RESUMEN

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Asunto(s)

Cobre , Hidrogeles , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Activación de Linfocitos , Triterpenos Pentacíclicos , Especies Reactivas de Oxígeno , Linfocitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacología , Hidrogeles/química , Animales , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Activación de Linfocitos/efectos de los fármacos , Cobre/química , Microambiente Tumoral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/química , Femenino , Triterpenos/farmacología , Triterpenos/química

RESUMEN

Inflammation involving adipose macrophages is an important inducer of obesity. Regulating macrophages polarization and improving the inflammatory microenvironment of adipose tissue is a new strategy for the treatment of obesity. An amphiphilic chondroitin sulfate phenylborate derivative (CS-PBE) was obtained by modifying the main chain of chondroitin sulfate with the hydrophobic small molecule phenylborate. Using CS-PBE self-assembly, macrophage targeting, reactive oxygen species (ROS) release and celastrol (CLT) encapsulation were achieved. The cytotoxicity, cellular uptake, internalization pathways and transmembrane transport efficiency of CS-PBE micelles were studied in Caco-2 and RAW264.7 cells. Hemolysis and organotoxicity tests were performed to assess the safety of the platform, while its therapeutic efficacy was investigated in high-fat diet-induced obese mice. Multifunctional micelles with macrophage targeting and ROS clearance capabilities were developed to improve the efficacy of CLT in treating obesity.In vitrostudies indicated that CS-PBE micelles had better ability to target M1 macrophages, better protective effects on mitochondrial function, better ability to reduce the number of LPS-stimulated M1 macrophages, better ability to reduce the number of M2 macrophages, and better ability to scavenge ROS in inflammatory macrophages.In vivostudies have shown that CS-PBE micelles improve inflammation and significantly reduce toxicity of CLT in the treatment of obesity. In summary, CS-PBE micelles could significantly improve the ability to target inflammatory macrophages and scavenge ROS in adipose tissue to alleviate inflammation, suggesting that CS-PBE micelles are a highly promising approach for the treatment of obesity.

Asunto(s)

Macrófagos , Micelas , Mitocondrias , Obesidad , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células RAW 264.7 , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Células CACO-2 , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Ratones Endogámicos C57BL , Masculino , Dieta Alta en Grasa/efectos adversos , Triterpenos/farmacología , Triterpenos/química

RESUMEN

Background: The formation of adhesion after tendon injury represents a major obstacle to tendon repair, and currently there is no effective anti-adhesion method in clinical practice. Oxidative stress, inflammation, and fibrosis can occur in tendon injury and these factors can lead to tendon adhesion. Antioxidant carbon dots and ursolic acid (UA) both possess antioxidant and anti-inflammatory properties. In this experiment, we have for the first time created RCDs/UA@Lipo-HAMA using red fluorescent carbon dots and UA co-encapsulated liposomes composite hyaluronic acid methacryloyl hydrogel. We found that RCDs/UA@Lipo-HAMA could better attenuate adhesion formation and enhance tendon healing in tendon injury. Materials and Methods: RCDs/UA@Lipo-HAMA were prepared and characterized. In vitro experiments on cellular oxidative stress and fibrosis were performed. Reactive oxygen species (ROS), and immunofluorescent staining of collagens type I (COL I), collagens type III (COL III), and α-smooth muscle actin (α-SMA) were used to evaluate anti-oxidative and anti-fibrotic abilities. In vivo models of Achilles tendon injury repair (ATI) and flexor digitorum profundus tendon injury repair (FDPI) were established. The major organs and blood biochemical indicators of rats were tested to determine the toxicity of RCDs/UA@Lipo-HAMA. Biomechanical testing, motor function analysis, immunofluorescence, and immunohistochemical staining were performed to assess the tendon adhesion and repair after tendon injury. Results: In vitro, the RCDs/UA@Lipo group scavenged excessive ROS, stabilized the mitochondrial membrane potential (ΔΨm), and reduced the expression of COL I, COL III, and α-SMA. In vivo, assessment results showed that the RCDs/UA@Lipo-HAMA group improved collagen arrangement and biomechanical properties, reduced tendon adhesion, and promoted motor function after tendon injury. Additionally, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the RCDs/UA@Lipo-HAMA group increased; the levels of cluster of differentiation 68 (CD68), inducible Nitric Oxide Synthase (iNOS), COL III, α-SMA, Vimentin, and matrix metallopeptidase 2 (MMP2) decreased. Conclusion: In this study, the RCDs/UA@Lipo-HAMA alleviated tendon adhesion formation and enhanced tendon healing by attenuating oxidative stress, inflammation, and fibrosis. This study provided a novel therapeutic approach for the clinical treatment of tendon injury.

Asunto(s)

Antioxidantes , Carbono , Hidrogeles , Liposomas , Ratas Sprague-Dawley , Traumatismos de los Tendones , Triterpenos , Ácido Ursólico , Animales , Triterpenos/farmacología , Triterpenos/química , Antioxidantes/farmacología , Antioxidantes/química , Liposomas/química , Traumatismos de los Tendones/tratamiento farmacológico , Adherencias Tisulares/tratamiento farmacológico , Carbono/química , Carbono/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Ratas , Estrés Oxidativo/efectos de los fármacos , Masculino , Cicatrización de Heridas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Puntos Cuánticos/química , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Tendón Calcáneo/efectos de los fármacos , Tendón Calcáneo/lesiones

RESUMEN

To explore new compounds with antitumour activity, fifteen phenolic nor-tripterpenes isolated from Celastraceae species, Maytenus jelskii, Maytenus cuzcoina, and Celastrus vulcanicola, have been studied. Their chemical structures were elucidated through spectroscopic and spectrometric techniques, resulting in the identification of three novel chemical compounds. Evaluation on human tumour cell lines (A549 and SW1573, non-small cell lung; HBL-100 and T-47D, breast; HeLa, cervix, and WiDr, colon) revealed that three compounds, named 6-oxo-pristimerol, demethyl-zeylasteral, and zeylasteral, exhibited significant activity (GI50 ranging from 0.45 to 8.6 µM) on at least five of the cell lines tested. Continuous live cell imaging identified apoptosis as the mode of action of selective cell killing in HeLa cells. Furthermore, their effect on a drug-sensitive Saccharomyces cerevisiae strain has been investigated to deepen on their mechanism of action. In dose-response growth curves, zeylasteral and 7α-hydroxy-blepharodol were markedly active. Additionally, halo assays were conducted to assess the involvement of oxidative stress and/or mitochondrial function in the anticancer profile, ruling out these modes of action for the active compounds. Finally, we also delve into the structure-activity relationship, providing insights into how the molecular structure of these compounds influences their biological activity. This comprehensive analysis enhances our understanding of the therapeutic potential of this triterpene type and underscores its relevance for further research in this field.

Asunto(s)

Antineoplásicos Fitogénicos , Apoptosis , Humanos , Apoptosis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Fenoles/farmacología , Fenoles/química , Triterpenos/farmacología , Triterpenos/química , Células HeLa , Celastraceae/química , Línea Celular Tumoral , Extractos Vegetales/farmacología , Extractos Vegetales/química , Saccharomyces cerevisiae/efectos de los fármacos , Células A549 , Estructura Molecular , Proliferación Celular/efectos de los fármacos

RESUMEN

Despite unquestionable advances in therapy, melanoma is still characterized by a high mortality rate. For years, high expectations have been raised by compounds of natural origin as a component of pharmacotherapy, particularly by triterpenes found in the bark of birch trees. In this study, 3,4-seco-dammara-4(29),20(21),24(25)-trien-3-oic acid (SDT) was isolated from buds of silver birch and its mechanisms of cell death induction, including apoptosis and autophagy, were determined. Cytotoxicity of SDT was evaluated by the cell viability test and clonogenic assay, whereas induction of apoptosis and autophagy was determined by annexin V staining and Western blot. The results revealed dose- and time-dependent reductions in viability of melanoma cells. Treatment of cells for 48 h led to an increase in the percentage of annexin V-positive cells, activation of caspase-8, caspase-9, and caspase-3, and cleavage of PARP, confirming apoptosis. Simultaneously, it was found that SDT increased the level of autophagy marker LC3-II and initiator of autophagy beclin-1. Pretreatment of cells with caspase-3 inhibitor or autophagy inhibitor significantly reduced the cytotoxicity of SDT and revealed that both apoptosis and autophagy contribute to a decrease in cell viability. These findings suggest that 3,4-seco-dammaranes may become a promising group of natural compounds for searching for anti-melanoma agents.

Asunto(s)

Apoptosis , Autofagia , Betula , Melanoma , Triterpenos , Humanos , Triterpenos/farmacología , Triterpenos/química , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Betula/química , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química

RESUMEN

The emergence of natural products has provided extremely valuable references for the treatment of various diseases. Cucurbitacin B, a tetracyclic triterpenoid compound isolated from cucurbitaceae and other plants, is the most abundant member of the cucurbitin family and exhibits a wide range of biological activities, including anti-inflammatory, anti-cancer, and even agricultural applications. Due to its high toxicity and narrow therapeutic window, structural modification and dosage form development are necessary to address these issues with cucurbitacin B. This paper reviews recent research progress in the pharmacological action, structural modification, and application of cucurbitacin B. This review aims to enhance understanding of advancements in this field and provide constructive suggestions for further research on cucurbitacin B.

Asunto(s)

Triterpenos , Triterpenos/química , Triterpenos/farmacología , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Animales , Cucurbitaceae/química , Estructura Molecular , Relación Estructura-Actividad , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología

RESUMEN

The goal of preparative chromatography is to isolate suitable amounts of compound(s) at the required purity in the most cost-effective way. This study analyses the power of High-performance thin-layer chromatography (HPTLC) guided preparative flash chromatography to separate and isolate bioactive compounds from an olive flower extract for their further characterisation via spectroscopy. The structure and purity of isolated bioactive compounds were assessed using Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Flash chromatography of the olive flower extract successfully isolated pure oleanolic and maslinic acids. Moreover, the flash chromatography of the extract allowed isolation and phytochemical analysis of the most lipophilic fraction of the extract, which was found to contain n-eicosane and n-(Z)-eicos-5-ene, that has not been isolated previously with preparative TLC.

Asunto(s)

Flores , Espectroscopía de Resonancia Magnética , Olea , Extractos Vegetales , Flores/química , Cromatografía en Capa Delgada/métodos , Olea/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Espectroscopía Infrarroja por Transformada de Fourier , Triterpenos/análisis , Triterpenos/aislamiento & purificación , Triterpenos/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/análisis , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos

RESUMEN

Platycodon grandiflorum roots (PGR), a widely recognized edible herbal medicine, are extensively used in traditional Chinese medicine for respiratory ailments. PGR are rich in bioactive compounds, particularly triterpenoid saponins, which possess significant pharmaceutical properties, including anti-inflammatory, antifungal, and antioxidant activities. Despite their recognized bioactivity, the purification and enrichment processes of triterpenoid saponins remain underexplored. This study aimed to optimize the extraction and purification of triterpenoid saponins from PGR to enhance resource utilization and minimize waste. Our method involved n-butanol extraction and macroporous adsorption resin, yielding four extracts with varying saponins contents. Qualitative analysis using LC-MS identified 8 triterpenoid saponins across the extracts. Further fragmentation analysis delineated characteristic ion patterns and cleavage pathways for these compounds. Quantitative analysis demonstrated that the separation and purification process effectively increased the triterpenoid saponins content, with the highest levels obtained through 30 % ethanol elution. Notably, the absence of Platycodin D in the 30 % ethanol eluate highlighted potential variations due to the origin, processing, and purification methods. These findings provide theoretical support for the development and utilization of triterpenoid saponins in PGR.

Asunto(s)

Raíces de Plantas , Platycodon , Saponinas , Triterpenos , Saponinas/química , Saponinas/aislamiento & purificación , Saponinas/análisis , Platycodon/química , Raíces de Plantas/química , Triterpenos/química , Triterpenos/aislamiento & purificación , Triterpenos/análisis , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Cromatografía Liquida/métodos

RESUMEN

Oxidative stress is considered one of the main reasons for the development of colorectal cancer (CRC). Depending on the stage of the disease, variable activity of the main antioxidant enzymes, i.e., superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), is observed. Due to limited treatment methods for CRC, new substances with potential antitumor activity targeting pathways related to oxidative stress are currently being sought, with substances of natural origin, including betulin, leading the way. The betulin molecule is chemically modified to obtain new derivatives with improved pharmacokinetic properties and higher biological activity. The aim of this study was to evaluate the effects of betulin and its new derivatives on viability and major antioxidant systems in colorectal cancer cell lines. The study showed that betulin and its derivative EB5 affect the antioxidant enzyme activity to varying degrees at both the protein and mRNA levels. The SW1116 cell line is more resistant to the tested compounds than RKO, which may be due to differences in the genetic and epigenetic profiles of these lines.

Asunto(s)

Antioxidantes , Catalasa , Supervivencia Celular , Neoplasias Colorrectales , Triterpenos , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Antioxidantes/farmacología , Triterpenos/farmacología , Triterpenos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , Superóxido Dismutasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido Betulínico

RESUMEN

Unlike most common pentacyclic plant triterpenes, glutinol has a methyl group at position C-9 and a Δ5 double bond. At the same time, it lacks a methyl at C-10. These features significantly modify its chemical behavior compared to other triterpenes, particularly under oxidative conditions. Although the isolation of glutinol from various plant species has been documented, its chemistry remains largely unexplored. In this study, glutinol was isolated from the bark of Balfourodendron riedelianum as a starting material for top-down strategies of structural diversification, which included ring fusion, oxidation, aromatization, and ring cleavage reactions. Glutinol, together with a library of 22 derivatives, was evaluated for antifungal activity against three phytopathogenic Fusarium strains, F. solani, F. graminearum, and F. tucumaniae. Some of the derivatives displayed antifungal activity; in particular, compound 12, featuring a triazine ring, displayed the best fungicidal properties against F. solani and F. graminearum, while the ring B cleavage product 23 showed the best activity against F. tucumaniae. This study highlights the potential of glutinol as a scaffold for structural diversification, and these results may contribute to the design of novel fungicidal agents against phytopathogenic strains.

Asunto(s)

Antifúngicos , Fusarium , Fusarium/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Estructura Molecular , Pruebas de Sensibilidad Microbiana , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Corteza de la Planta/química

RESUMEN

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.

Asunto(s)

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 fármacos

RESUMEN

Hollongdione is the first recorded example of the occurrence of a dammarane hexanor-triterpene in nature possessing antiviral and cytotoxic activity. Its simple one-stage transformation into compounds with terminal alkyne and vinyl chloride fragments via the interaction with phosphorus halides is reported. The copper(I)-catalyzed Mannich reaction of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20(21)-in 3 led to a series of aminomethylated products, while 17-carboxylic acid was obtained by ozone oxidation of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20-chloro-20(21)-en 4; the following direct amidation of the latter has been developed. The structures of all new molecules were established by spectroscopic studies that included 2D NMR correlation methods; the molecular structures of compounds 2-5 were determined by X-ray analysis.

Asunto(s)

Alquinos , Ácidos Carboxílicos , Bases de Mannich , Cloruro de Vinilo , Alquinos/química , Ácidos Carboxílicos/química , Bases de Mannich/química , Cloruro de Vinilo/química , Triterpenos/química , Estructura Molecular , Catálisis , Espectroscopía de Resonancia Magnética

RESUMEN

Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound (21o) significantly inhibited the proliferation of MCF-7 cells with an IC50 value of 2.0 µM, 1.5-fold more potent than pristimerin (IC50 = 3.0 µM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o. Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.

Asunto(s)

Autofagia , Neoplasias de la Mama , Triterpenos Pentacíclicos , Quinoxalinas , Triterpenos , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células MCF-7 , Estructura Molecular , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Quinoxalinas/farmacología , Quinoxalinas/química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Triterpenos/farmacología , Triterpenos/química

RESUMEN

Centella asiatica (L.) Urban is a medical plant rich in triterpenoids, frequently used in Asia to treat skin conditions such as acne. To search for anti-photoaging agents, 16 known triterpenoids and five undescribed triterpenoids, including three ursane, one oleanane and one nor-ursane were isolated from the whole herb of C. asiatica. The structures and relative stereochemistry of these compounds were elucidated by detailed NMR spectra and HRESIMS. Compounds 1 and 2 were isomers of ursane-type and oleane-type triterpenes with rare aldehyde groups on C-23. Compound 4 was a unique example of a nor-ursane type triterpenoid. The Ultraviolet B (UVB) induced HaCaT cell damage model was used to measure the in vitro anti-photoaging activity of all 21 compounds. Twenty compounds significantly increased HaCaT viability and inhibited lactate dehydrogenase (LDH) release after UVB exposure. These findings highlight the protective effects of C. asiatica-derived triterpenoids against UVB damage and indicate their potential as natural agents that can protect the skin against photoaging.

Asunto(s)

Centella , Triterpenos , Rayos Ultravioleta , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Centella/química , Humanos , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Envejecimiento de la Piel/efectos de los fármacos , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , L-Lactato Deshidrogenasa/metabolismo , Células HaCaT

RESUMEN

The process of wound healing is intricate and complex, necessitating the intricate coordination of various cell types and bioactive molecules. Despite significant advances, challenges persist in achieving accelerated healing and minimizing scar formation. Herein, a multifunctional hydrogel engineered via dynamic Schiff base crosslinking between oxidized dextran and quaternized chitosan, reinforced with reduced graphene oxide (rGO) is reported. The resulting OQG hydrogels demonstrated injectability to aid in conforming to irregular wound geometries, rapid self-healing to maintain structural integrity and adhesion for intimate integration with wound beds. Moreover, the developed hydrogels possessed antioxidant and antibacterial activities, mitigating inflammation and preventing infection. The incorporation of conductive rGO further facilitated the transmission of endogenous electrical signals, stimulating cell migration and tissue regeneration. In addition, the polydopamine-encapsulated asiaticoside (AC@PDA) nanoparticles were encapsulated in OQG hydrogels to reduce scar formation during in vivo evaluations. In vitro results confirmed the histocompatibility of the hydrogels to promote cell migration. The recovery of the full-thickness rat wounds revealed that these designed OQG hydrogels with the incorporation of AC@PDA nanoparticles could accelerate wound healing, reduce inflammation, facilitate angiogenesis, and minimize scarring when implemented. This multifunctional hydrogel system offers a promising strategy for enhanced wound management and scarless tissue regeneration, addressing the multifaceted challenges in wound care.

Asunto(s)

Vendajes , Quitosano , Dextranos , Grafito , Hidrogeles , Polímeros , Triterpenos , Cicatrización de Heridas , Hidrogeles/química , Hidrogeles/farmacología , Quitosano/química , Cicatrización de Heridas/efectos de los fármacos , Dextranos/química , Animales , Ratas , Triterpenos/química , Triterpenos/farmacología , Grafito/química , Polímeros/química , Ratones , Masculino , Antioxidantes/farmacología , Antioxidantes/química , Humanos , Inyecciones , Antibacterianos/farmacología , Antibacterianos/química , Ratas Sprague-Dawley , Cicatriz , Indoles

RESUMEN

Betulinic acid (BA) is a lupinane-type pentacyclic triterpenoid natural product derived from lupeol that has favorable anti-inflammatory and anti-tumor activities. Currently, BA is mainly produced via botanical extraction, which significantly limits its widespread use. In this study, we investigated the de novo synthesis of BA in Saccharomyces cerevisiae, and to facilitate the synthesis and storage of hydrophobic BA, we adopted a dual-engineering strategy involving peroxisomes and lipid droplets to construct the BA biosynthetic pathway. By expressing Betula platyphylla-derived lupeol C-28 oxidase (BPLO) and Arabidopsis-derived ATR1, we succeeded in developing a BA-producing strain and following multiple expression optimizations of the linker between BPLO and ATR1, the BA titer reached 77.53 mg/L in shake flasks and subsequently reached 205.74 mg/L via fed-batch fermentation in a 5-L bioreactor. In this study, we developed a feasible approach for the de novo synthesis of BA and its direct precursor lupeol in engineered S. cerevisiae.

Asunto(s)

Ácido Betulínico , Triterpenos Pentacíclicos , Saccharomyces cerevisiae , Triterpenos , Saccharomyces cerevisiae/metabolismo , Triterpenos Pentacíclicos/metabolismo , Triterpenos Pentacíclicos/química , Triterpenos/metabolismo , Triterpenos/química , Estructura Molecular , Ingeniería Metabólica

RESUMEN

The efficacy of single chemotherapy drugs in cancer treatment is often limited. Combining administration targeting multiple targets has emerged as an effective strategy to improve cancer treatment. Ursolic acid, a triterpenoid compound in various natural foods, was identified as a novel inhibitor of lung cancer specific target TMEM16A. The IC50 of ursolic acid on the whole-cell current of TMEM16A was 13.85 ± 1.64 µM. Molecular dynamics simulations and site-directed mutagenesis experiments indicated the binding sites of ursolic acid on TMEM16A as L381, R535, E623, and C625. Ursolic acid significantly inhibited the proliferation and migration of LA795 cells, while promoting cancer cell apoptosis. Mechanistic studies revealed that ursolic acid inhibited lung cancer through the MAPK and EMT pathways, and induced DNA and membrane damage. Next, a degradable and self-repairing hydrogel drug-loading system was designed to enhance the targeting effect of the ursolic acid and cisplatin drug combination. In vivo experiments showed that the hydrogel-loaded ursolic acid and cisplatin enhanced the antitumor activity and reduced the toxicity. This study presents a novel approach of multi-target combination therapy using ursolic acid and cisplatin, combined with the targeted delivery capability of the hydrogel system, which significantly improves the therapeutic efficacy in lung cancer.

Asunto(s)

Cisplatino , Hidrogeles , Neoplasias Pulmonares , Triterpenos , Ácido Ursólico , Triterpenos/farmacología , Triterpenos/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Cisplatino/farmacología , Humanos , Hidrogeles/química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ratones , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Simulación de Dinámica Molecular , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos

RESUMEN

This manuscript describes the isolation of nine new nor-3,4-seco-dammarane triterpenoids, norqingqianliusus A-I (1-9) and one known nortriterpenoid (10) from Cyclocarya paliurus leaves. Norqingqianliusus A and B (1 and 2) possess a unique 3,4-seco-dammarane-type C26 tetranortriterpenoid skeleton. The compounds were structurally characterized through modern spectroscopic techniques. Moreover, the potential mechanism of hypoglycemic activity was further explored by studying the effects on glucosamine-induced insulin resistant HepG2 cells. In vitro hypoglycemic effects of all of the isolates were investigated using insulin resistant HepG2 cells. The glucose consumption was significantly promoted by compound 10, in a dose-dependent manner, thus alleviating damage in IR-HepG2 cells. Besides, it reduced the PEPCK and GSK3ß gene expression, involved in glucose metabolism. The anti-diabetic effects of the plant, utilized traditionally, can hence be attributed to the presence of nor-3,4-seco-dammarane triterpenoids in the leaves.

Asunto(s)

Damaranos , Hipoglucemiantes , Juglandaceae , Hojas de la Planta , Triterpenos , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Hojas de la Planta/química , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Juglandaceae/química , Células Hep G2 , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga

RESUMEN

Ursolic acid (UA) and its derivatives have garnered significant attention due to their extensive pharmacological activity. UA is a pentacyclic triterpenoid found in a variety of plants, such as apples, rosemary, thyme, etc., and it possesses a range of pharmacological properties. Researchers have synthesized various derivatives of UA through structural modifications to enhance its potential pharmacological properties. Various in vitro and in vivo studies have indicated that UA and its derivatives possess diverse biological activities, such as anticancer, antifungal, antidiabetic, antioxidant, antibacterial, anti-inflammatory and antiviral properties. This review article provides a review of the biological activities of UA and its derivatives to show their valuable therapeutic properties useful in the treatment of different diseases, mainly focusing on the relevant structure-activity relationships (SARs), the underlying molecular targets/pathways, and modes of action.

Asunto(s)

Triterpenos , Ácido Ursólico , Triterpenos/farmacología , Triterpenos/química , Humanos , Relación Estructura-Actividad , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Antivirales/farmacología , Antivirales/química , Estructura Molecular , Antiinfecciosos/farmacología , Antiinfecciosos/química

RESUMEN

Four previously unreported triterpenoid saponins named 3ß-hydroxy-23-oxours-12-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside G) (1), 23-O-acetyl-3ß-hydroxyurs-12-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside H) (2), ursolic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl] ester (mannioside I) (3), and 3ß-hydroxy-23-oxolup-20(29)-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside J) (4) were isolated as minor constituents from the EtOAc soluble fraction of the MeOH extract of the leaves of Schefflera mannii along with the known compounds 23-hydroxyursolic acid 28-O-ß-D-glucopyranosyl ester (5), ursolic acid 28-O-ß-D-glucopyranosyl ester (6), pulsatimmoside B (7) betulinic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl] ester (8), 23-hydroxy-3-oxo-urs-12-en-28-oic acid (9), hederagenin (10), ursolic acid (11), betulinic acid (12), and lupeol (13). Their structures were elucidated by a combination of 1D and 2D NMR analysis and mass spectrometry. The MeOH extract, the EtOAc and n-BuOH fractions, and some of the isolated compounds were evaluated for their antibacterial activity against four bacteria: Staphylococcus aureus ATCC1026, Staphylococcus epidermidis ATCC 35984, Escherichia coli ATCC10536, and Klepsiella pnemoniae ATCC13882. They were also screened for their antioxidant properties, but no significant results were obtained.

Asunto(s)

Antibacterianos , Saponinas , Triterpenos , Triterpenos/química , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Saponinas/química , Saponinas/farmacología , Saponinas/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Extractos Vegetales/farmacología , Estructura Molecular , Hojas de la Planta/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Araliaceae/química