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1.
J Med Chem ; 66(23): 16002-16017, 2023 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-38015459

RESUMEN

Wound healing is a complex process and remains a considerable challenge in clinical trials due to the lack of ideal therapeutic drugs. Here, a new peptide TK-HR identified from the skin of the frog Hoplobatrachus rugulosus was tested for its ability to heal cutaneous wounds in mice. Topical application of TK-HR at doses of 50-200 µg/mL significantly accelerated wound closure without causing any adverse effects in the animals. In vitro and in vivo investigations proved the regulatory role of the peptide on neutrophils, macrophages, keratinocytes, and vein endothelial cells involved in the inflammatory, proliferative, and remodeling phases of wound healing. Notably, TK-HR activated the MAPK and TGF-ß-Smad signaling pathways by acting on NK1R in RAW264.7 cells and mice. The current work has identified that TK-HR is a potent wound healing regulator that can be applied for the treatment of wounds, including diabetic foot ulcers and infected wounds, in the future.


Asunto(s)
Células Endoteliales , Receptores de Neuroquinina-1 , Ratones , Animales , Receptores de Neuroquinina-1/metabolismo , Piel/metabolismo , Cicatrización de Heridas , Péptidos/farmacología , Medicina Tradicional
2.
Free Radic Biol Med ; 208: 309-318, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37611644

RESUMEN

Phenolic compounds are promising agents for the prevention of osteoporosis. 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DHPV) is the major microbiota metabolite of the flavan-3-ols phenolic compound. Herein, we aimed to investigate the potential mechanisms underlying the effects of DHPV on an osteoblast cell model with H2O2-induced oxidative injury. The MC3T3-E1 cell cultured with H2O2 was used as an oxidative injury model after pretreating with DHPV. Pretreatment with DHPV significantly attenuated cell viability decline, enhanced the activity of alkaline phosphatase and mineralization capacity in MC3T3-E1 cells. Reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels as well as increased in mitochondrial membrane potential and superoxide dismutase (SOD) activities indicated that DHPV affected both the oxidative and antioxidative processes in the cells. DHPV administration increased the LC3-II/I ratio and Beclin-1 protein levels, thereby promoting autophagy, which perhaps contributes to ROS elimination. However, the inhibition of Sirtuin 1 (SIRT1) by SIRT1 small interfering RNA reduced the protective effect of DHPV or SRT1720, as revealed by the increased ROS and MDA levels and decreased SOD, LC3-II/I ratio and Beclin-1 levels. DHPV may promote autophagy and reduce oxidative stress through the SIRT1-mediated pathway, thereby protecting MC3T3-E1 cells from H2O2-induced oxidative damage.


Asunto(s)
Flavonoides , Peróxido de Hidrógeno , Sirtuina 1 , Autofagia , Diferenciación Celular , Línea Celular , Flavonoides/metabolismo , Flavonoides/farmacología , Peróxido de Hidrógeno/metabolismo , Microbiota/fisiología , Osteoblastos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Ratones
3.
Front Nutr ; 9: 918944, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35967769

RESUMEN

Evidence suggests that plant-based diets are beneficial for alleviating metabolic diseases. Childhood is a crucial period for body growth and development. However, it is unknown whether adherence to a plant-based diet is related to a healthy body composition in children. We aimed to assess the relationship between a plant-based diet and body composition in children. A total of 452 Chinese children aged 6-9 years old participated in this cross-sectional study. Lean mass (LM), fat mass, and fat mass percentage (FMP) were assessed via dual-energy X-ray absorptiometry. An age- and sex-specific abdominal FMP ≥85th percentile was defined as abdominal obesity. Handgrip strength was measured using a hydraulic hand dynamometer. A validated 79-item food frequency questionnaire was used to collect dietary information. Overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI) scores were calculated. After adjusting for potential covariates, a higher hPDI score (per 10-score increment) was associated with a higher LM in the android area (0.038 kg, 3.2%), gynoid area (0.048 kg, 1.9%), and trunk (0.102 kg, 1.2%) and with a lower FMP (1.18%) in the android area. In contrast, a higher uPDI score (per 10-score increment) was associated with a lower LM in the trunk (0.091 kg, 1.1%) and android area (0.023 kg, 1.9%) and with a higher FMP (0.74%) in the android area. No significant associations were observed between the overall PDI and body composition or abdominal obesity. After stratifying by sex, higher (vs. lower) hPDI scores was associated with lower abdominal obesity risk in girls and higher handgrip strength in boys. In conclusion, in this cross-sectional study, we found that stronger adherence to a healthful plant-based diet, and less adherence to an unhealthful plant-based diet was associated with better body composition in Chinese omnivorous children aged 6-9 years old. Our results highlight the need to distinguish between healthy and unhealthy plant foods within investigating how to obtain a healthy body composition in children.

4.
Phytother Res ; 35(5): 2691-2702, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33440461

RESUMEN

The continued global rise in papillary thyroid carcinoma (PTC) combined with potential adverse effects of regular treatments calls for an alternative therapy. Prunella vulgaris L. (PV) is commonly used as a herbal remedy for thyroid diseases in China, but its influence on PTC is unclear. This study investigated the effect of PV aqueous extract on PTC and its underlying mechanism using a mouse xenograft model and the human PTC cell line K1. PV suppressed tumor growth in PTC-bearing mice at 0.05 and 0.1 g/kg bw, accompanied by improvements in autophagy-related protein expressions in xenografts. In K1 cells, PV inhibited cell growth and induced autophagic flux, manifesting as changes in autophagy-related proteins, the presence of autophagosomes, and a further increase in LC3-II by co-incubation with bafilomycin A1. Autophagy inhibitor 3-methyladenine ameliorated the autophagic cell death caused by PV. The mammalian target of rapamycin (mTOR) activator MHY1485 blocked the antiproliferative activity of PV by regulating mTOR, unc-51-like autophagy activating kinase 1 (ULK1), autophagosomes formation, and autophagy-related proteins. The adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C attenuated PV-induced inhibition of mTOR. Our results suggest that PV inhibits the growth of PTC in vivo and in vitro via autophagy, which is associated with the AMPK/mTOR/ULK1 pathway. Thus, PV has the potential to function as a therapeutic agent against PTC.

5.
Clin Nutr ; 40(5): 3379-3390, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33277072

RESUMEN

BACKGROUND & AIMS: Previous studies linking the gut microbiome with childhood obesity largely used the body mass index to measure obesity and reached inconsistent findings. Little evidence has linked the gut microbiome to regional body fat deposition. We investigated whether the abundance of specific taxa in the gut microbiota and the concentrations of short-chain fatty acids (SCFAs) were associated with the content and regional deposition of body fat in children. METHODS: This cross-sectional study involved 236 children aged 6-9 years. The fat mass contents/percentages in the total body and the android, gynoid, and limb regions were determined by dual-energy X-ray absorptiometry, and the android-to-gynoid fat mass ratio and fat-to-lean mass ratios were calculated. Fecal samples were subjected to16S rRNA amplicon sequencing, and the fecal SCFA concentrations were quantified via high-performance liquid chromatography. RESULTS: A weighted gene co-expression network analysis identified seven modules of co-expressed operational taxonomic units (OTUs). A total of 57 OTUs from 4 key modules were selected for further analysis. After adjustment of covariates and controlling for the false discovery rate (FDR), a multiple linear regression analysis revealed significant correlations of the abundances of some OTUs with obesity and body fat measures. For instance, the OTUs classified to the species Ruminococcus gnavus and Flavonifractor plautii showed significant negative correlations with the total and regional body fat (ß: -0.250 to -0.180, PFDR: 0.041-0.049), whereas OTUs belonging to the genera Blautia and Romboutsia exhibited positive correlations with body fat measures (ß: 0.184-0.222, PFDR: 0.041-0.049). The fecal concentrations of acetic, propionic, and butyric acids and total SCFAs were significantly positively correlated with various parameters of body fat distribution (ß: 0.160-0.275, PFDR: <0.001-0.042). CONCLUSION: The gut microbiome and SCFAs are significantly associated with obesity and body fat distribution in pediatric population.


Asunto(s)
Distribución de la Grasa Corporal/estadística & datos numéricos , Ácidos Grasos Volátiles/análisis , Microbioma Gastrointestinal/fisiología , Índice de Masa Corporal , Niño , China , Estudios Transversales , Dieta/estadística & datos numéricos , Heces/química , Heces/microbiología , Femenino , Humanos , Masculino , Obesidad Infantil/epidemiología
6.
Food Funct ; 11(3): 1919-1932, 2020 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-32175534

RESUMEN

Previous randomized controlled trials (RCTs) made direct comparisons between EPA/DHA versus ALA on improving cardiovascular risk factors and have reached inconsistent findings. The aim of this meta-analysis was to compare the effects of EPA/DHA vs. ALA supplementation on cardiometabolic disturbances. Databases including MEDLINE, Embase, PubMed and Cochrane Trials were searched until December 2019. The pooled effects (weighted mean difference, WMD) of outcomes with moderate and high heterogeneity were calculated with a random-effects model, while low heterogeneity was calculated with a fixed-effect model. Fourteen RCTs with 1137 participants who met the eligibility criteria were pooled. Compared with participants supplemented with ALA, those who received EPA/DHA supplementation experienced a greater reduction in triglycerides (TG) (WMD -0.191 mmol l-1; 95% CI -0.249, -0.133) but a greater increase in high-density lipoprotein (HDL) (WMD 0.033 mmol l-1; 95% CI 0.004, 0.062), low-density lipoprotein (LDL) (WMD 0.130 mmol l-1; 95% CI 0.006, 0.253) and total cholesterol (TC) (WMD 0.179 mmol l-1; 95% CI 0.006, 0.352). In subgroup analyses, the WMD for TG was much lower in trials with participants >40 years old (-0.246 mmol l-1; 95% CI -0.325, -0.167). When DHA and EPA were separately administered, modest increases in HDL were observed in trials that used DHA as a supplement (0.161 mmol l-1; 95% CI 0.017, 0.304), but not in trials using EPA (0.040 mmol l-1; 95% CI -0.132, 0.212). In conclusion, dietary EPA/DHA supplementation improved the TG and HDL status but increased LDL levels in comparison with ALA.


Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Ácidos Grasos Omega-3/administración & dosificación , Enfermedades Cardiovasculares/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Triglicéridos/sangre , Ácido alfa-Linolénico/administración & dosificación
7.
Front Neurosci ; 13: 1216, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31849574

RESUMEN

Evidence from animal models supports a link between short-chain fatty acids (SCFAs), a key subset of gut microbial metabolites, and autism spectrum disorders (ASD). However, findings from human studies on this topic are unclear. We aimed to investigate whether fecal SCFAs are associated with ASD in Chinese children aged 6-9 years old. A total of 45 ASD children aged 6-9 years and 90 sex- and age-matched neurotypical controls were enrolled. High-performance liquid chromatography was applied to quantify 10 SCFA subtypes in feces. Dietary and other socio-demographic information were obtained via face-to-face interview using questionnaires. After adjustment for multiple comparisons, paired t-test analysis indicated that the fecal total and subtype SCFA concentrations were comparable in autistic children and the controls. Conditional logistic regression analysis showed that there was no significant relationship between the fecal concentration of SCFAs and the risk of ASD after adjustment for age, sex, BMI, breastfeeding, mode of delivery, parental education level, and daily energy, protein, fat, and fiber intake. In conclusion, our results did not support the hypothesis that fecal SCFA levels might be associated with the presence of ASD. However, SCFA measurement was based on a single stool sample test, so this conclusion should be treated with caution. Further studies with measurement of long-term bodily SCFA concentrations are needed to examine this relationship.

8.
Breast Cancer ; 26(6): 835-845, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31264076

RESUMEN

BACKGROUND: FAM64A is a mitotic regulator promoting cell metaphase-anaphase transition, and it is frequently reported to be highly expressed in cancer cells. However, the role of FAM64A in human breast cancer (BrC) is poorly studied. METHODS: The expression of FAM64A mRNA in BrC samples was determined by RT-qPCR assay and TCGA database mining. Kaplan-Meier plotter was used to analyze whether FAM64A expression impacted prognosis. Then, the expression of FAM64A was silenced using RNA interference. Cell-counting assay, colony formation assay and flow cytometry assay were conducted to detect proliferation; transwell migration assay, EMT-related proteins expression (E-cadherin, N-cadherin and vimentin), and EMT-related transcription factors mRNA expression (Snail, Twist, Slug) were conducted to evaluate the migration ability. RESULTS: FAM64A was highly expressed in human BrC samples, which was negatively associated with poor survival time. Analysis of FAM64A expression in BrC cell lines demonstrated that the expression of FAM64A was significantly correlated with the proliferation rate and migration ability of BrC cells. Indeed, knockdown of FAM64A suppressed the proliferation of MDA-MB-231 and MCF-7 cells. Importantly, we also found that silencing of FAM64A inhibited the migration of BrC cells via impeding epithelial-mesenchymal transition. CONCLUSIONS: Our findings suggest that FAM64A plays an important role in the proliferation and migration of BrC cells, which might serve as a potential target for BrC treatment.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Silenciamiento del Gen , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Antígenos CD/metabolismo , Cadherinas/metabolismo , Transición Epitelial-Mesenquimal/genética , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Células MCF-7 , Pronóstico , Interferencia de ARN , Factores de Transcripción de la Familia Snail/metabolismo , Transfección , Proteína 1 Relacionada con Twist/metabolismo , Vimentina/metabolismo
9.
Mol Nutr Food Res ; 62(19): e1800205, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30070430

RESUMEN

SCOPE: Obesity is linked to a chronic low-grade inflammatory state that contributes to the development of obesity-associated metabolic disorders. The anti-inflammatory activities and mechanisms of soyasaponin monomers (A1 , A2 , and I) have been recently demonstrated in cell models. However, their potential in vivo abilities to reduce chronic inflammation and alleviate metabolic disorders in obese status remain unclear. METHODS AND RESULTS: High fat diet (HFD)-fed obese male C57BL/6J mice are intervened by aspirin (0.1 mg kg-1 body weight) or 20 mg kg-1 of soyasaponins A1 , A2 , or I for 8 weeks. Soyasaponins A1 , A2 , and I significantly reduce pro-inflammatory cytokines/mediators in serum, liver, and white adipose tissues (WATs), improve serum lipid profiles, decrease liver cholesterol, triglyceride and steatosis, and promote fecal excretion of cholesterol, triglycerides, and bile acids. Soyasaponins A1 , A2 , and I also decrease IKKα/ß phosphorylation in liver and WATs and reduce NF-κB p65 phosphorylation and CD68 mRNA and protein expression in WATs. Soyasaponins A1 and A2 but not I decrease NF-κB p65 phosphorylation in liver and adipocytes hypertrophy in WATs. In addition, Soyasaponin A2 but not A1 nor I decreases fasting blood glucose and improved insulin resistance. CONCLUSION: Soyasaponins reduce inflammation and improve serum lipid profiles and glucose homeostasis in HFD-induced obese mice.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Inflamación/dietoterapia , Lípidos/sangre , Obesidad/metabolismo , Ácido Oleanólico/análogos & derivados , Saponinas/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/patología , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/patología , Animales , Ingestión de Alimentos , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/dietoterapia , Obesidad/etiología , Ácido Oleanólico/farmacología
10.
Mol Immunol ; 87: 23-32, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28388446

RESUMEN

During an inflammatory response, polarization of neutrophils is necessary for effective chemotaxis and bacterial endocytosis. Ca2+ uptake into mitochondria through the mitochondrial calcium uniporter (MCU) is crucial for cell metabolism, signaling and survival; however, the physiological role of MCU in human neutrophils remains unclear. Here we show that MCU is vital for the polarization and chemotaxis of neutrophils. Activation of MCU by spermine promotes neutrophil polarization and chemotaxis, whereas inhibition of MCU by Ru360 blunts both processes. We also provide evidence that this role of the MCU in neutrophils may result from modulation of mitochondrial fission by increased levels of pDrp1 S616 via accumulation of Ca2+ into the mitochondrial matrix. Thus, our study identifies the dependence of neutrophil polarization and chemotaxis on the MCU and highlights the importance of regulating mitochondrial fission during the anti-inflammatory cascade in human neutrophils.


Asunto(s)
Canales de Calcio/metabolismo , Quimiotaxis/fisiología , Dinaminas/metabolismo , GTP Fosfohidrolasas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Neutrófilos/metabolismo , Fosforilación/fisiología , Calcio/metabolismo , Línea Celular , Humanos , Dinámicas Mitocondriales/fisiología , Transducción de Señal/fisiología
11.
Mol Nutr Food Res ; 60(7): 1532-43, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27005845

RESUMEN

SCOPE: We and others recently showed that soyasaponin Bb (SSBb ) inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages. Since the recruitment of toll-like receptor 4 (TLR4) into lipid rafts is vital for LPS-initiated signaling, we investigated whether this process would be modulated by SSBb . METHODS AND RESULTS: By using sucrose gradient ultracentrifuge, we found that pretreatment of macrophages with SSBb inhibited LPS-induced recruitments of TLR4, myeloid differentiation primary response protein 88 (MyD88) and Toll/IL-1 receptor domain-containing adaptor inducing interferon-ß (TRIF) into fractions enriched with lipid rafts marker flotillin-1. We also found SSBb decreased co-localization of TLR4 and lipid rafts by utilizing confocal immunofluorescence microscopy. Additionally, we observed that SSBb suppressed LPS-induced formation of TLR4/MyD88 and TLR4/TRIF complexes, production of pro-inflammatory molecules, and activation of nuclear factor kappa B (NF-κB). Furthermore, we found that these inhibitory effects of SSBb were associated with reduced reactive oxygen species (ROS) because pretreating cells with N-acetyl-L-cysteine and NADPH oxidase inhibitor diphenyleneiodonium (DPI) inhibited LPS-induced TLR4 recruitment into lipid rafts and NF-κB activation. SSBb also inhibited NADPH oxidase activation by blocking interaction between gp91(phox) and p47(phox) similarly as DPI. CONCLUSION: SSBb can inhibit TLR4 recruitment into lipid rafts and its signaling by suppressing the NADPH oxidase-dependent ROS generation.


Asunto(s)
Microdominios de Membrana/efectos de los fármacos , NADPH Oxidasas/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Saponinas/farmacología , Receptor Toll-Like 4/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/antagonistas & inhibidores , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Acetilcisteína/antagonistas & inhibidores , Acetilcisteína/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/genética , ADN Helicasas/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , FN-kappa B/metabolismo , Compuestos Onio/farmacología , Células RAW 264.7 , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética
13.
PLoS One ; 11(1): e0147218, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26784903

RESUMEN

PURPOSE: Butyrate, a short-chain fatty acid derived from dietary fiber, inhibits proliferation and induces cell death in colorectal cancer cells. However, clinical trials have shown mixed results regarding the anti-tumor activities of butyrate. We have previously shown that sodium butyrate increases endoplasmic reticulum stress by altering intracellular calcium levels, a well-known autophagy trigger. Here, we investigated whether sodium butyrate-induced endoplasmic reticulum stress mediated autophagy, and whether there was crosstalk between autophagy and the sodium butyrate-induced apoptotic response in human colorectal cancer cells. METHODS: Human colorectal cancer cell lines (HCT-116 and HT-29) were treated with sodium butyrate at concentrations ranging from 0.5-5mM. Cell proliferation was assessed using MTT tetrazolium salt formation. Autophagy induction was confirmed through a combination of Western blotting for associated proteins, acridine orange staining for acidic vesicles, detection of autolysosomes (MDC staining), and electron microscopy. Apoptosis was quantified by flow cytometry using standard annexinV/propidium iodide staining and by assessing PARP-1 cleavage by Western blot. RESULTS: Sodium butyrate suppressed colorectal cancer cell proliferation, induced autophagy, and resulted in apoptotic cell death. The induction of autophagy was supported by the accumulation of acidic vesicular organelles and autolysosomes, and the expression of autophagy-associated proteins, including microtubule-associated protein II light chain 3 (LC3-II), beclin-1, and autophagocytosis-associated protein (Atg)3. The autophagy inhibitors 3-methyladenine (3-MA) and chloroquine inhibited sodium butyrate induced autophagy. Furthermore, sodium butyrate treatment markedly enhanced the expression of endoplasmic reticulum stress-associated proteins, including BIP, CHOP, PDI, and IRE-1a. When endoplasmic reticulum stress was inhibited by pharmacological (cycloheximide and mithramycin) and genetic (siRNA targeting BIP and CHOP) methods, the induction of BIP, PDI, IRE1a, and LC3-II was blocked, but PARP cleavage was markedly enhanced. DISCUSSION: Taken together, these results suggested that sodium butyrate-induced autophagy was mediated by endoplasmic reticulum stress, and that preventing autophagy by blocking the endoplasmic reticulum stress response enhanced sodium butyrate-induced apoptosis. These results provide novel insights into the anti-tumor mechanisms of butyric acid.


Asunto(s)
Adenocarcinoma/patología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Ácido Butírico/farmacología , Neoplasias Colorrectales/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Humanos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas
14.
Nutr Cancer ; 66(8): 1342-51, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25268883

RESUMEN

It appears to be more practical and effective to prevent carcinogenesis by targeting the tumor promotion stage. Gap junctional intercellular communication (GJIC) is strongly involved in carcinogenesis, especially the tumor promotion stage. Considerable interest has been focused on the chemoprevention activities of soyasaponin (SS), which are major phytochemicals found in soybeans and soy products. However, less is known about the preventive effects of SS (especially SS with different chemical structures) against tumor promoter-induced inhibition of GJIC. We investigated the protective effects of SS-A1, SS-A2, and SS-I against hydrogen peroxide (H2O2)-induced GJIC inhibition and reactive oxygen species (ROS) production in Buffalo rat liver (BRL) cells. The present results clearly show for the first time that SS-A1, SS-A2, and SS-I prevent the H2O2-induced GJIC inhibition by scavenging ROS in BRL cells in a dose-dependent manner at the concentration range of from 25 to 100 µg/mL. Soyasaponins attenuated the H2O2-induced ROS through potentiating the activities of superoxide dismutase and glutathione peroxidase. This may be an important mechanism by which SS protects against tumor promotion. In addition, various chemical structures of SS appear to exhibit different protective abilities against GJIC inhibition. This may partly attribute to their differences in ROS-scavenging activities.


Asunto(s)
Comunicación Celular/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Uniones Comunicantes/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Saponinas/farmacología , Animales , Catalasa/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Daño del ADN/efectos de los fármacos , Uniones Comunicantes/metabolismo , Glutatión Peroxidasa/metabolismo , Hepatocitos/metabolismo , Peróxido de Hidrógeno/efectos adversos , Peroxidación de Lípido/efectos de los fármacos , Hígado/citología , Hígado/efectos de los fármacos , Malondialdehído/metabolismo , Ratas , Glycine max/química , Superóxido Dismutasa/metabolismo
15.
PLoS One ; 9(9): e107655, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25233217

RESUMEN

We and others have recently shown that soyasaponins abundant in soybeans can decrease inflammation by suppressing the nuclear factor kappa B (NF-kB)-mediated inflammation. However, the exact molecular mechanisms by which soyasaponins inhibit the NF-kB pathway have not been established. In this study in macrophages, soyasaponins (A1, A2 and I) inhibited the lipopolysaccharide (LPS)-induced release of inflammatory marker prostaglandin E2 (PGE2) to a similar extent as the NF-kB inhibitor (BAY117082). Soyasaponins (A1, A2 and I) also suppressed the LPS-induced expression of cyclooxygenase 2 (COX-2), another inflammatory marker, in a dose-dependent manner by inhibiting NF-kB activation. In defining the associated mechanisms, we found that soyasaponins (A1, A2 and I) blunted the LPS-induced IKKα/ß phosphorylation, IkB phosphorylation and degradation, and NF-kB p65 phosphorylation and nuclear translocation. In studying the upstream targets of soyasaponins on the NF-kB pathway, we found that soyasaponins (A1, A2 and I) suppressed the LPS-induced activation of PI3K/Akt similarly as the PI3K inhibitor LY294002, which alone blocked the LPS-induced activation of NF-kB. Additionally, soyasaponins (A1, A2 and I) reduced the LPS-induced production of reactive oxygen species (ROS) to the same extent as the anti-oxidant N-acetyl-L-cysteine, which alone inhibited the LPS-induced phosphorylation of Akt, IKKα/ß, IkBα, and p65, transactivity of NF-kB, PGE2 production, and malondialdehyde production. Finally, our results show that soyasaponins (A1, A2 and I) elevated SOD activity and the GSH/GSSG ratio. Together, these results show that soyasaponins (A1, A2 and I) can blunt inflammation by inhibiting the ROS-mediated activation of the PI3K/Akt/NF-kB pathway.


Asunto(s)
Macrófagos/inmunología , Ácido Oleanólico/análogos & derivados , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Saponinas/farmacología , Animales , Línea Celular , Cromonas/farmacología , Ciclooxigenasa 2/biosíntesis , Dinoprostona/metabolismo , Quinasa I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Lipopolisacáridos , Malondialdehído/metabolismo , Ratones , Morfolinas/farmacología , Nitrilos/farmacología , Ácido Oleanólico/farmacología , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Glycine max/metabolismo , Sulfonas/farmacología , Superóxido Dismutasa/biosíntesis , Factor de Transcripción ReIA/metabolismo
16.
Tumour Biol ; 35(2): 935-42, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23982878

RESUMEN

Epidemiological studies have evaluated the association between transforming growth factor-ß1 (TGF-ß1) -509C/T polymorphisms and breast cancer risk. However, the results remain conflicting rather than conclusive. The aim of this study was to comprehensively clarify the association between TGF-ß1 -509C/T polymorphisms and breast cancer risk. All relevant studies were searched in the electronic databases. The potential sources of heterogeneity were detected with the chi-square-based Q test. The strength of associations between TGF-ß1 -509C/T polymorphisms and breast cancer risk was measured by odds ratio (OR) and 95 % confidence intervals (CI). Publication bias was tested by Begg's test and Egger's test. A total of 10 studies including 10,913 cases and 14,187 controls were included in the meta-analysis. Overall, there was no evidence of significant association of TGF-ß1 -509C/T polymorphisms with breast cancer risk (TT vs. CC [OR = 0.97, 95 % CI = 0.83-1.14]; CT vs. CC [OR = 1.05, 95 % CI = 0.90-1.22]; TT + CT vs. CC [OR = 0.99, 95 % CI = 0.91-1.08]; T allele vs. C allele [OR = 0.99, 95 % CI = 0.93-1.06]). Similar results were also found in the subgroup analyses by ethnicity and source of control. When stratified by estrogen receptor (ER) status, TT genotype and T allele were associated with a decreased ER-positive breast cancer risk (OR = 0.66, 95 % CI = 0.49-0.90 and OR = 0.85, 95 % CI = 0.75-0.96, respectively). The present meta-analysis results suggest that TGF-ß1 -509C/T variants may not contribute to the risk of breast cancer overall. However, T allele may be a potential protective factor for developing ER-positive breast cancer. Well-designed studies with larger sample size were required to verify our findings further.


Asunto(s)
Neoplasias de la Mama/genética , Estudios de Asociación Genética , Factor de Crecimiento Transformador beta1/genética , Alelos , Neoplasias de la Mama/patología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo
17.
PLoS One ; 8(10): e77898, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24205020

RESUMEN

BACKGROUND: Epidemiologic studies have reported the association of X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln polymorphisms with susceptibility to squamous cell carcinoma of the head and neck (HNSCC). However, the results were conflictive rather than conclusive. The purpose of this study was to clarify the association of XRCC1 Arg399Gln variants with HNSCC risk. METHODS: Systematic searches were performed through the search engines of PubMed, Elsevier, Science Direct, CNKI and Chinese Biomedical Literature Database. Summary odds ratio (OR) with 95% confidence intervals (CI) was computed to estimate the strength association. RESULTS: Overall, we did not observe any association of XRCC1 Arg399Gln polymorphisms with HNSCC risk in total population (OR = 0.95, 95% CI: 0.76-1.19 for Gln/Gln vs. Arg/Arg, OR = 1.05, 95% CI: 0.92-1.20 for Arg/Gln vs. Arg/Arg, and OR = 1.03, 95% CI: 0.90-1.18 for Gln/Gln+Arg/Gln vs. Arg/Arg) based on 18 studies including 3917 cases and 4560 controls. In subgroup analyses, we observed an increased risk of XRCC1 399 Arg/Gln genotype for HNSCC in Caucasians (OR = 1.20, 95% CI: 1.00-1.44) and Gln/Gln genotype for larynx squamous cell carcinoma (OR = 1.63, 95% CI: 1.10-2.40). We did not observe any association between XRCC1 Arg399Gln variants and HNSCC risk in additional subgroup analyses. CONCLUSION: The results from this present meta-analysis suggest that XRCC1 Arg399Gln variants may contribute to HNSCC risk among Caucasians and to the risk of larynx squamous cell carcinoma. Further, well-designed studies with larger sample sizes are required to verify our findings.


Asunto(s)
Carcinoma de Células Escamosas/etiología , Proteínas de Unión al ADN/genética , Neoplasias de Cabeza y Cuello/etiología , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Pronóstico , Factores de Riesgo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X
18.
Cell Physiol Biochem ; 30(1): 221-37, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22759969

RESUMEN

Neutrophil polarization is a basic activity involved in the innate immune response, and it may be initiated by extracellular Ca(2+) entry, a process primarily mediated through store-operated Ca(2+) entry (SOCE). Yet, the mechanisms by which SOCE participates in cell polarization remain unclear. We hypothesized that Akt- and Src-dependent pathways, traditionally linked to neutrophil polarization, may interact with SOCE in this event. In this study, SKF96365 and 2-APB, inhibitors of SOCE as proved by their inhibition on Mn(2+) influx, were observed to inhibit the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced influx of Ca(2+), the activation of Akt, Src, Rac1, Rac2, and Cdc42, and the polarization of differentiated HL-60 (dHL-60) cells. Downregulation of stromal interaction molecule 1 (STIM1), a Ca(2+) sensor identified to induce SOCE, by siRNA led to decreases in the following indexes: Ca(2+) entry, activation of Akt, Src, Rac2 (rather than Rac1) and Cdc42, and fMLP-induced polarization. This study suggests that SOCE might be the predominant form of Ca(2+) entry involved in the regulation of cell polarization, and it may act through the Akt/Src/Rac pathways, as modeled in dHL-60 cells. It also suggests that STIM1 is a key modulator of cell polarization, potentially serving as a target for the designation of anti-immune deficiency therapies.


Asunto(s)
Señalización del Calcio , Polaridad Celular , Activación Enzimática , Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Familia-src Quinasas/metabolismo , Compuestos de Boro/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Técnicas de Silenciamiento del Gen , Células HL-60 , Humanos , Imidazoles/farmacología , Manganeso/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neutrófilos/fisiología , Interferencia de ARN , Molécula de Interacción Estromal 1
19.
Inflamm Res ; 61(8): 853-62, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22588279

RESUMEN

OBJECTIVES: Neutrophil polarization is critical for the inflammatory response. AKT is a serine/threonine protein kinase and has been implicated in cell migration. However, it is not completely clear whether AKT affects neutrophil polarization. In this study, we tested the hypothesis that AKT regulates the polarization of neutrophil-like differentiated HL-60 cells (dHL-60) in response to fMLP. METHODS: HL-60 cells were differentiated into dHL-60 by incubation in medium containing 1.3 % DMSO for up to 6 days. Polarization of dHL-60 cells and primary human neutrophils were measured by Zigmond chamber. Phospho-Akt was analyzed by immunofluorescence and Western blot analysis. F-actin polymerization was detected by Rhodamine-Phalloidine staining. Rac2 activation was evaluated using GST Pull-down assay. RESULTS: We found that changes in the rate of cell polarization were consistent with the changes in AKT phosphorylation levels during HL-60 cell differentiation in response to fMLP. Moreover, cell polarization and AKT phosphorylation were reduced in fMLP-stimulated dHL-60 cells pretreated with the PI3 kinase inhibitors or the AKT inhibitors, which was confirmed in the primary human neutrophils. The AKT inhibitors altered fMLP-induced F-actin polymerization. Rac2 GTPases was also decreased by the AKT inhibitors in fMLP-stimulated dHL-60 cells. CONCLUSION: This study demonstrates that AKT activation plays a crucial role in dHL-60 cell polarization.


Asunto(s)
Diferenciación Celular/fisiología , Neutrófilos/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Actinas/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Quimiotaxis , Células HL-60 , Humanos , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas de Unión al GTP rac/metabolismo , Proteína RCA2 de Unión a GTP
20.
Bioorg Med Chem Lett ; 21(8): 2415-8, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21397503

RESUMEN

The anti-inflammatory properties of soyasaponins (especially soyasaponins with different chemical structures) have scarcely been investigated. We investigated the inhibitory effects of five structural types of soyasaponins (soyasaponin A(1), A(2), I and soyasapogenol A, B) on the induction of nitric oxide (NO) and inducible NO synthase (iNOS) in murine RAW 264.7 cells activated with lipopolysaccharide (LPS). Soyasaponin A(1), A(2) and I (25-200 µg/mL) dose-dependently inhibited the production of NO and tumor necrosis factor α (TNF-α) in LPS-activated macrophages, whereas soyasapogenol A and B did not. Furthermore, soyasaponin A(1), A(2) and I suppressed the iNOS enzyme activity and down-regulated the iNOS mRNA expression both in a dose-dependent manner. The reporter gene assay revealed that soyasaponin A(1), A(2) and I decreased LPS-induced nuclear factor kappa B (NF-κB) activity. Soyasaponin A(1), A(2) and I exhibit anti-inflammatory properties by suppressing NO production in LPS-stimulated RAW 264.7 cells through attenuation of NF-κB-mediated iNOS expression. It is proposed that the sugar chains present in the structures of soyasaponins are important for their anti-inflammatory activities. These results have important implication for using selected soyasaponins towards the development of effective chemopreventive and anti-inflammatory agents.


Asunto(s)
Antiinflamatorios/química , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Saponinas/química , Animales , Antiinflamatorios/farmacología , Línea Celular Tumoral , Lipopolisacáridos/toxicidad , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Saponinas/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
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