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1.
Molecules ; 28(21)2023 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-37959750

RESUMEN

Echinacea purpurea (L.) Moench is a medicinal plant commonly used for the treatment of upper respiratory tract infections, the common cold, sore throat, migraine, colic, stomach cramps, and toothaches and the promotion of wound healing. Based on the known pharmacological properties of essential oils (EOs), we hypothesized that E. purpurea EOs may contribute to these medicinal properties. In this work, EOs from the flowers of E. purpurea were steam-distilled and analyzed by gas chromatography-mass spectrometry (GC-MS), GC with flame-ionization detection (GC-FID), and chiral GC-MS. The EOs were also evaluated for in vitro antimicrobial and innate immunomodulatory activity. About 87 compounds were identified in five samples of the steam-distilled E. purpurea EO. The major components of the E. purpurea EO were germacrene D (42.0 ± 4.61%), α-phellandrene (10.09 ± 1.59%), ß-caryophyllene (5.75 ± 1.72%), γ-curcumene (5.03 ± 1.96%), α-pinene (4.44 ± 1.78%), δ-cadinene (3.31 ± 0.61%), and ß-pinene (2.43 ± 0.98%). Eleven chiral compounds were identified in the E. purpurea EO, including α-pinene, sabinene, ß-pinene, α-phellandrene, limonene, ß-phellandrene, α-copaene, ß-elemene, ß-caryophyllene, germacrene D, and δ-cadinene. Analysis of E. purpurea EO antimicrobial activity showed that they inhibited the growth of several bacterial species, although the EO did not seem to be effective for Staphylococcus aureus. The E. purpurea EO and its major components induced intracellular calcium mobilization in human neutrophils. Additionally, pretreatment of human neutrophils with the E. purpurea EO or (+)-δ-cadinene suppressed agonist-induced neutrophil calcium mobilization and chemotaxis. Moreover, pharmacophore mapping studies predicted two potential MAPK targets for (+)-δ-cadinene. Our results are consistent with previous reports on the innate immunomodulatory activities of ß-caryophyllene, α-phellandrene, and germacrene D. Thus, this study identified δ-cadinene as a novel neutrophil agonist and suggests that δ-cadinene may contribute to the reported immunomodulatory activity of E. purpurea.


Asunto(s)
Antiinfecciosos , Echinacea , Aceites Volátiles , Humanos , Aceites Volátiles/química , Calcio , Vapor , Cromatografía de Gases y Espectrometría de Masas , Antiinfecciosos/química
2.
Molecules ; 27(15)2022 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-35956847

RESUMEN

Grindelia squarrosa (Pursh) Dunal is used in traditional medicine for treating various diseases; however, little is known about the immunomodulatory activity of essential oils from this plant. Thus, we isolated essential oils from the flowers (GEOFl) and leaves (GEOLv) of G. squarrosa and evaluated the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of these essential oils revealed that the main components were α-pinene (24.7 and 23.2% in GEOFl and GEOLv, respectively), limonene (10.0 and 14.7%), borneol (23.4 and 16.6%), p-cymen-8-ol (6.1 and 5.8%), ß-pinene (4.0 and 3.8%), bornyl acetate (3.0 and 5.1%), trans-pinocarveol (4.2 and 3.7%), spathulenol (3.0 and 2.0%), myrtenol (2.5 and 1.7%), and terpinolene (1.7 and 2.0%). Enantiomer analysis showed that α-pinene, ß-pinene, and borneol were present primarily as (-)-enantiomers (100% enantiomeric excess (ee) for (-)-α-pinene and (-)-borneol in both GEOFl and GEOLv; 82 and 78% ee for (-)-ß-pinene in GEOFl and GEOLv), while limonene was present primarily as the (+)-enantiomer (94 and 96 ee in GEOFl and GEOLv). Grindelia essential oils activated human neutrophils, resulting in increased [Ca2+]i (EC50 = 22.3 µg/mL for GEOFl and 19.4 µg/mL for GEOLv). In addition, one of the major enantiomeric components, (-)-borneol, activated human neutrophil [Ca2+]i (EC50 = 28.7 ± 2.6), whereas (+)-borneol was inactive. Since these treatments activated neutrophils, we also evaluated if they were able to down-regulate neutrophil responses to subsequent agonist activation and found that treatment with Grindelia essential oils inhibited activation of these cells by the N-formyl peptide receptor 1 (FPR1) agonist fMLF and the FPR2 agonist WKYMVM. Likewise, (-)-borneol inhibited FPR-agonist-induced Ca2+ influx in neutrophils. Grindelia leaf and flower essential oils, as well as (-)-borneol, also inhibited fMLF-induced chemotaxis of human neutrophils (IC50 = 4.1 ± 0.8 µg/mL, 5.0 ± 1.6 µg/mL, and 5.8 ± 1.4 µM, respectively). Thus, we identified (-)-borneol as a novel modulator of human neutrophil function.


Asunto(s)
Grindelia , Aceites Volátiles , Canfanos , Grindelia/química , Humanos , Limoneno/análisis , Neutrófilos , Aceites Volátiles/química , Hojas de la Planta/química , Aceites de Plantas/química
3.
Molecules ; 26(12)2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-34203809

RESUMEN

Rhododendron (Ericaceae) extracts contain flavonoids, chromones, terpenoids, steroids, and essential oils and are used in traditional ethnobotanical medicine. However, little is known about the immunomodulatory activity of essential oils isolated from these plants. Thus, we isolated essential oils from the flowers and leaves of R. albiflorum (cascade azalea) and analyzed their chemical composition and innate immunomodulatory activity. Compositional analysis of flower (REOFl) versus leaf (REOLv) essential oils revealed significant differences. REOFl was comprised mainly of monoterpenes (92%), whereas sesquiterpenes were found in relatively low amounts. In contrast, REOLv was primarily composed of sesquiterpenes (90.9%), with a small number of monoterpenes. REOLv and its primary sesquiterpenes (viridiflorol, spathulenol, curzerene, and germacrone) induced intracellular Ca2+ mobilization in human neutrophils, C20 microglial cells, and HL60 cells transfected with N-formyl peptide receptor 1 (FPR1) or FPR2. On the other hand, pretreatment with these essential oils or component compounds inhibited agonist-induced Ca2+ mobilization and chemotaxis in human neutrophils and agonist-induced Ca2+ mobilization in microglial cells and FPR-transfected HL60 cells, indicating that the direct effect of these compounds on [Ca2+]i desensitized the cells to subsequent agonist activation. Reverse pharmacophore mapping suggested several potential kinase targets for these compounds; however, these targets were not supported by kinase binding assays. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the R. albiflorum essential oils and suggest that essential oils from leaves of this plant may be effective in modulating some innate immune responses, possibly by inhibition of neutrophil migration.


Asunto(s)
Aceites Volátiles/química , Rhododendron/química , Flores/química , Células HL-60 , Humanos , Factores Inmunológicos/aislamiento & purificación , Factores Inmunológicos/metabolismo , Inmunomodulación/efectos de los fármacos , Monoterpenos/farmacología , Neutrófilos/efectos de los fármacos , Aceites Volátiles/farmacología , Hojas de la Planta/química , Receptores de Formil Péptido/efectos de los fármacos , Receptores de Formil Péptido/metabolismo , Rhododendron/metabolismo , Sesquiterpenos/farmacología
4.
Biomolecules ; 10(6)2020 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-32560389

RESUMEN

Hypericum L. (Hypericaceae) extracts have been used for their therapeutic effects; however, not much is known about the immunomodulatory activity of essential oils extracted from this plant. We isolated essential oils from the flowers and leaves of H. perforatum and analyzed their chemical composition and innate immunomodulatory activity. Analysis of flower (HEOFl) versus leaf (HEOLv) essential oils using gas chromatography-mass spectrometry revealed that HEOFl was comprised mainly of monoterpenes (52.8%), with an abundance of oxygenated monoterpenes, including cis-p-menth-3-en-1,2-diol (9.1%), α-terpineol (6.1%), terpinen-4-ol (7.4%), and limonen-4-ol (3.2%), whereas the sesquiterpenes were found in trace amounts. In contrast, HEOLv was primarily composed of sesquiterpenes (63.2%), including germacrene D (25.7%) and ß-caryophyllene (9.5%). HEOLv also contained oxygenated monoterpenes, including terpinen-4-ol (2.6%), while monoterpene hydrocarbons were found in trace amounts. Both HEOFl and HEOLv inhibited neutrophil Ca2+ mobilization, chemotaxis, and reactive oxygen species (ROS) production, with HEOLv being much more active than HEOFl. Furthermore, the pure sesquiterpenes germacrene D, ß-caryophyllene, and α-humulene also inhibited these neutrophil responses, suggesting that these compounds represented the active components of HEOLv. Although reverse pharmacophore mapping suggested that potential protein targets of germacrene D, ß-caryophyllene, bicyclogermacrene, and α-humulene could be PIM1 and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAK2), a kinase binding affinity assay did not support this finding, implying that other biological targets are involved. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the H. perforatum essential oils.


Asunto(s)
Hypericum/química , Inmunomodulación/efectos de los fármacos , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Flores/química , Humanos , Inmunomodulación/inmunología , Modelos Moleculares , Conformación Molecular , Neutrófilos/efectos de los fármacos , Aceites Volátiles/química , Aceites Volátiles/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Células Tumorales Cultivadas
5.
Molecules ; 24(9)2019 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-31083328

RESUMEN

Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (Allium sativum) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/ß (GSK-3α/ß), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.


Asunto(s)
Factores Inmunológicos/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Compuestos Orgánicos/farmacología , Compuestos de Azufre/farmacología , Compuestos Alílicos/farmacología , Antioxidantes/metabolismo , Disulfuros/farmacología , Ajo/química , Células HL-60 , Compuestos Heterocíclicos/farmacología , Humanos , Proteínas Quinasas Activadas por Mitógenos , Neutrófilos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Quinoxalinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sulfuros/farmacología , Tiazolidinedionas/farmacología
6.
Molecules ; 23(7)2018 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-29996498

RESUMEN

Essential oils (EOs) were obtained by hydrodistillation of various parts of Ferula ovina (Boiss.) Boiss., Ferula iliensis Krasn. ex. Korovin, and Ferula akitschkensis B. Fedtsch. ex Koso-Pol., collected in the flowering/budding and fruiting stages. Eight samples of EOs isolated from F. ovina and four samples from F. akitsckensis were analyzed by gas chromatography⁻mass spectrometry (GC-MS). The major constituents of F. ovina EOs were α-pinene (6.9⁻47.8%), ß-pinene (1.5⁻7.1%), sabinene (0.1⁻20.5%), ß-phellandrene (0⁻6.5%), trans-verbenol (0.9⁻7.4%), eremophilene (3.1⁻12%), and 6Z-2,5,5,10-tetramethyl-undeca-2,6,9-trien-8-one (0⁻13.7%). The major constituents of F. akitsckensis EOs were α-pinene (0⁻46.2%), ß-pinene (0⁻47.9%), sabinene (0⁻28.3%), eremophilene (0⁻10.6), ß-caryophyllene (0⁻7.5%), himachalen-7-ol (0⁻28.2%), and an himachalol derivative (0⁻8.3%). Samples of EOs from F. ovina, F. iliensis, and F. akitsckensis were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) pulse-field gel electrophoresis type USA300 (LAC). EOs from F. ovina exhibited the highest antibacterial activity compared to samples from other Ferula spp., with the most potent EOs being isolated from roots at the flowering and fruiting stages and stems at the fruiting stage (IC50 values of 19.1, 20.9, and 22.9 µg/mL, respectively). Although EOs demonstrated concentration-dependent inhibition of MRSA growth, analysis of the major constituents (α-pinene, ß-pinene, and sabinene) showed that they had low activity, suggesting that other components were likely responsible for the observed bioactivity of the unfractionated EOs. Indeed, correlation of the GC-MS data with antibacterial activity suggested that the putative components responsible for antibacterial activity were, either individually or in combination, eremophilene and trans-verbenol. Overall, these results suggest that the EOs from F. ovina could have potential for use as alternative remedies for the treatment of infectious diseases caused by MRSA.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Ferula/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Aceites Volátiles/química , Aceites Volátiles/farmacología , Modelos Lineales , Pruebas de Sensibilidad Microbiana
7.
Molecules ; 23(4)2018 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-29587351

RESUMEN

Although humic acids (HAs) from peat exhibit various therapeutic properties, there is little information available concerning their physicochemical and antioxidant properties. To address this issue, nine different types of peat, including oligotrophic, mesotrophic, and minerotrophic peat samples, were used for isolation of HA fractions by basic (HAb) and pyrophosphate (HAp) extractions. Physical parameters of the HAs were analyzed by UV-Vis, fluorescent, infrared (IR), and electron paramagnetic resonance (EPR) spectroscopy. Average Mr of the fractions ranged from 17.2 to 39.7 kDa, while their humification index (HIX) varied from 0.49 to 1.21. HAp fractions had a higher content of aromatic structures compared to HAb fractions. Moreover, HAp fractions had a significantly higher content of phenolic OH groups (3.6 ± 0.5 mmol/g) versus HAb (3.1 ± 0.5 mmol/g). All HA fractions exhibited antioxidant activity in radical scavenging and electrochemical assays, and their EPR signal had a single line with g = 2.0035, which is consistent with semiquinone type radicals. Furthermore, the HIX was found to be important in determining the number of semiquinone-type free radicals in the HA structures. Overall, these data provide a molecular basis to explain at least part of the beneficial therapeutic properties of peat-derived HAs.


Asunto(s)
Antioxidantes/farmacología , Sustancias Húmicas/análisis , Suelo/química , Antioxidantes/química , Espectroscopía de Resonancia por Spin del Electrón , Fenoles/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Espectrometría de Fluorescencia , Espectrofotometría Infrarroja
8.
J Leukoc Biol ; 101(6): 1361-1371, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28258152

RESUMEN

Essential oil extracts from Ferula iliensis have been used traditionally in Kazakhstan for treatment of inflammation and other illnesses. Because little is known about the biologic activity of these essential oils that contributes to their therapeutic properties, we analyzed their chemical composition and evaluated their phagocyte immunomodulatory activity. The main components of the extracted essential oils were (E)-propenyl sec-butyl disulfide (15.7-39.4%) and (Z)-propenyl sec-butyl disulfide (23.4-45.0%). Ferula essential oils stimulated [Ca2+]i mobilization in human neutrophils and activated ROS production in human neutrophils and murine bone marrow phagocytes. Activation of human neutrophil [Ca2+]i flux by Ferula essential oils was dose-dependently inhibited by capsazepine, a TRPV1 channel antagonist, indicating that TRPV1 channels mediate this response. Furthermore, Ferula essential oils stimulated Ca2+ influx in TRPV1 channel-transfected HEK293 cells and desensitized the capsaicin-induced response in these cells. Additional molecular modeling with known TRPV1 channel agonists suggested that the active component is likely to be (Z)-propenyl sec-butyl disulfide. Our results provide a cellular and molecular basis to explain at least part of the beneficial therapeutic properties of FEOs.


Asunto(s)
Ferula/química , Neutrófilos/inmunología , Aceites Volátiles/química , Aceites Volátiles/farmacología , Fagocitos/inmunología , Animales , Calcio/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Fagocitos/efectos de los fármacos , Fagocitos/metabolismo , Canales Catiónicos TRPV/metabolismo
9.
J Agric Food Chem ; 64(38): 7156-70, 2016 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-27586050

RESUMEN

Essential oils were obtained by hydrodistillation of the umbels+seeds and stems of Ferula akitschkensis (FAEOu/s and FAEOstm, respectively) and analyzed by gas chromatography and gas chromatography-mass spectrometry. Fifty-two compounds were identified in FAEOu/s; the primary components were sabinene, α-pinene, ß-pinene, terpinen-4-ol, eremophilene, and 2-himachalen-7-ol, whereas the primary components of FAEOstm were myristicin and geranylacetone. FAEOu/s, ß-pinene, sabinene, γ-terpinene, geranylacetone, isobornyl acetate, and (E)-2-nonenal stimulated [Ca(2+)]i mobilization in human neutrophils, with the most potent being geranylacetone (EC50 = 7.6 ± 1.9 µM) and isobornyl acetate 6.4 ± 1.7 (EC50 = 7.6 ± 1.9 µM). In addition, treatment of neutrophils with ß-pinene, sabinene, γ-terpinene, geranylacetone, and isobornyl acetate desensitized the cells to N-formyl-Met-Leu-Phe (fMLF)- and interleukin-8 (IL-8)-induced [Ca(2+)]i flux and inhibited fMLF-induced chemotaxis. The effects of ß-pinene, sabinene, γ-terpinene, geranylacetone, and isobornyl acetate on neutrophil [Ca(2+)]i flux were inhibited by transient receptor potential (TRP) channel blockers. Furthermore, the most potent compound, geranylacetone, activated Ca(2+) influx in TRPV1-transfected HEK293 cells. In contrast, myristicin inhibited neutrophil [Ca(2+)]i flux stimulated by fMLF and IL-8 and inhibited capsaicin-induced Ca(2+) influx in TRPV1-transfected HEK293 cells. These findings, as well as pharmacophore modeling of TRP agonists, suggest that geranylacetone is a TRPV1 agonist, whereas myristicin is a TRPV1 antagonist. Thus, at least part of the medicinal properties of Ferula essential oils may be due to modulatory effects on TRP channels.


Asunto(s)
Ferula/química , Factores Inmunológicos/farmacología , Neutrófilos/efectos de los fármacos , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Aldehídos/farmacología , Canfanos/farmacología , Capsaicina/farmacología , Movimiento Celular/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Células HEK293 , Células HL-60 , Humanos , Interleucina-8/metabolismo , N-Formilmetionina Leucil-Fenilalanina/análogos & derivados , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Neutrófilos/metabolismo , Aceites Volátiles/química , Aceites de Plantas/química , Semillas/química , Canales Catiónicos TRPV/metabolismo , Terpenos/farmacología , Canales de Potencial de Receptor Transitorio/metabolismo
10.
Phytother Res ; 30(8): 1287-97, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27215200

RESUMEN

Epilobium angustifolium is a medicinal plant used around the world in traditional medicine for the treatment of many disorders and ailments. Experimental studies have demonstrated that Epilobium extracts possess a broad range of pharmacological and therapeutic effects, including antioxidant, anti-proliferative, anti-inflammatory, antibacterial, and anti-aging properties. Flavonoids and ellagitannins, such as oenothein B, are among the compounds considered to be the primary biologically active components in Epilobium extracts. In this review, we focus on the biological properties and the potential clinical usefulness of oenothein B, flavonoids, and other polyphenols derived from E. angustifolium. Understanding the biochemical properties and therapeutic effects of polyphenols present in E. angustifolium extracts will benefit further development of therapeutic treatments from this plant. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Epilobium/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Polifenoles/química , Humanos
11.
J Agric Food Chem ; 63(20): 4999-5007, 2015 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-25959257

RESUMEN

Essential oils were obtained by hydrodistillation of the flowers+leaves and stems of Artemisia kotuchovii Kupr. (AKEO(f+l) and AKEO(stm), respectively) and analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The primary components of the oils were estragole, (E)- and (Z)-ß-ocimenes, methyleugenol, limonene, spathulenol, ß-pinene, myrcene, and (E)-methyl cinnamate. Seventy-four constituents were present at concentrations from 0.1 to 1.0%, and 34 compounds were identified in trace (<0.1%) amounts in one or both plant components. Screening of the essential oils for biological activity showed that AKEO(stm), but not AKEOf+l, inhibited N-formyl-Met-Leu-Phe (fMLF)-stimulated Ca(2+) flux and chemotaxis and phorbol-12-myristate-13-acetate (PMA)-induced reactive oxygen species (ROS) production in human neutrophils. Selected pure constituents, representing >96% of the AKEO(stm) composition, were also tested in human neutrophils and HL-60 cells transfected with N-formyl peptide receptor 1 (FPR1). One component, 6-methyl-3,5-heptadien-2-one (MHDO), inhibited fMLF- and interleukin 8 (IL-8)-stimulated Ca(2+) flux, fMLF-induced chemotaxis, and PMA-induced ROS production in human neutrophils. MHDO also inhibited fMLF-induced Ca(2+) flux in FPR1-HL60 cells. These results suggest that MHDO may be effective in modulating some innate immune responses, possibly by inhibition of neutrophil migration and ROS production.


Asunto(s)
Artemisia/química , Neutrófilos/efectos de los fármacos , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Aceites de Plantas/farmacología , Movimiento Celular/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Células HL-60 , Humanos , Neutrófilos/citología , Neutrófilos/inmunología , Aceites Volátiles/química , Extractos Vegetales/química , Hojas de la Planta/química , Aceites de Plantas/química
12.
Int Immunopharmacol ; 26(2): 367-77, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25887271

RESUMEN

Several plant extracts, including certain polyphenols, prime innate lymphocytes and enhance responses to secondary stimuli. Oenothein B, a polyphenol isolated from Epilobium angustifolium and other plant sources, enhances IFNγ production by both bovine and human NK cells and T cells, alone and in response to secondary stimulation by cytokines or tumor cells. Innate immune cell responsiveness is known to be affected by aging, but whether polyphenol responses by these cells are also impacted by aging is not known. Therefore, we examined oenothein B responsiveness in T cells from cord blood, young, and adult donors. We found that oenothein B stimulates bovine and human T cells from individuals over a broad range of ages, as measured by increased IL-2Rα and CD69 expression. However, clear differences in induction of cytokine production by T cells were seen. In T cells from human cord blood and bovine calves, oenothein B was unable to induce IFNγ production. However, oenothein B induced IFNγ production by T cells from adult humans and cattle. In addition, oenothein B induced GM-CSF production by human adult T cells, but not cord blood T cells. Within the responsive T cell population, we found that CD45RO+ memory T cells expressed more cytokines in response to oenothein B than CD45RO- T cells. In summary, our data suggest that the immunostimulation of T cells by oenothein B is influenced by age, particularly with respect to immune cytokine production.


Asunto(s)
Envejecimiento/efectos de los fármacos , Epilobium/inmunología , Taninos Hidrolizables/farmacología , Células Asesinas Naturales/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Adulto , Envejecimiento/inmunología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Bovinos , Sangre Fetal/efectos de los fármacos , Sangre Fetal/inmunología , Humanos , Inmunidad Celular/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Recién Nacido , Interferón gamma/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Células Asesinas Naturales/inmunología , Lectinas Tipo C/metabolismo , Linfocitos T/inmunología
13.
Bioorg Med Chem ; 23(14): 3913-24, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-25549897

RESUMEN

N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist (S)-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Several of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds.


Asunto(s)
Amidas/química , Evaluación Preclínica de Medicamentos/métodos , Receptores de Formil Péptido/agonistas , Receptores de Lipoxina/agonistas , Amidas/síntesis química , Animales , Calcio/metabolismo , Técnicas de Química Sintética , Estabilidad de Medicamentos , Células HL-60/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Activación Neutrófila/efectos de los fármacos , Ratas , Receptores de Formil Péptido/química , Receptores de Lipoxina/química , Especificidad de la Especie , Estereoisomerismo
14.
BMC Complement Altern Med ; 13: 149, 2013 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-23806004

RESUMEN

BACKGROUND: Extracts of leaves from Clerodendrum have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. METHODS: Polysaccharides from the leaves of Clerodendrum splendens were extracted and fractionated by ion exchange and size-exclusion chromatography. Molecular weight determination, sugar analysis, degree of methyl esterification, and other chemical characterization of the fractions were performed. Immunomodulatory activity of the fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO), cytokine production, and mitogen-activated protein kinase (MAPK) phosphorylation. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice, and severity of EAE was monitored in mice treated with intraperitoneal (i.p.) injections of the most active polysaccharide fraction. Lymph nodes (LN) and spleen were harvested, and levels of cytokines in supernatants from LN cells and splenocytes challenged with myelin oligodendrocyte glycoprotein peptide were determined. RESULTS: Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the high-molecular weight sub-fraction CSP-AU1 (average of 38.5 kDa) induced NO and cytokine [interleukin (IL)-1α, -1ß, -6, -10, tumor necrosis factor (TNF; designated previously as TNF-α), and granulocyte macrophage-colony stimulating factor (GM-CSF)] production by human peripheral blood mononuclear cells (PBMCs) and monocyte/macrophages. CSP-AU1-induced secretion of TNF was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS, indicating a role for TLR4 signaling. Treatment with CSP-AU1 also induced phosphorylation of a number of MAPKs in human PBMC and activated AP-1/NF-κB. In vivo treatment of mice with CSP-AU1 and CSP-NU1 resulted in increased serum IL-6, IL-10, TNF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α/CCL3, and MIP-1ß/CCL4. CSP-AU1 treatment of mice with EAE (50 mg/kg, i.p., daily, 13 days) resulted in significantly reduced disease severity in this experimental model of multiple sclerosis. Levels of IL-13, TNF, interferon (IFN)-γ, IL-17, and GM-CSF were also significantly decreased, whereas transforming growth factor (TGF)-ß was increased in LN cells from CSP-AU1-treated EAE mice. CONCLUSIONS: Polysaccharide CSP-AU1 is a potent natural innate immunomodulator with a broad spectrum of agonist activity in vitro and immunosupressive properties after chronic administration in vivo.


Asunto(s)
Clerodendrum/química , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Polisacáridos/administración & dosificación , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Citocinas/genética , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Humanos , Factores Inmunológicos/aislamiento & purificación , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Polisacáridos/aislamiento & purificación , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología
15.
Int Immunopharmacol ; 15(3): 628-37, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23380150

RESUMEN

Extracts of leaves of different species of the genus Combretum have been used historically to treat a variety of medicinal problems. However, little is known about the active components conferring therapeutic properties to these extracts. In the present studies, we evaluated biochemical properties and immunomodulatory activity of polysaccharides isolated from the leaves of Combretum racemosum. Water-soluble polysaccharides from leaves of C. racemosum were extracted and fractionated by DEAE-cellulose and Diaion HP-20 to obtain a Diaion-bound fraction, designated Combretum polysaccharide-acidic bound or CP-AB, which was eluted with methanol, and an unbound fraction, designated as CP-AU. Molecular weight determination, sugar analysis, and other physical and chemical characterization of the fractions were performed. Fraction CP-AU (mol. weight 5.0 kDa) contained type II arabinogalactan and had potent immunomodulatory activity, inducing the production of interleukin (IL)-1ß, -6, -10, and tumor necrosis factor-α (TNF-α) by human peripheral blood mononuclear cells (PBMC) and MonoMac-6 monocytic cells. Likewise, intraperitoneal administration of CP-AU increased in vivo serum levels of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in mice. CP-AU-induced secretion of TNF-α in PBMC was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS. Treatment with CP-AU induced phosphorylation of Akt2, Akt3, GSK-3ß, HSP27, mTOR, and all p38 MAPK isoforms (α, ß, δ, and γ), as well as stimulation of AP-1/NF-κB transcriptional activity. In addition, CP-AU effectively agglutinated erythrocytes from several species, including human, mouse, and rabbit. In contrast, fraction CP-AB was inactive in all biological tests, including cytokine production and hemagglutination. These data suggest that at least part of the beneficial therapeutic effects reported for the water extracts of leaves from C. racemosum are due to modulation of leukocyte functions.


Asunto(s)
Combretum/química , Galactanos/administración & dosificación , Leucocitos Mononucleares/efectos de los fármacos , Monocitos/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Polisacáridos/administración & dosificación , Aglutinación/efectos de los fármacos , Animales , Línea Celular , Citocinas/metabolismo , Eritrocitos/efectos de los fármacos , Galactanos/química , Galactanos/aislamiento & purificación , Humanos , Leucocitos Mononucleares/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/inmunología , Extractos Vegetales/química , Hojas de la Planta/química , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/antagonistas & inhibidores
16.
J Ethnopharmacol ; 146(1): 232-42, 2013 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-23291534

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of leaves from different species of the genus Alchornea have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. OBJECTIVE: The aim of this study was to evaluate the immunomodulatory activity of polysaccharides isolated from the leaves of Alchornea cordifolia. MATERIALS AND METHODS: Water-soluble polysaccharides from leaves of Alchornea cordifolia were extracted and fractionated by DEAE-cellulose, Diaion HP-20, and size-exclusion chromatography. Molecular weight, sugar analysis, and other physical and chemical characterization of the fractions were performed. Immunomodulatory activity of the polysaccharide fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO) and cytokine production. Activation of mitogen activated protein kinases (MAPK) was also assessed using a phospho-MAPK array. Activation of nuclear factor κB (NF-κB) was measured using an alkaline phosphatase reporter gene assay in THP1-Blue monocytic cells. RESULTS: Six polysaccharide fractions from Alchornea cordifolia were isolated. Fractions containing type II arabinogalactan had potent immunomodulatory activity. Particularly, the parent fraction AP-AU and its high-molecular weight sub-fraction AP-AU1 (average M(r) was estimated to be 39.5kDa) induced production of NO and cytokines [interleukin (IL)-1ß, -6, -10, tumor necrosis factor (TNF)-α, and granulocyte-macrophage-colony stimulating factor (GM-CSF)] in human peripheral blood mononuclear cells and human and murine monocyte/macrophages cell lines in vitro. Furthermore, treatment with AP-AU1 induced phosphorylation of Akt2, p38δ/p38γ, p70S6K1, RSK2, and mTOR, as well as stimulation of NF-κB transcriptional activity. CONCLUSION: Our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of water extracts from Alchornea cordifolia leaves in traditional folk medicine of Africa.


Asunto(s)
Euphorbiaceae , Factores Inmunológicos/farmacología , Extractos Vegetales/farmacología , Polisacáridos/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Factores Inmunológicos/aislamiento & purificación , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Medicinas Tradicionales Africanas , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Extractos Vegetales/química , Hojas de la Planta , Polisacáridos/aislamiento & purificación , Proteínas Proto-Oncogénicas c-akt/metabolismo
17.
J Immunol ; 183(10): 6754-66, 2009 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-19846877

RESUMEN

Epilobium angustifolium has been traditionally used to treat of a number of diseases; however, not much is known regarding its effect on innate immune cells. In this study, we report that extracts of E. angustifolium activated functional responses in neutrophils and monocyte/macrophages. Activity-guided fractionation, followed by mass spectroscopy and NMR analysis, resulted in the identification of oenothein B as the primary component responsible for phagocyte activation. Oenothein B, a dimeric hydrolysable tannin, dose-dependently induced a number of phagocyte functions in vitro, including intracellular Ca(2+) flux, production of reactive oxygen species, chemotaxis, NF-kappaB activation, and proinflammatory cytokine production. Furthermore, oenothein B was active in vivo, inducing keratinocyte chemoattractant production and neutrophil recruitment to the peritoneum after intraperitoneal administration. Biological activity required the full oenothein B structure, as substructures of oenothein B (pyrocatechol, gallic acid, pyrogallol, 3,4-dihydroxybenzoic acid) were all inactive. The ability of oenothein B to modulate phagocyte functions in vitro and in vivo suggests that this compound is responsible for at least part of the therapeutic properties of E. angustifolium extracts.


Asunto(s)
Taninos Hidrolizables/farmacología , Factores Inmunológicos/farmacología , Activación de Macrófagos , Macrófagos/efectos de los fármacos , FN-kappa B/inmunología , Animales , Calcio/agonistas , Calcio/inmunología , Calcio/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Quimiotaxis/efectos de los fármacos , Quimiotaxis/inmunología , Citocinas/efectos de los fármacos , Citocinas/inmunología , Citocinas/metabolismo , Epilobium/química , Femenino , Humanos , Taninos Hidrolizables/aislamiento & purificación , Factores Inmunológicos/aislamiento & purificación , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/agonistas , FN-kappa B/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo
18.
Int Immunopharmacol ; 9(11): 1313-22, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19671448

RESUMEN

Yamoa (ground bark of Funtumia elastica tree) is marketed and sold as a dietary supplement with anecdotal therapeutic effects in the treatment of asthma and hay fever. We determined that Yamoa and Yamoa-derived polysaccharides affected innate immunity, in part, by priming gammadelta T cells. Gene expression patterns in purified bovine gammadelta T cells and monocytes induced by Yamoa were similar to those induced by ultrapure lipopolysaccharide (uLPS). In the presence of accessory cells, Yamoa had priming effects that were similar to those of LPS on bovine and murine gammadelta T cells, but much more potent than LPS on human gammadelta T cells. The bioactive component of Yamoa was delineated to a complex polysaccharide fraction (Yam-I). Intraperitoneal injection of Yamoa and Yam-I in mice induced rapid increases in peritoneal neutrophils directed by changes in chemokine expression. In support of a unique agonist found in Yam-I, similar peritonitis responses were also observed in TLR4- and MyD88-deficient mice. Therapeutic treatment with Yam-I resulted in decreased bacterial counts in feces from mice with Salmonella enterica serotype typhimurium (ST)-induced enterocolitis. This characterization of the immune stimulatory properties of polysaccharides derived from Yamoa suggests mechanisms for the anecdotal positive effects of its ingestion and that these polysaccharides show potential for application in innate protection from disease.


Asunto(s)
Inmunidad Innata/efectos de los fármacos , Extractos Vegetales/inmunología , Polisacáridos/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Animales , Bovinos , Enterocolitis/tratamiento farmacológico , Enterocolitis/inmunología , Perfilación de la Expresión Génica , Humanos , Lipopolisacáridos/química , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos BALB C , Factor 88 de Diferenciación Mieloide/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Polisacáridos/química , Polisacáridos/uso terapéutico , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/prevención & control , Salmonella typhimurium , Subgrupos de Linfocitos T/metabolismo , Receptor Toll-Like 4/metabolismo
19.
Phytother Res ; 23(3): 373-84, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19107845

RESUMEN

Shilajit has been used traditionally in folk medicine for the treatment of a variety of disorders, including syndromes involving excessive complement activation. Extracts of Shilajit contain significant amounts of fulvic acid (FA), and it has been suggested that FA is responsible for many therapeutic properties of Shilajit. However, little is known regarding the physical and chemical properties of Shilajit extracts, and nothing is known about their effects on the complement system. To address this issue, extracts of commercial Shilajit were fractionated using anion exchange and size-exclusion chromatography. One neutral (S-I) and two acidic (S-II and S-III) fractions were isolated, characterized and compared with standardized FA samples. The most abundant fraction (S-II) was further fractionated into three sub-fractions (S-II-1 to S-II-3). The van Krevelen diagram showed that the Shilajit fractions are the products of polysaccharide degradation, and all fractions, except S-II-3, contained type II arabinogalactan. All Shilajit fractions exhibited dose-dependent complement-fixing activity in vitro with high potency. Furthermore, a strong correlation was found between the complement-fixing activity and carboxylic group content in the Shilajit fractions and other FA sources. These data provide a molecular basis to explain at least part of the beneficial therapeutic properties of Shilajit and other humic extracts.


Asunto(s)
Benzopiranos/química , Pruebas de Fijación del Complemento , Sustancias Húmicas , Extractos Vegetales/química , Animales , Benzopiranos/aislamiento & purificación , Cromatografía en Gel , Eritrocitos/efectos de los fármacos , Galactanos/metabolismo , Modelos Lineales , Medicina Tradicional , Extractos Vegetales/aislamiento & purificación , Ovinos
20.
Phytochemistry ; 69(6): 1359-71, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18325553

RESUMEN

The leaves of Artemisia species have been traditionally used for prevention and treatment of a number of diseases. In this study, five polysaccharide fractions (designated A-I-A-V) were isolated from the leaves of Artemisia tripartita Rydb. by the sequential use of hot-water extraction, ethanol precipitation, ultra-filtration, and chromatography. The homogeneity and average molecular weight of each fraction were determined by high performance size-exclusion chromatography. Sugar composition analysis revealed that Artemisia polysaccharides consisted primarily of xylose, glucose, arabinose, galactose, and galactosamine. Moreover, all fractions contained at least 3.4% sulfate, and fractions A-II-A-V contained an arabinogalactan type II structure. All fractions exhibited macrophage-activating activity, enhancing production of intracellular reactive oxygen species and release of nitric oxide, interleukin 6, interleukin 10, tumor necrosis factor alpha, and monocyte chemotactic protein 1. In addition, all fractions exhibited scavenging activity for reactive oxygen species generated enzymatically or produced extracellularly by human neutrophils. Finally, fractions A-I and A-V exhibited complement-fixing activity. Taken together, our results provide a molecular basis to explain at least part of the beneficial therapeutic effects of Artemisia extracts, and suggest the possibility of using Artemisia polysaccharides as an immunotherapeutic adjuvant.


Asunto(s)
Artemisia/química , Polisacáridos/química , Polisacáridos/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo
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