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Recent explorations into rice bran oil (RBO) have highlighted its potential, owing to an advantageous fatty acid profile in the context of health and nutrition. Despite this, the susceptibility of rice bran lipids to oxidative degradation during storage remains a critical concern. This study focuses on the evolution of lipid degradation in RBO during storage, examining the increase in free fatty acids (FFAs), the formation of oxylipids, and the generation of volatile secondary oxidation products. Our findings reveal a substantial rise in FFA levels, from 109.55 to 354.06 mg/g, after 14 days of storage, highlighting significant lipid deterioration. Notably, key oxylipids, including 9,10-EpOME, 12,13(9,10)-DiHOME, and 13-oxoODE, were identified, with a demonstrated positive correlation between total oxylipids and free polyunsaturated fatty acids (PUFAs), specifically linoleic acid (LA) and α-linolenic acid (ALA). Furthermore, the study provides a detailed analysis of primary volatile secondary oxidation products. The insights gained from this study not only sheds light on the underlying mechanisms of lipid rancidity in rice bran but also offers significant implications for extending the shelf life and preserving the nutritional quality of RBO, aligning with the increasing global interest in this high-quality oil.
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Lipidómica , Lipólisis , Ácidos Grasos , Ácidos Grasos no Esterificados , Ácido Linoleico , Aceite de Salvado de ArrozRESUMEN
Rice bran, recognized for its rich lipids and health-beneficial bioactive compounds, holds considerable promise in applications such as rice bran oil production. However, its susceptibility to lipid hydrolysis and oxidation during storage presents a significant challenge. In response, we conducted an in-depth metabolic profiling of rice bran over a storage period of 14 days. We focused on the identification of bioactive compounds and functional lipid species (25 acylglycerols and 53 phospholipids), closely tracking their dynamic changes over time. Our findings revealed significant reductions in these lipid molecular species, highlighting the impact of rancidity processes. Furthermore, we identified 19 characteristic lipid markers and elucidated that phospholipid and glycerolipid metabolism were key metabolic pathways involved. By shedding light on the mechanisms driving lipid degradation in stored rice bran, our study significantly advanced the understanding of lipid stability. These information provided valuable insights for countering rancidity and optimizing rice bran preservation strategies.
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Lipidómica , Oryza , Hidrólisis , Oxidación-Reducción , Fosfolípidos , Lipólisis , Aceite de Salvado de ArrozRESUMEN
Nervonic acid (NA) is a monounsaturated fatty acid vital for brain health and is of emerging importance in various industrial applications, including therapeutics, food, and cosmetics. Given the growing demands of the food and pharmaceutical industries, there's a pressing need for high-purity NA. Previously, NA constituents in plant seed oils were chemically transformed into nervonic acid ethyl ester (NAEE) to facilitate extraction from seed oils. In this study, we present an enzymatic approach to convert NA constituents in Malania oleifera seed oil to NAEE. Combined with the utilization of the semi-preparative chromatography, we achieved a remarkable purity of 97.52% NAEE. Compared to conventional chemical preparations characterized by multiple steps, prolonged processing times, and low yields and purities, our enzymatic method stands out as a more efficient and advantageous alternative. On top of that, this innovative approach is environmentally friendly and circumvents health and safety issues associated with chemical processes.
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Ácidos Grasos Monoinsaturados , Aceites de Plantas , Aceites de Plantas/química , Ácidos Grasos Monoinsaturados/análisis , Semillas/química , Ácidos Grasos/análisisRESUMEN
This study aimed to produce stable plastic fat with desired physicochemical characteristics and ω-6/ω-3 fatty acid ratio (1:1-4:1) from palm stearin (PS), flaxseed oil (FSO) and cottonseed stearin (CS) via enzymatic interesterification (EIE). For the first time, the EIE variables of the blends containing PS, FSO and CS were investigated and optimized through single-factor experiments and response surface design to achieve a high interesterification degree. The optimized enzymatic interesterification conditions were: 60°C, 6 wt% Lipase UM1, and 6 h. Lipase UM1 had a similar effect on ID values with commercial lipases. The EIE improved the compatibility of the lipid blends, with the interesterified product EIE-721 (7:2:1, PS: FSO:CS) being the best candidate base stock for shortening considering its solid fat content, desired ω-6/ω-3 fatty acid ratio, wide melting range, abundant ß' form crystal, and compact microstructure. This study provides a strategy to produce balanced ω-6/ω-3 fatty acid plastic fat through enzymatic interesterification and validates the application of Lipase UM1 in the preparation of plastic fat.
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Ácidos Grasos Omega-3 , Aceite de Linaza , Aceites de Plantas/química , Aceite de Semillas de Algodón , Ácidos Grasos/química , Lipasa/química , Esterificación , Aceite de PalmaRESUMEN
α-Tocopherol has been widely used in medicine, cosmetics, and food industry as a nutritional supplement and antioxidant. However, α-tocopherol showed low bioaccessibility, and there is a widespread α-tocopherol deficiency in society today. The preparation of oil-in-water emulsions with high safety and low-calorie property is necessary. The aim of this research was to investigate the effects of different protein emulsifiers (whey protein isolate (WPI), soy protein isolate (SPI), and sodium casein (SC)) on the properties of emulsions delivery system, and diacylglycerol (DAG) was picked as a low-accumulated lipid. The interfacial changes, microstructural alterations, and possible interactions of the protein-stabilized DAG emulsions were investigated during the in vitro digestion. The results show that different proteins affect the degree of digestibility and α-tocopherol bioaccessibility of the emulsions. Both WPI- and SPI-coated emulsions showed good digestibility and α-tocopherol bioaccessibility (77.64 ± 2.93%). This might be due to the strong hydrolysis resistance of WPI (ß-lactoglobulin) and the good emulsification ability of SPI. The SC-coated emulsion showed the lowest digestibility and α-tocopherol bioaccessibility, this might be due to the emulsification property of hydrolysis products of SC and the potential interaction with calcium ions. This study provides new possibilities for the application of DAG emulsions in delivery systems.
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BACKGROUND: Brain-derived neurotrophic factor (BDNF) acts as a neuromodulator to regulate gut motility, but the role of BDNF in diabetes-related dysmotility is uncertain. The aim of this study was to investigate the possible involvement of BDNF and its receptor TrkB in the colonic hypomotility of mice with streptozotocin (STZ)-induced diabetes. METHODS: A single intraperitoneal injection of STZ was used to establish a type 1 diabetes model. An organ bath system was applied to observe the contractile activities of colonic muscle strips. Immunofluorescence and western blotting were performed to evaluate the expression of BDNF and TrkB in the colon. ELISA was used to detect BDNF and SP levels in the serum and colon. The patch-clamp technique was applied to record the currents of L-type calcium channels and large conductance Ca2+ -activated K+ channels on smooth muscle cells. KEY RESULTS: Compared with healthy controls, diabetic mice showed attenuated colonic muscle contraction (p < 0.001), which was partly reversed by BDNF supplementation. TrkB protein expression was significantly reduced in diabetic mice (p < 0.05). In addition, both BDNF and substance P (SP) levels were decreased, and exogenous administration of BDNF increased SP levels in diabetic mice (p < 0.05). Both the TrkB antagonist and the TrkB antibody inhibited the spontaneous contraction of colonic muscle strips (p < 0.01). Moreover, the BDNF-TrkB signaling system enhanced SP-induced muscle contraction. CONCLUSIONS: Downregulation of BDNF/TrkB signaling and reduced SP release from the colon may contribute to the colonic hypomotility associated with type 1 diabetes. Brain-derived neurotrophic factor supplementation may have therapeutic potential for diabetes-related constipation.
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Enfermedades del Colon , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Estreptozocina , Regulación hacia Abajo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Sustancia P/metabolismoRESUMEN
Diacylglycerol (DAG) is commonly known as one of the precursors for the 3-monochloro-1,2-propanediol esters (3-MCPDE) and glycidyl esters (GE) formation. However, due to its health-promoting effects, its potential as alternative frying medium was examined. This study aimed to assess the frying performance of soybean oil-based diacylglycerol oil (DO) and its oil blends with palm olein (PO), in comparison with PO. Four different oil types (DO, PO, OB I (DO:PO, 1:1, w/w) and OB II (DO:PO, 1:2, w/w)) were used to fry potato chips for five consecutive days at 180â. The formation of oxidation compounds, acylglycerol composition, 3-MCPDE and GE changes throughout the frying study were investigated. Both OB I and OB II exhibited lower oxidation compounds' formation rates than PO. Besides, significant (p < 0.05) reductions of 3-MCPDE and increments of GE levels were observed in all frying systems throughout the frying study. After 25 frying cycles, the 3-MCPDE levels in all frying oils were below 0.13 mg/kg, while the GE levels ranged from 1.51 mg/kg to 1.89 mg/kg. Despite the poorer oxidative stability of DO, its 3-MCPDE and GE levels were much lower compared to PO. In comparison to DO, the 3-MCPDE degradation and GE formation rates were enhanced and reduced, respectively with the blending of PO and DO. This study showed the potential of DO:PO oil blend in deep-fat frying application. With appropriate blending ratio of DO and PO, an alternative frying medium with enhanced nutritional value and oxidative stability could be developed.
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Diglicéridos , Aceite de Soja , Ésteres , Aceite de Palma , Estrés OxidativoRESUMEN
BACKGROUND: Co-encapsulation of probiotics and omega-3 oil using complex coacervation is an effective method for enhancing the tolerance of probiotics under adverse conditions, whereas complex coacervation of omega-3 oil was found to have low lipid digestibility. In the present study, gelatin (GE, 30 g kg-1 ) and gum arabic (GA, 30 g kg-1 ) were used to encapsulate Lactobacillus plantarum WCFS1 and algal oil by complex coacervation to produce microcapsules containing probiotics (GE-P-GA) and co-microcapsules containing probiotics and algal oil (GE-P-O-GA), and soy lecithin (SL) was added to probiotics-algal oil complex coacervates [GE-P-O(SL)-GA] to enhance its stability and lipolysis. Then, we evaluated the viability of different microencapsulated probiotics exposed to freeze-drying and long-term storage, as well as the survival rate and release performance of encapsulated probiotics and algal oil during in vitro digestion. RESULTS: GE-P-O(SL)-GA had a smaller particle size (51.20 µm), as well as higher freeze-drying survival (90.06%) of probiotics and encapsulation efficiency of algal oil (75.74%). Moreover, GE-P-O(SL)-GA showed a higher algal oil release rate (79.54%), lipolysis degree (74.63%) and docosahexaenoic acid lipolysis efficiency (64.8%) in the in vitro digestion model. The viability of microencapsulated probiotics after simulated digestion and long-term storage at -18,4 and 25 °C was in the order: GE-P-O(SL)-GA > GE-P-O-GA > GE-P-GA. CONCLUSION: As a result of its amphiphilic properties, SL strongly affected the physicochemical properties of probiotics and algal oil complex coacervates, resulting in higher stability and more effective lipolysis. Thus, the GE-P-O(SL)-GA can more effectively deliver probiotics and docosahexaenoic acid to the intestine, which provides a reference for the preparation of high-viability and high-lipolysis probiotics-algal oil microcapsules. © 2022 Society of Chemical Industry.
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Lecitinas , Probióticos , Ácidos Docosahexaenoicos , Cápsulas/química , Lipólisis , Probióticos/química , Composición de Medicamentos/métodosRESUMEN
Enzymatic degumming is an essential refining process to improve oil quality. In this study, a monoacylglycerol lipase GMGL was derived from marine Geobacillus sp., and was found that not only took monoacylglycerol (MAG) as substrate, but also had activity toward lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) and glycerolphosphatidylcholine (GPC). Binding free energy showed LPC and LPE could bind with enzyme stably as MAG. It presented great potential in the field of enzymatic degumming. The phosphorus content in crude soybean oil decreased from 680.50 to 2.01â¯mg/kg and the yield of oil reached to 98.80â¯% after treating with phospholipase A1 (Lecitase Ultra) combined with lipase GMGL. An ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was developed to identify 21 differential phospholipids between crude soybean oil and enzymatic treatment. This work might shed some light on understanding the catalytic mechanism of monoacylglycerol lipase and provide an effective strategy for enzymatic degumming.
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Geobacillus , Aceite de Soja , Aceite de Soja/química , Lisofosfolipasa/metabolismo , Monoacilglicerol Lipasas , Lisofosfatidilcolinas , Glycine max/metabolismoRESUMEN
Furan fatty acids (FuFAs) have been recognized as beneficial food ingredients to human health. Herein, a targeted quantitation approach by gas chromatography coupled to triple quadrupole tandem mass spectrometry (GC-TQ/MS) was developed for the identification of FuFAs in common marine and other edible oils in multiple reaction monitoring (MRM) mode without any isolation and enrichment. The limit-of-quantitation (LOQ, 0.6 pg) was determined under the optimized parameters in MRM mode. Identification of FuFAs in common edible oils demonstrated that marine fish oils were concentrated sources of 9-(3-methyl-5-pentylfuran-2-yl)nonanoic acid (9M5), 11-(3,4-dimethyl-5-propylfuran-2-yl)undecanoic acid (11D3) and 11-(3,4-dimethyl-5-pentylfuran-2-yl)undecanoic acid (11D5). However, FuFAs were not identified in common plant oils. Additionally, 11D5 was identified in the lipids of Schizochytrium limacinum at a comparable level with that in marine fish oil. We believe that this protocol could facilitate the qualitative and quantitative analysis of FuFAs in food and biological samples.
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Aceites de Plantas , Espectrometría de Masas en Tándem , Humanos , Cromatografía de Gases y Espectrometría de Masas/métodos , Aceites de Plantas/química , Ácidos Grasos/química , Aceites de Pescado/química , Furanos/químicaRESUMEN
Diacylglycerol (DAG) is commonly known as one of the precursors for 3-monochloropropane-1,2-diol esters (3-MCPDE) and glycidyl esters (GE) formation. Besides, 3-MCPDE and GE are heat-induced contaminants which can be formed in fat-containing baked products during the baking process. This study attempted to replace the conventional palm-based shortening (SH) with a healthier fat, namely soybean oil-based diacylglycerol stearin (SDAG) in producing biscuits. The effects of different baking temperatures (200, 210 and 220 °C) and SDAG:SH fat blend ratios (0:100, 60:40 (D64S), 80:20 (D82S), 100:0, w/w) towards the biscuits' physical properties were evaluated. Moreover, the oxidative stability, 3-MCPDPE and GE formation in the fats extracted from the biscuits were also investigated. SDAG-produced biscuit showed slight reductions in the spread ratio compared to the SH-produced biscuit. The elevated baking temperatures resulted in biscuits with increased hardness and low moisture content. Pure SDAG and the other fat blends exhibited significant (p < 0.05) poorer oxidative stability than SH. However, D64S was found to be more oxidative stable compared to SDAG and D82S. The D64S fat blend exhibited the lowest 3-MCPDE and GE formation rates among all fat samples with the increasing baking temperatures. Furthermore, the amount of 3-MCPDE and GE detected in the fats extracted from the biscuits baked at highest temperature (220 °C) were still within the safety limit. In overall, better quality biscuits were produced when lower baking temperature (200 °C) was used as all biscuits baked with different fats showed similar textural properties (hardness and cohesiveness), higher oxidative stability and lower formation of 3-MCPDE and GE compared to biscuits baked at higher temperatures. The findings justified the potential of D64S fat blend in replacing the conventional SH in producing healthier biscuits.
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alfa-Clorhidrina , Diglicéridos , Aceite de Soja , Ésteres , TemperaturaRESUMEN
This study developed an alpha-linolenic acid (ALA) supplement with emulsion form using ALA-rich diacylglycerol (ALA-DAG) and ALA-DAG stearin (DAG-SF) as a new source of ALA and emulsifier. Stable, commercial surfactant-free W/O emulsions with 90 wt% oil phase (including DAG-SF and ALA-DAG with 10:90 - 20:80 wt ratio) was fabricated. Microstructure and Raman spectra revealed that the compact crystal networks and high amounts of solid acyl chains were responsible for high emulsion stability. These emulsions exhibited good potential in improving the ALA nutritional status (with ALA release level of 60.49% - 62.98%). Furthermore, the emulsifier-to-oil ratio greatly impacted the emulsion texture (solid-like or liquid-like) and emulsions showed great oxidation stability (2.80 - 3.09 meq/kg lipid of peroxide value at 6th week). The tunable texture and high oxidation stability make this emulsion system useful for a wide range of food products. This developed emulsion system could provide valuable information for other important fatty acids supplement.
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Diglicéridos , Ácido alfa-Linolénico , Digestión , Diglicéridos/química , Emulsionantes , Emulsiones/química , Agua/químicaRESUMEN
This research synthesized structure lipids (SL) from blends of fully hydrogenated palm kernel oil (FHPKO), coconut oil (CNO) and fully hydrogenated palm stearin (FHPS) by enzymatic interesterification (EIE)using rProROL, an sn-1,3-specific lipase from Rhizopus oryzae, as a catalyst. Five physical blends of FHPKO:CNO:FHPS were prepared with the following wt. ratios: 40:10:50, 50:10:40, 60:10:30, 70:10:20 and 80:10:10. The EIE reactions were carried out at 60â for 6 h in a batch-type reactor using rProROL 10% wt. of the substrate. It was found that EIE significantly modified the triacylglycerol compositions of the fat blends resulting in changes in the crystallization and melting behavior. In particular, SL obtained from EIE of blend 70:10:20 exhibited high potential to be used as a cocoa butter substitute (CBS) because it showed similar solid fat content curve to the commercial CBS and crystallized into fine spherulites and desirable ß' polymorph.
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Aceites de Plantas , Aceite de Coco/química , Grasas de la Dieta , Esterificación , Aceite de Palma/química , Aceites de Plantas/química , TriglicéridosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cardiac hypertrophy (CH) is an incurable heart disease, contributing to an increased risk of heart failure due to the lack of safe and effective strategies. Therefore, searching for new approaches to treat CH is urgent. Centella asiatica (L.) Urb. (CA), a traditional food and medicinal natural plant, has been turned out to be effective in the treatment of cardiovascular disease, but its efficacy and potential mechanisms in alleviating CH have not yet been investigated. AIM OF STUDY: In this study, we aimed to elucidate the multi-level mechanisms underlying the effect of CA against CH. STUDY DESIGN AND METHODS: A systems pharmacology approach was employed to screen active ingredients, identify potential targets, construct visual networks and systematically investigate the pathways and mechanisms of CA for CH treatment. The cardiac therapeutic potential and mechanism of action of CA on CH were verified with in vivo and in vitro experiments. RESULTS: Firstly, we demonstrated the therapeutic effect of CA on CH and then screened 13 active compounds of CA according to the pharmacokinetic properties. Then, asiatic acid (AA) was identified as the major active molecule of CA for CH treatment. Afterwards, network and functional enrichment analyses showed that CA exerted cardioprotective effects by modulating multiple pathways mainly involved in anti-apoptotic, antioxidant and anti-inflammatory processes. Finally, in vivo, the therapeutic effects of AA and its action on the YAP/PI3K/AKT axis and NF-κB signaling pathway were validated using an isoproterenol-induced CH mouse model. In vitro, AA decreased ROS levels in hydrogen peroxide-treated HL-1 cells. CONCLUSION: Overall, the multi-level mechanisms of CA for CH treatment were demonstrated by systems pharmacology approach, which provides a paradigm for systematically deciphering the mechanisms of action of natural plants in the treatment of diseases and offers a new idea for the development of medicinal and food products.
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Centella , Animales , Cardiomegalia/tratamiento farmacológico , Ratones , Farmacología en Red , Fosfatidilinositol 3-Quinasas , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Docosahexaenoic acid (DHA) is a major constituent of neural and visual membranes and is required for optimal neural and visual function. DHA is derived from food or by endogenous synthesis from α-linolenic acid (ALA), an essential fatty acid. Low blood levels of DHA in some westernised populations have led to speculations that child development disorders and various neurological conditions are associated with sub-optimal neural DHA levels, a proposition which has been supported by the supplement industry. This review searched for evidence of deficiency of DHA in human populations, based on elevated levels of the biochemical marker of n-3 deficiency, docosapentaenoic acid (22:5n-6). Three scenarios/situations were identified for the insufficient supply of DHA, namely in the brain of new-born infants fed with high-linoleic acid (LA), low-ALA formulas, in cord blood of women at birth who were vegetarians and in the milk of women from North Sudan. Twenty post-mortem brain studies from the developed world from adults with various neurological disorders revealed no evidence of raised levels of 22:5n-6, even in the samples with reduced DHA levels compared with control subjects. Human populations most likely at risk of n-3 deficiency are new-born and weanling infants, children and adolescents in areas of dryland agriculture, in famines, or are refugees, however, these populations have rarely been studied. This is an important topic for future research.
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Ácidos Docosahexaenoicos , Ácidos Grasos Esenciales , Recién Nacido , Lactante , Embarazo , Adulto , Niño , Humanos , Femenino , Adolescente , Animales , Encéfalo , Leche , Parto , Ácido alfa-Linolénico/farmacologíaRESUMEN
The dysfunction of regulatory B cells (Breg) may result in immune inflammation such as allergic rhinitis (AR); the underlying mechanism is not fully understood yet. Short-chain fatty acids, such as propionic acid (PA), have immune regulatory functions. This study is aimed at testing a hypothesis that modulates PA production alleviating airway allergy through maintaining Breg functions. B cells were isolated from the blood obtained from AR patients and healthy control (HC) subjects. The stabilization of IL-10 mRNA in B cells was tested with RT-qPCR. An AR mouse model was developed to test the role of PA in stabilizing the IL-10 expression in B cells. We found that the serum PA levels were negatively correlated with the serum Th2 cytokine levels in AR patients. Serum PA levels were positively associated with peripheral CD5+ B cell frequency in AR patients; the CD5+ B cells were also IL-10+. The spontaneous IL-10 mRNA decay was observed in B cells, which was prevented by the presence of PA through activating GPR43. PA counteracted the effects of Tristetraprolin (TTP) on inducing IL-10 mRNA decay in B cells through the AKT/T-bet/granzyme B pathway. Administration of Yupinfeng San, a Chinese traditional medical formula, or indole-3-PA, induced PA production by intestinal bacteria to stabilize the IL-10 expression in B cells, which promoted the allergen specific immunotherapy, and efficiently alleviated experimental AR. In summary, the data show that CD5+ B cells produce IL-10. The serum lower PA levels are associated with the lower frequency of CD5+ B cells in AR patients. Administration with Yupinfeng San or indole-3-PA can improve Breg functions and alleviate experimental AR.
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Linfocitos B Reguladores/inmunología , Desensibilización Inmunológica , Propionatos/metabolismo , Rinitis Alérgica/terapia , Adolescente , Adulto , Animales , Linfocitos B Reguladores/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Microbioma Gastrointestinal/inmunología , Voluntarios Sanos , Humanos , Indoles/administración & dosificación , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Cultivo Primario de Células , Propionatos/sangre , Estabilidad del ARN , Receptores de Superficie Celular/metabolismo , Rinitis Alérgica/sangre , Rinitis Alérgica/inmunología , Células Th2/inmunología , Células Th2/metabolismo , Adulto JovenRESUMEN
Because of the complex etiology, the treatment of gastric cancer is a formidable challenge for contemporary medical. The current treatment method focuses on traditional surgical procedures, supplemented by other treatments. Among these other treatments, Traditional Chinese Medicine (TCM) plays an important role. Here, we used the systems pharmacology approach to reveal the potential molecular mechanism of PRGRC on gastric cancer which composes of Pinellia ternata (Thunb.) Breit., Rheum palmatum L., Gentiana scabra Bunge, Radix Aucklandiae and Citrus aurantium L. This approach combines pharmacokinetics analysis with pharmacodynamics evaluation for the active compounds screening, targets prediction and pathways assessing. Firstly, through pharmacokinetic evaluation and target prediction models, 83 potential compounds and 184 gastric cancer-related targets were screened out. Then, the results of network analysis suggested that the targets of PRGRC were mainly involved two aspects: apoptosis and inflammation. Finally, we verified the reliability of the above analysis at the cellular level by using naringenin and luteolin with good pharmacokinetic activity as representative compounds. Overall, we found that PRGRC could influence the development of gastric cancer from a multi-scale perspective. This study provided a new direction for analyzing the mechanism of TCM.
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Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional China/métodos , Neoplasias Gástricas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacocinética , Flavanonas/farmacocinética , Flavanonas/farmacología , Humanos , Inflamación/tratamiento farmacológico , Luteolina/farmacocinética , Luteolina/farmacología , Farmacología en Red , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacologíaRESUMEN
Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation in vitro and in vivo. PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-γ production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/MEK/ERK/c-Jun pathway to impair T cell function.
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Although the main focus of immuno-oncology has been manipulating the adaptive immune system, tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment (TME) and play a critical role in cancer progression. TAMs are mainly divided into two different subtypes: macrophages with antitumor or killing activity are called M1 while tumor-promoting or healing macrophages are named M2. Therefore, controlling the polarization of TAMs is an important strategy for cancer treatment, but there is no particularly effective means to regulate the polarization process. Here, combined systems pharmacology targets and pathways analysis strategy, we uncovered Scutellariae Radix (SR) has the potential to regulate TAMs polarization to inhibit the growth of non-small cell lung cancer (NSCLC). Firstly, systems pharmacology approach was used to reveal the active components of SR targeting macrophages in TME through compound target prediction and target-microenvironment phenotypic association analysis. Secondly, in vitro experiment verified that WBB (wogonin, baicalein and baicalin), major active ingredients of SR are significantly related to macrophages and survival, initiated macrophages programming to M1-like macrophages to promoted the apoptosis of tumor cells. Finally, we evidenced that WBB effectively inhibited tumor growth in LLC (Lewis lung carcinoma) tumor-bearing mice and increased the infiltration of M1-type macrophages in TME. Overall, the systems pharmacology strategy offers a paradigm to understand the mechanism of polypharmacology of natural products targeting TME.
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Antineoplásicos Fitogénicos/farmacología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunidad Innata/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Farmacología en Red , Macrófagos Asociados a Tumores/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Cocultivo , Bases de Datos Genéticas , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Fenotipo , Células RAW 264.7 , Carga Tumoral/efectos de los fármacos , Microambiente Tumoral , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.