RESUMEN
To evaluate the efficacy of yellow light-emitting diode (LED) irradiation at 590 nm, alone or in combination with anti-inflammatory active substances against ultraviolet (UV)-induced inflammation in keratinocytes. HaCaT keratinocytes were pretreated with LED yellow light (590 nm) alone or in combination with an antiinflammatory active substance such as glycerophosphoinositol choline (GC), extract of grains of paradise (Aframomum melegueta Schum, AM), or a bisabolol and ginger root extract mixture (Bb-GE) before UVB irradiation. Following each treatment, we measured the levels of inflammatory mediators secreted by keratinocytes. HaCaT keratinocytes treated with UVB (300 mJ cm-²) and then cultured for 24 h exhibited significantly upregulated expression of proinflammatory factors, including interleukin (IL)-1α, prostaglandin E2 (PGE2), and IL-8. After pretreatment with 590 nm LED, UVB-induced inflammatory responses were significantly inhibited. Co-pretreatment with 590 nm LED irradiation and GC further inhibited the expression of IL-1α and IL-8. IL-8 expression was inhibited by co-pretreatment with 590 nm LED irradiation and AM, whereas PGE2 expression was inhibited by co-pretreatment with 590 nm LED irradiation and Bb-GE. Co-treatment with 590 nm LED irradiation and various active substances modulated UVB-induced inflammation in keratinocytes, suggesting the potential application of this approach to prevent damage caused by voluntary sun exposure in daily life.
Asunto(s)
Inflamación , Interleucina-8 , Queratinocitos , Rayos Ultravioleta , Humanos , Queratinocitos/efectos de la radiación , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Rayos Ultravioleta/efectos adversos , Interleucina-8/metabolismo , Dinoprostona/metabolismo , Interleucina-1alfa/metabolismo , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , Láseres de Semiconductores/uso terapéutico , Antiinflamatorios/farmacología , Sesquiterpenos Monocíclicos/farmacología , Células HaCaTRESUMEN
Collagen and hyaluronic acid are essential components of the dermis that collaborate to maintain skin elasticity and hydration due to their unique biochemical properties and interactions within the extracellular matrix. Prolonged exposure to glucocorticoids can induce skin aging, which manifests as diminished collagen content and hyaluronic acid levels in the dermis. Nerol, a monoterpene alcohol found in essential oils, was examined in this study for its potential to counteract glucocorticoid-induced skin aging and the underlying mechanism behind its effects. Our findings reveal that non-toxic concentrations of nerol treatment can reinstate collagen content and hyaluronic acid levels in human dermal fibroblasts treated with dexamethasone. Mechanistically, nerol mitigates dexamethasone-induced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effects of nerol were significantly abrogated when the Nrf2 pathway was inhibited using the specific inhibitor ML385. In conclusion, nerol protects human dermal fibroblasts against glucocorticoid-induced skin aging by ameliorating oxidative stress via activation of the Nrf2 pathway, thereby highlighting its potential as a therapeutic agent for preventing and treating glucocorticoid-induced skin aging.
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Dexametasona , Fibroblastos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Transducción de Señal , Envejecimiento de la Piel , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Envejecimiento de la Piel/efectos de los fármacos , Dexametasona/farmacología , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Glucocorticoides/farmacología , Piel/efectos de los fármacos , Piel/metabolismo , Células Cultivadas , Sesquiterpenos/farmacología , Colágeno/metabolismoRESUMEN
Bemisia tabaci poses a severe threat to plants, and the control of B. tabaci mainly relies on pesticides, which causes more and more rapidly increasing resistance. ß-Caryophyllene is a promising ingredient for agricultural pest control, but its feature of poor water solubility need to be improved in practical applications. Nanotechnology can enhance the effectiveness and dispersion of volatile organic compounds (VOCs). In this study, a nanoliposome carrier was constructed by ethanol injection and ultrasonic dispersion method, and ß-caryophyllene was wrapped inside it, thus solving the defect of poor solubility of ß-caryophyllene. The size of the ß-caryophyllene nanoliposomes (C-BT-NPs) was around 200 nm, with the absolute value of the zeta potential exceeding 30 mV and a PDI below 0.5. The stability was also maintained over a 14-d storage period. C-BT-NPs showed effective insecticidal activity against B. tabaci, with an LC50 of 1.51 g/L, outperforming thiamethoxam and offering efficient agricultural pest control. Furthermore, C-BT-NPs had minimal short-term impact on the growth of tomato plants, indicating that they are safety on plants. Therefore, the VOCs using nanoliposome preparation technology show promise in reducing reliance on conventional pesticides and present new approaches to managing agricultural pests.
Asunto(s)
Hemípteros , Insecticidas , Liposomas , Sesquiterpenos Policíclicos , Animales , Hemípteros/efectos de los fármacos , Sesquiterpenos Policíclicos/farmacología , Sesquiterpenos Policíclicos/química , Insecticidas/farmacología , Insecticidas/química , Nanopartículas/química , Sesquiterpenos/farmacología , Sesquiterpenos/química , Solanum lycopersicum/parasitología , Compuestos Orgánicos Volátiles/química , Compuestos Orgánicos Volátiles/farmacologíaRESUMEN
MAIN CONCLUSION: New findings are presented for Chaerophyllum coloratum L. on the volatile composition of the essential oil, based on data of hydrosol and fresh plant material, light and electron microscopy of leaves, and cytotoxic and antiviral activity. The widespread Apiaceae family includes many well-known and economically important plants that are cultivated as food or spices. Many produce essential oils and are generally a source of secondary metabolites and compounds that have numerous applications in daily life. In this study, the chemical composition of volatile organic compounds (VOCs), ultrastructure and biological activity of the Mediterranean endemic species Cheaerophyllum coloratum L. are investigated, as literature data for this plant species are generally very scarce. The essential oil and hydrosol were extracted from the air-dried leaves by hydrodistillation and the chemical composition of both extracts was analysed by GC-MS in conjunction with headspace solid-phase microextraction (HS-SPME) of VOCs from the hydrosol and the fresh plant material. In the composition of the essential oil, the oxygenated sesquiterpenes spathulenol and caryophyllene oxide were the most abundant components. In the fresh plant material, non-oxygenated sesquiterpenes dominated, with ß-caryophyllene and germacrene D being the main components. The hydrosol was dominated by monoterpenes, with the oxygenated monoterpene p-cymen-8-ol being the most abundant. Light and electron micrographs of the leaf of C. coloratum show secretory structures, and we hypothesize that glandular leaf trichomes, secretory epidermal cells and secretory canals are involved in the production of volatiles and their secretion on the leaf surface. Since the biological potential of C. coloratum is poorly investigated, we tested its cytotoxic activity on cancer and healthy cell lines and its antiviral activity on plants infected with tobacco mosiac virus (TMV). Our results dealing with the composition, ultrastructure and biological activity show that C. coloratum represent a hidden valuable plant species with a potential for future research.
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Aceites Volátiles , Hojas de la Planta , Compuestos Orgánicos Volátiles , Hojas de la Planta/química , Hojas de la Planta/ultraestructura , Compuestos Orgánicos Volátiles/farmacología , Compuestos Orgánicos Volátiles/metabolismo , Compuestos Orgánicos Volátiles/química , Aceites Volátiles/farmacología , Aceites Volátiles/química , Cromatografía de Gases y Espectrometría de Masas , Humanos , Antivirales/farmacología , Microextracción en Fase Sólida , Sesquiterpenos/farmacología , Sesquiterpenos/metabolismoRESUMEN
Prion diseases, known as a group of fatal neurodegenerative disorders caused by prions, remain incurable despite extensive research efforts. In a recent study, crude extract from Curcuma phaeocaulis Valeton (Cp) showed promising anti-prion efficacy in in vitro and in vivo models, prompting further investigation into their active compounds. We endeavored to identify the chemical constituents of the Cp extract and discover potential anti-prion agents. With the use of centrifugal partition chromatography (CPC), major constituents were isolated from the n-hexane (HX) fraction of the extract in a single step. Spectroscopic analysis confirmed the presence of curcumenone, curcumenol, and furanodienone. Subsequent efficacy testing in a cell culture model of prion disease identified curcumenol and furanodienone as active compounds. This study underscores the potential of natural products in the search for effective treatments against prion diseases.
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Curcuma , Extractos Vegetales , Curcuma/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Priones/antagonistas & inhibidores , Enfermedades por Prión/tratamiento farmacológico , Ratones , Humanos , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificaciónRESUMEN
Hepatocellular carcinoma (HCC) is caused by various factors including toxic substances and xenobiotics. Numerous treatment strategies are used to address toxicity to the liver and HCC, yet their adverse effects are drawbacks. This study aimed to assess the effect of DEN/CCl4 on morphological changes in the liver, body weight, tumor incidence, and hematological tumor incidence, hematological parameters, hepatic markers, and histopathological analysis in mice following a preventive measure by using ß-caryophyllene (BCP). Adult Balb/c mice were administered a single dose of DEN 1-mg/kg body weight and 0.2-mL CCl4/kg body weight intraperitoneal twice a week (i.p.) for 22 weeks. BCP was treated in one group of mice at 30-mg/kg body weight, intraperitoneal, for 7 weeks. BCP alone was treated in one group of mice at 300-mg/kg body weight intraperitoneal for 22 weeks. DEN/CCl4 caused a reduction in mice's body weight, which was significantly attenuated by BCP administration. BCP supplementation attenuated the tumor incidence DEN/CCl4 (100%) to about 25%. DEN/CCl4 caused alterations in the hematological parameters, serum total protein albumin globulin, A/G ratio, liver function markers (AST, ALT, ALP, GGT, ACP, and bilirubin), and lipid profile markers that were significantly reinstated by BCP administration. Oxidative stress markers (MDA, SOD, CAT, NO, LDH, and GST) were reduced by DEN/CCl4, which were significantly increased in BCP-treated groups. The liver histopathology alterations caused by DEN/CCl4 were amended considerably by BCP treatment. Immunohistochemical studies suggest that AFP, caspase-3, and COX-2 were chronically overexpressed in DEN/CCl4-exposed mice, notably attenuated by BCP administration. BCP suppressed tumor incidence by downregulating inflammation and inducing caspase-3-mediated apoptosis. Conclusively, BCP appears to be a potent natural supplement capable of repressing liver inflammation and carcinoma through the mitigation of oxidative stress and inflammation pathways.
Asunto(s)
Carcinoma Hepatocelular , Inflamación , Ratones Endogámicos BALB C , Estrés Oxidativo , Sesquiterpenos Policíclicos , Animales , Sesquiterpenos Policíclicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratones , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/inducido químicamente , Masculino , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/prevención & control , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéutico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/tratamiento farmacológico , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Tetracloruro de Carbono/toxicidadRESUMEN
Renal fibrosis (RF) represents the most widespread pathological condition in chronic kidney disease (CKD). Recently, protein prenylation has been implicated in the fibrosis's progression. The research examined the renoprotective effect of zoledronic acid (ZA) (50 µg/kg/week) in a rat model of carbon tetrachloride (CCl4)-induced RF through targeting protein prenylation. Forty Wistar male rats were split up into the control group, vehicle-treated group, model-RF group, and RF-ZA group. Mean arterial blood pressure (MBP), BUN, serum creatinine, and urine albumin-creatinine ratio (uACR), protein levels of farnesyl pyrophosphate (FPP), tumour necrosis factor-alpha (TNF-α), transforming growth factor-ß (TGF-ß), and malondialdehyde (MDA), and catalase and gene expression of farnesyl pyrophosphate synthase (FPPS) and nuclear factor-kB (NF-κB) were measured. Immunohistochemical staining for renal interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and caspase-3, as well as histopathological alterations, were assessed. ZA considerably ceased the reduction in MBP, markedly reduced uACR, serum creatinine, BUN, and expression of FPPS, FPP, NF-κB, TGF-ß, TNF-α, and MDA, and significantly increased catalase levels compared to the model-RF rats. ZA ameliorated the CCl4-induced histopathological alterations and suppressed the expression of caspase-3, α-SMA, and IL-6. In conclusion, ZA preserved renal function and prevented renal fibrosis in a rat model. These were achieved through targeting protein prenylation mainly by inhibiting FPPS.
Asunto(s)
Fibrosis , Geraniltranstransferasa , Riñón , Prenilación de Proteína , Ratas Wistar , Ácido Zoledrónico , Animales , Ácido Zoledrónico/farmacología , Masculino , Ratas , Prenilación de Proteína/efectos de los fármacos , Geraniltranstransferasa/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Tetracloruro de Carbono , Fosfatos de Poliisoprenilo/metabolismo , Fosfatos de Poliisoprenilo/farmacología , Modelos Animales de Enfermedad , Factor de Crecimiento Transformador beta/metabolismo , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Cartilage metabolism dysregulation is a crucial driver in knee osteoarthritis (KOA). Modulating the homeostasis can mitigate the cartilage degeneration in KOA. Curcumenol, derived from traditional Chinese medicine Curcuma Longa L., has demonstrated potential in enhancing chondrocyte proliferation and reducing apoptosis. However, the specific mechanism of Curcumenol in treating KOA remains unclear. This study aimed to demonstrate the molecular mechanism of Curcumenol in treating KOA based on the transcriptomics and metabolomics, and both in vivo and in vitro experimental validations. MATERIALS AND METHODS: In this study, a destabilization medial meniscus (DMM)-induced KOA mouse model was established. And the mice were intraperitoneally injected with Curcumenol at 4 and 8 mg/kg concentrations. The effects of Curcumenol on KOA cartilage and subchondral was evaluated using micro-CT, histopathology, and immunohistochemistry (IHC). In vitro, OA chondrocytes were induced with 10 µg/mL lipopolysaccharide (LPS) and treated with Curcumenol to evaluate the proliferation, apoptosis, and extracellular matrix (ECM) metabolism through CCK8 assay, flow cytometry, and chondrocyte staining. Furthermore, transcriptomics and metabolomics were utilized to identify differentially expressed genes (DEGs) and metabolites. Finally, integrating multi-omics analysis, virtual molecular docking (VMD), and molecular dynamics simulation (MDS), IHC, immunofluorescence (IF), PCR, and Western blot (WB) validation were conducted to elucidate the mechanism by which Curcumenol ameliorates KOA cartilage degeneration. RESULTS: Curcumenol ameliorated cartilage destruction and subchondral bone loss in KOA mice, promoted cartilage repair, upregulated the expression of COL2 while downregulated MMP3, and improved ECM synthesis metabolism. Additionally, Curcumenol also alleviated the damage of LPS on the proliferation activity and suppressed apoptosis, promoted ECM synthesis. Transcriptomic analysis combined with weighted gene co-expression network analysis (WGCNA) identified a significant downregulation of 19 key genes in KOA. Metabolomic profiling showed that Curcumenol downregulates the expression of d-Alanyl-d-alanine, 17a-Estradiol, Glutathione, and Succinic acid, while upregulating Sterculic acid and Azelaic acid. The integrated multi-omics analysis suggested that Curcumenol targeted KDM6B to regulate downstream protein H3K27me3 expression, which inhibited methylation at the histone H3K27, consequently reducing Succinic acid levels and improving KOA cartilage metabolism homeostasis. Finally, both in vivo and in vitro findings indicated that Curcumenol upregulated KDM6B, suppressed H3K27me3 expression, and stimulated collagen II expression and ECM synthesis, thus maintaining cartilage metabolism homeostasis and alleviating KOA cartilage degeneration. CONCLUSION: Curcumenol promotes cartilage repair and ameliorates cartilage degeneration in KOA by upregulating KDM6B expression, thereby reducing H3K27 methylation and downregulating Succinic Acid, restoring metabolic stability and ECM synthesis.
Asunto(s)
Condrocitos , Curcuma , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Osteoartritis de la Rodilla , Ácido Succínico , Animales , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Ratones , Masculino , Curcuma/química , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoartritis de la Rodilla/metabolismo , Ácido Succínico/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sesquiterpenos/farmacología , Simulación del Acoplamiento Molecular , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , HumanosRESUMEN
Basidiomycetes with a wide variety of skeletons of secondary metabolites can be expected to be the source of new interesting biological compounds. During our research on basidiomycetes, two new C-29 oxygenated oleanane-type triterpenes (1 and 2) and torulosacid (3), a muurolene type sesquiterpenoid with a five-membered ether ring along with nine known compounds (4-12), were isolated from the MeOH extract of the fruiting bodies of Fuscoporia torulosa. The structures of 1-3 were determined by NMR and HREIMS analysis. Further studies on the stereochemistry of 3 were conducted using X-ray crystallographic analysis and comparison of experimental and calculated ECD spectra. In the antimicrobial assay of isolates, 1, 7, and 9 showed growth inhibitory activity against methicillin-resistant Staphylococcus aureus and other gram-positive strains. Isolation of oleanane type triterpenes from fungi including basidiomycetes, is a unique report that could lead to further isolation of new compounds and the discovery of unique biosynthetic enzymes.
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Cuerpos Fructíferos de los Hongos , Pruebas de Sensibilidad Microbiana , Sesquiterpenos , Cuerpos Fructíferos de los Hongos/química , Sesquiterpenos/química , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Estructura Molecular , Basidiomycota/química , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Cristalografía por Rayos X , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacosRESUMEN
Ginger is an important cooking spice and herb worldwide, and scientific research has gradually confirmed the effect of ginger on preventing hair loss. Cedrol (CE) is a small sesquiterpene molecule in ginger and its external administration (EA) has shown hope in promoting hair growth, and alternative administration mode has become a potential treatment scheme to improve the efficacy of CE. The purpose of this study is to evaluate the effects of oral administration (OA) and EA of CE on hair regeneration of C57BL/6 alopecia areata (AA) mice induced by cyclophosphamide (CP) and to clarify the potential hair growth mechanism of CE in AA model in vitro and in vivo. The results showed that CE-OA has a shorter hair-turning black time and faster hair growth rate, and can lessen hair follicle damage induced by CP and promote hair follicle cell proliferation. Its effect is superior to CE-EA. At the same time, CE can increase the cytokines IFN-γ, IL-2, and IL-7 in the serum of mice, and decrease the expression of adhesion factors ICAM-1 and ELAM-1, thus alleviating the immunosuppression induced by CP. Mechanism research shows that CE regulates the JAK3/STAT3 signaling pathway, activates the Wnt3α/ß-catenin germinal center, and ameliorates oxidative stress induced by CP, thus promoting the proliferation of hair follicle cells and reversing AA. These results provide a theoretical basis for understanding the anti-AA mechanism of CE-OA, indicating that CE can be used as raw material for developing oral hair growth drugs.
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Ratones Endogámicos C57BL , Sesquiterpenos , Zingiber officinale , Animales , Zingiber officinale/química , Administración Oral , Ratones , Sesquiterpenos/farmacología , Sesquiterpenos/química , Cabello/efectos de los fármacos , Cabello/química , Proliferación Celular/efectos de los fármacos , Regeneración/efectos de los fármacos , Folículo Piloso/efectos de los fármacos , Folículo Piloso/metabolismo , Estructura Molecular , Masculino , Relación Dosis-Respuesta a Droga , Alopecia Areata/tratamiento farmacológico , Relación Estructura-Actividad , Ciclofosfamida/farmacología , Sesquiterpenos PolicíclicosRESUMEN
Twenty-nine sesquiterpenoids, including pseudoguaiane-type (1-11), eudesmane-type (12-23), and carabrane-type (24-29), have been identified from the plant Carpesium abrotanoides. Of them, compounds 1-4, 12-15, and 24-27, namely carpabrotins A-L, are twelve previously undescribed ones. Compound 3 possessed a pseudoguaiane backbone with a rearrangement modification at C-11, C-12 and C-13, while compound 4 suffered a carbon bond break between the C-4 and C-5 to form a rare 4,5-seco-pseudoguaiane lactone. Compounds 1-3, 5, 13-16 and 25-27 exhibited anti-inflammatory activity by inhibiting NO production in LPS-induced RAW264.7 macrophages with IC50 values less than 40 µM, while compounds 1, 2, 5, 13, 14, 16, and 25-27 showed significant inhibitory activity comparable to that of dexamethasone. The anti-atopic dermatitis (AD) effects of compounds 5 and 16 were tested according to 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in KM mice, and the results revealed that the major products 5 and 16 improved the histological features of AD-like skin lesions and mast cell infiltration in mice. This study suggested that sesquiterpenoids in C. abrotanoides should play a key role in its anti-inflammatory use.
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Asteraceae , Óxido Nítrico , Sesquiterpenos , Animales , Ratones , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Asteraceae/química , Células RAW 264.7 , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Macrófagos/efectos de los fármacos , MasculinoRESUMEN
Sepsis, characterized by high mortality rates, causes over 50 % of acute lung injury (ALI) cases, primarily due to the heightened susceptibility of the lungs during this condition. Suppression of the excessive inflammatory response is critical for improving the survival of patients with sepsis; nevertheless, no specific anti-sepsis drugs exist. Huperzine A (HupA) exhibits neuroprotective and anti-inflammatory properties; however, its underlying mechanisms and effects on sepsis-induced ALI have yet to be elucidated. In this study, we demonstrated the potential of HupA for treating sepsis and explored its mechanism of action. To investigate the in vivo impacts of HupA, a murine model of sepsis was induced through cecal ligation and puncture (CLP) in both wild-type (WT) and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. Our results showed that HupA ameliorates sepsis-induced acute lung injury by activating the α7nAChR. We used the CLP sepsis model in wild-type and α7nAChR -/- mice and found that HupA significantly increased the survival rate through α7nAChR, reduced the pro-inflammatory cytokine levels and oxidative stress, ameliorated histopathological lung injury, altered the circulating immune cell composition, regulated gut microbiota, and promoted short-chain fatty acid production through α7nAChR in vivo. Additionally, HupA inhibited Toll-like receptor NF-κB signaling by upregulating the α7nAChR/protein kinase B/glycogen synthase kinase-3 pathways. Our data elucidate HupA's mechanism of action and support a "new use for an old drug" in treating sepsis. Our findings serve as a basis for further in vivo studies of this drug, followed by application to humans. Therefore, the findings have the potential to benefit patients with sepsis.
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Lesión Pulmonar Aguda , Alcaloides , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Sepsis , Sesquiterpenos , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/patología , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/inmunología , Estrés Oxidativo/efectos de los fármacos , Alcaloides/uso terapéutico , Alcaloides/farmacología , Ratones , Masculino , Sesquiterpenos/uso terapéutico , Sesquiterpenos/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/tratamiento farmacológicoRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disorder primarily targeting peripheral joints. The global prevalence of RA is increasing, posing a significant challenge in patient care management. Despite therapeutic advancements, their inherent limitations highlight the need for further research on safer treatment interventions. Among potential candidates, sesquiterpenes, a subclass of plant secondary metabolites composed of three isoprene units, have exhibited remarkable efficacy in treating various inflammatory disorders, including RA. In this systematic review, we summarized the treatment evidence of sesquiterpenes and their derivatives on RA. Specific major sesquiterpenoids have been discussed in detail, as well as the possible mechanisms by which cells and chemical messengers are involved in treating RA. Our review indicated that sesquiterpenes are potential novel, bioactive compounds for RA prevention and treatment strategies.
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Artritis Reumatoide , Sesquiterpenos , Artritis Reumatoide/tratamiento farmacológico , Humanos , Sesquiterpenos/uso terapéutico , Sesquiterpenos/farmacología , Animales , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Antirreumáticos/uso terapéuticoRESUMEN
Management of inflammatory bowel disease (IBD) poses significant challenges, and there is a need for innovative therapeutic approaches. This study investigates the anti-inflammatory properties of the dietary sesquiterpene lactone (SL) 11ß,13-dihydrolactucin, which can be found in chicory, in three distinct complementary models of intestinal inflammation (two cell models and a zebrafish model), offering comprehensive insights into its potential application for IBD treatment alternatives. In a triple cell co-culture composed of Caco-2, HT29-MTX-E12, and Raji B, 11ß,13-dihydrolactucin demonstrated remarkable anti-inflammatory activity at several levels of the cellular inflammatory response. Notably, 11ß,13-dihydrolactucin prevented the activation of critical signalling pathways associated with inflammation, namely NF-κB and MAPK p38. This SL also decreased the release of the neutrophil-recruiting chemokine IL-8. Additionally, the compound reduced the gene expression of IL-6 and TNF-α, as well as the gene and protein expression of the inflammatory inducible enzymes iNOS and COX-2. In a myofibroblast-like human cell model, 11ß,13-dihydrolactucin decreased the release of the cytokine TNF-α and the COX-2-derived inflammation mediator PGE2. Finally, in a zebrafish model of gut inflammation, 11ß,13-dihydrolactucin effectively reduced neutrophil infiltration, further supporting its anti-inflammatory efficacy in a physiological context. Collectively, our findings highlight the promising anti-inflammatory potential of 11ß,13-dihydrolactucin across various facets of intestinal inflammation, providing a foundation for the consideration of chicory as a promising candidate for incorporation in food or nutraceutical products for the potential prevention of IBD.
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Antiinflamatorios , Enfermedades Inflamatorias del Intestino , Sesquiterpenos , Pez Cebra , Animales , Humanos , Antiinflamatorios/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Sesquiterpenos/farmacología , Células CACO-2 , FN-kappa B/metabolismo , FN-kappa B/genética , Lactonas/farmacología , Cichorium intybus/química , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Células HT29 , Modelos Animales de Enfermedad , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Metisa plana is a widespread insect pest infesting oil palm plantations in Malaysia. Farnesyl acetate (FA), a juvenile hormone analogue, has been reported to exert in vitro and in vivo insecticidal activity against other insect pests. However, the insecticidal mechanism of FA on M. plana remains unclear. Therefore, this study aims to elucidate responsive genes in M. plana in response to FA treatment. The RNA-sequencing reads of FA-treated M. plana were de novo-assembled with existing raw reads from non-treated third instar larvae, and 55,807 transcripts were functionally annotated to multiple protein databases. Several insecticide detoxification-related genes were differentially regulated among the 321 differentially expressed transcripts. Cytochrome P450 monooxygenase, carboxylesterase, and ATP-binding cassette protein were upregulated, while peptidoglycan recognition protein was downregulated. Innate immune response genes, such as glutathione S-transferases, acetylcholinesterase, and heat shock protein, were also identified in the transcriptome. The findings signify that changes occurred in the insect's receptor and signaling, metabolic detoxification of insecticides, and immune responses upon FA treatment on M. plana. This valuable information on FA toxicity may be used to formulate more effective biorational insecticides for better M. plana pest management strategies in oil palm plantations.
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Insecticidas , Animales , Insecticidas/farmacología , Perfilación de la Expresión Génica , Inactivación Metabólica , Transcriptoma/efectos de los fármacos , Sesquiterpenos/farmacología , Sesquiterpenos/metabolismo , Sesquiterpenos/química , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Larva/efectos de los fármacosRESUMEN
This study aimed to develop microemulsions (MEs) containing α-bisabolol for the topical treatment of cutaneous leishmaniasis (CL). Initially, pseudoternary phase diagrams were developed using α-bisabolol as the oil phase, Eumulgin® CO 40 as the surfactant, Polymol® HE as the co-surfactant, and distilled water as the aqueous phase. Two transparent liquid systems (TLS) containing 5% of α-bisabolol were selected and characterized (F5E25 and F5EP25). Next, skin permeation and retention assays were performed using Franz cells. The interaction of the formulation with the stratum corneum (SC) was evaluated using the FTIR technique. The cytotoxicity was evaluated in murine peritoneal macrophages. Finally, the antileishmanial activity of microemulsions was determined in promastigotes and amastigotes of L. amazonensis (strain MHOM/BR/77/LTB 0016). As a result, the selected formulations showed isotropy, nanometric size (below 25 nm), Newtonian behavior and pH ranging from 6.5 to 6.9. The MEs achieved a 2.5-fold increase in the flux and skin-permeated amount of α-bisabolol. ATR-FTIR results showed that microemulsions promoted fluidization and extraction of lipids and proteins of the stratum corneum, increasing the diffusion coefficient and partition coefficient of the drug in the skin. Additionally, F5E25 and F5EP25 showed higher activity against promastigotes (IC50 13.27 and 18.29, respectively) compared to unencapsulated α-bisabolol (IC50 53.8). Furthermore, F5E25 and F5EP25 also showed antileishmanial activity against intracellular amastigotes of L. amazonensis, with IC50 50 times lower than free α-bisabolol and high selectivity index (up to 15). Therefore, the systems obtained are favorable to topical administration, with significant antileishmanial activity against L. amazonensis promastigotes and amastigotes, being a promising system for future in vivo trials.
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Emulsiones , Macrófagos Peritoneales , Sesquiterpenos Monocíclicos , Sesquiterpenos , Piel , Animales , Sesquiterpenos Monocíclicos/farmacología , Sesquiterpenos Monocíclicos/química , Emulsiones/química , Ratones , Sesquiterpenos/farmacología , Sesquiterpenos/química , Piel/parasitología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/parasitología , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Espectroscopía Infrarroja por Transformada de Fourier , Absorción Cutánea/efectos de los fármacos , Ratones Endogámicos BALB C , Femenino , Leishmania/efectos de los fármacos , Tensoactivos/farmacología , Tensoactivos/química , Antiprotozoarios/farmacología , Antiprotozoarios/químicaRESUMEN
A multi-component paclitaxel (PTX) -loaded ß-elemene nanoemulsion by transferrin modification (Tf-PE-MEs) was developed to enhance non-small-cell lung cancer (NSCLC) treatment. After transferrin modification, the particle size of Tf-PE-MEs was (14.87 ± 1.84) nm, and the zeta potential was (-10.19 ± 0.870) mV, respectively. In vitro experiments showed that Tf-PE-MEs induced massive apoptosis in A549 cells, indicating that it had significant cytotoxicity to A549 cells. Through transferrin modification, Tf-PE-MEs accumulated at the tumor site efficiently with overexpressed transferrin receptor (TfR) on the surface of A549 cells. This will allow increasing PTX and ß-elemene concentration in the target cells, enhancing the therapeutic effect. Compared to PTX alone, Tf-PE-MEs displayed good anti-tumor efficacy and diminished systemic toxicity in vivo studies. With favourable therapeutic potential, this study provides a new strategy for the combined anticancer treatment of non-small cell lung cancer.
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Antineoplásicos Fitogénicos , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Emulsiones , Neoplasias Pulmonares , Nanopartículas , Paclitaxel , Sesquiterpenos , Transferrina , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Paclitaxel/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Transferrina/química , Transferrina/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Células A549 , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/administración & dosificación , Apoptosis/efectos de los fármacos , Nanopartículas/química , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Ratones Endogámicos BALB C , Ratones Desnudos , Receptores de Transferrina/metabolismo , Tamaño de la Partícula , Ratones , Línea Celular Tumoral , Masculino , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
BACKGROUND: Thyroid Cancer (TC) is an endocrine organ malignancy that has become more common in recent decades. Vernodalin (VN), a cytotoxic sesquiterpene, has been reported to exhibit anticancer properties against human breast and liver cancer cells. However, no study has explored the efficacy of VN with respect to its antiproliferative and apoptotic action on human Papillary Thyroid Cancer cells (PTC). OBJECTIVE: The study intended to examine the antitumor and antiproliferative effects of VN and the apoptosis mechanisms underlying its action on TPC-1 human PTC cells. METHODS: In this study, we examined the VN cell viability by MTT assay; performed ROS measurement by DCFH staining method, MMP identification by Rh-123 staining method, and apoptotic morphological assay by employing AO/EB and DAPI stain method, and further, p38 MAPK/ERK/JNK cell proliferation markers were determined by western blotting technique. RESULTS: The findings showed that VN could inhibit the growth of PTC cells by increasing intracellular ROS, damaging MMP, and stimulating apoptosis in a concentration-dependent manner. The study demonstrated how VN inhibited TPC-1 cell viability by causing ROS-induced cell death via the MAPK signaling pathway. CONCLUSION: VN may serve as an agonist to impact apoptosis in PTC cells. In human PTC, VN could play an effective role in chemotherapy. More studies pertaining to animal tumor models are needed to prove its anti-cancer effectiveness in vivo.
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Apoptosis , Proliferación Celular , Sistema de Señalización de MAP Quinasas , Especies Reactivas de Oxígeno , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Cáncer Papilar Tiroideo/tratamiento farmacológico , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Sesquiterpenos/farmacología , Sesquiterpenos/química , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Relación Dosis-Respuesta a DrogaRESUMEN
Ferroptosis is a form of regulated cell death triggered by iron-dependent lipid peroxidation and has been associated with heart diseases. However, there are currently no approved drugs that specifically inhibit ferroptosis in clinical practice, which largely limits the translational potential of this novel target. Here, we demonstrated that ß-caryophyllene (BCP; 150 µM), a natural dietary cannabinoid, protects cardiomyocytes against ferroptotic cell death induced by cysteine deprivation or glutathione peroxidase 4 (GPX4) inactivation. Moreover, BCP preserved the mitochondrial morphology and function during ferroptosis induction. Unexpectedly, BCP supported ferroptosis resistance independent of canonical antiferroptotic pathways. Our results further suggested that BCP may terminate radical chain reactions through interactions with molecular oxygen, which also explains why its oxidation derivative failed to suppress ferroptosis. Finally, oral BCP administration (50 mg/kg, daily) significantly alleviated doxorubicin (15 mg/kg, single i.p. injection)-induced cardiac ferroptosis and cardiomyopathy in mice. In conclusion, our data revealed the role of BCP as a natural antiferroptotic compound and suggest pharmacological modification based on BCP as a promising therapeutic strategy for treating ferroptosis-associated heart disorders.
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Ferroptosis , Ratones Endogámicos C57BL , Sesquiterpenos Policíclicos , Ferroptosis/efectos de los fármacos , Animales , Ratones , Sesquiterpenos Policíclicos/farmacología , Sesquiterpenos Policíclicos/química , Humanos , Masculino , Cardiotónicos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Sesquiterpenos/farmacología , Sesquiterpenos/metabolismo , Ratas , Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacosRESUMEN
Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is one of the most important neglected diseases in Latin America. The limited use of the current nitro-derivative-based chemotherapy highlights the need for alternative drugs and the identification of their molecular targets. In this study, we investigated the trypanocidal effect of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives, focusing on the antioxidative defense of the parasites. DhL and two derivatives, at lesser extent, displayed antiproliferative effect on the parasites. This effect was blocked by the reducing agent glutathione (GSH). Treated parasites exhibited increased intracellular ROS concentration and trypanothione synthetase activity, accompanied by mitochondrial swelling. Although molecular dynamics studies predicted that GSH would not interact with DhL, 1H-NMR analysis confirmed that GSH could protect parasites by interacting with the lactone. When parasites overexpressing mitochondrial tryparedoxin peroxidase were incubated with DhL, its effect was attenuated. Overexpression of cytosolic tryparedoxin peroxidase also provided some protection against DhL. These findings suggest that DhL induces oxidative imbalance in T. cruzi, offering new insights into potential drug targets against this parasite.