including a cascade complex. In solution, the dimercury(II) perchlorato complex of L2 as a metalloligand shows a preferential binding of dabco (1,4-diazabicyclo[2,2,2]octane), but its dimercury(II) iodo complex has a much smaller affinity for dabco. In order to explain these results, the solid dimercury(II) complexes with different anions [Hg2(L2)X4] (7: X = I, 8: X = ClO4) were prepared and characterized. Further, the dimercury(II) perchlorato complex 8 reacts with dabco to forms a cascade complex [Hg2(L2)(µ-dabco)(ClO4)2](ClO4)2·2DMF·2ether (9), exhibiting its formation being metal-driven and coordinated anion-regulated. The observed cascade complexation both in solution and solid states is an example of the adaptive guest binding.