RESUMEN

Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-ß-D-glucopyranoside, and limonin 17-O-ß-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-ß-D-glucopyranoside and limonin 17-O-ß-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-ß-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-ß-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism.

Asunto(s)

Antioxidantes , Citrus , Hipoglucemiantes , Limoninas , Simulación de Dinámica Molecular , Extractos Vegetales , Limoninas/farmacología , Limoninas/química , Citrus/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Simulación del Acoplamiento Molecular , Humanos , Frutas/química , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , Benzoxepinas

RESUMEN

Swietenia macrophylla fruit is a valuable and historically significant medicinal plant with anti-hypertension and anti-diabetes. We identified a toxic component, Febrifugin, from the edible part of the nut following zebrafish toxicity-guided isolation. Febrifugin is a mexicanolide-type limonoid compound. The toxic factor induced acute toxicity in zebrafish, including yolk sac edema and pericardial edema, reduced body length, decreased melanin deposition, and presented acute skeletal developmental issues. Further exploration of the acute toxicity mechanism through metabolomics revealed that Febrifugin caused significant changes in 13 metabolites in zebrafish larvae, which are involved in the pentose phosphate, tricarboxylic acid (TCA) cycle, and amino acid biosynthesis. The bioassay of oxidative stress capacity and qRT-PCR measurement showed that the compound significantly affected the h6pd gene in the pentose phosphate pathway and the mRNA expression of cs, idh3a, fh, and shda genes in the TCA cycle, leading to reactive oxygen species (ROS) accumulation and a notable decrease in glutathione (GSH) activity in zebrafish. These findings provide a basis for the rational use of S. macrophylla as a medicinal plant and raise awareness of the safety of medicinal plants.

Asunto(s)

Metabolómica , Pez Cebra , Animales , Pez Cebra/metabolismo , Metabolómica/métodos , Estrés Oxidativo/efectos de los fármacos , Meliaceae/química , Limoninas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Nueces/química , Larva/efectos de los fármacos , Larva/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Metaboloma , Plantas Medicinales/química , Ciclo del Ácido Cítrico/efectos de los fármacos , Glutatión/metabolismo

RESUMEN

Azadirachtin is a widely used botanical pesticide for agricultural pest control worldwide. However, the molecular mechanisms of azadirachtin in insects are not fully understood. In this study, histological analysis and RNA sequencing were conducted to investigate the impact of azadirachtin on the larval development of Spodoptera frugiperda. Under azadirachtin exposure, the development was completely inhibited, and the major internal tissues, fat body, and midgut were strongly damaged under histological analysis. Differential gene expression analysis demonstrated that nutrient absorption and detoxification metabolism-related genes are differentially expressed. Interestingly, the expression of the apoptosis-related gene, caspase-8, was significantly inhibited under exposure to azadirachtin. In addition, after knocking down the expression of the caspase-8 gene, the fat body displayed a similar apoptotic phenotype as azadirachtin treatment; the distribution of chromatin and lipid droplets was uneven in the fat body cells. Thus, the results in this study demonstrated that exposure to azadirachtin rapidly activates apoptosis, resulting in innate tissue disruption, ultimately arresting larval development in S. frugiperda.

Asunto(s)

Apoptosis , Caspasa 8 , Cuerpo Adiposo , Proteínas de Insectos , Insecticidas , Larva , Limoninas , Spodoptera , Animales , Spodoptera/efectos de los fármacos , Spodoptera/genética , Spodoptera/crecimiento & desarrollo , Limoninas/farmacología , Apoptosis/efectos de los fármacos , Cuerpo Adiposo/efectos de los fármacos , Cuerpo Adiposo/metabolismo , Larva/crecimiento & desarrollo , Larva/efectos de los fármacos , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Insecticidas/farmacología , Caspasa 8/metabolismo , Caspasa 8/genética

RESUMEN

Epoxyazadiradione is an important limonoid with immense pharmacological potential. We have reported previously that epoxyazadiradione (EAD) induces apoptosis in triple negative breast cancer cells (MDA-MB 231) by modulating diverse cellular targets. Here, we identify the key genes/pathways responsible for this effect through next-generation sequencing of the transcriptome from EAD treated cells and integrated molecular data analysis using bioinformatics. In silico analysis indicated that EAD displayed favourable drug-like properties and could target multiple macromolecules relevant to TNBC. RNA sequencing revealed that EAD treatment results in the differential expression of 1838 genes in MDA-MB 231 cells, with 752 downregulated and 1086 upregulated. Gene set enrichment analysis of these genes suggested that EAD disrupts protein folding in the endoplasmic reticulum, triggering the unfolded protein response (UPR) and potentially leading to cell death. EAD also induced oxidative stress and DNA damage, downregulated pathways linked to metabolism, cell cycle progression, pro-survival signalling, cell adhesion, motility and inflammatory response. The identification of protein cluster and hub genes were also done. The validation of the identified hub genes gave an inverse correlation between their expression in EAD treated cells and TNBC patient samples. Thus, the identified hub genes could be explored as therapeutic or diagnostic markers for TNBC. Hence, EAD appears to be a promising therapeutic candidate for TNBC by targeting various hallmarks of cancer, including cell death resistance, uncontrolled proliferation and metastasis. To conclude, the identified pathways and validated targets for EAD will provide a roadmap for further in vivo studies and preclinical/clinical validation required for potential drug development.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Apoptosis/efectos de los fármacos , Limoninas/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Biología Computacional/métodos

RESUMEN

The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What's more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin's binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.

Asunto(s)

Antineoplásicos , Berberina , Curcumina , Limoninas , Simulación del Acoplamiento Molecular , Unión Proteica , Albúmina Sérica Humana , Espectrometría de Fluorescencia , Humanos , Berberina/farmacología , Berberina/química , Berberina/metabolismo , Curcumina/farmacología , Curcumina/metabolismo , Curcumina/química , Limoninas/farmacología , Limoninas/química , Limoninas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Albúmina Sérica Humana/metabolismo , Albúmina Sérica Humana/química , Sitios de Unión , Termodinámica , Línea Celular Tumoral , Dicroismo Circular

RESUMEN

UPLC-Q-TOF-MS combined with mass defect filtering strategies were applied for the phytochemical investigation of Harrisonia perforata, leading to the isolation of thirteen undescribed limonoids named haperforatones A-M (1-13) and seventeen known compounds (14-30). Particularly, haperforatones D-E (4-5) have an unprecedented A, B, C, D-seco-6, 7-nor-C-24-limonoid skeleton, structurally stripped of the five-membered lactone ring B and formed a double bond at the C-5 and C-10 positions. Their 2D structures and relative configurations were identified using spectroscopic data. The absolute configurations of 1, 4, and 6 were established via X-ray diffraction crystallography. All 30 compounds were evaluated for anti-inflammatory potential in LPS-induced Raw 264.7 cell lines. Among those tested compounds, the most potent activity against LPS-induced NO generation was demonstrated by haperforatone F (6), with the IC50 value of inhibition NO production of 7.2 µM. Additionally, 6 could significantly inhibit IL-1ß and IL-6 release and markedly downregulate the protein expression level of iNOS in the LPS-stimulated RAW264.7 cells at 10 µM. The possible mechanism of NO inhibition of 6 was also investigated using molecular docking, which revealed the interaction of compound 6 with the iNOS protein.

Asunto(s)

Limoninas , Lipopolisacáridos , Óxido Nítrico , Ratones , Limoninas/farmacología , Limoninas/química , Limoninas/aislamiento & purificación , Animales , Células RAW 264.7 , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Relación Estructura-Actividad , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Relación Dosis-Respuesta a Droga , Meliaceae/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo

RESUMEN

Nimbolide has been demonstrated to possess protective properties against gestational diabetes mellitus and diabetic retinopathy. However, the role and molecular mechanism of nimbolide in diabetic cardiomyopathy (DCM) remain unknown. Diabetes was induced in rats via a single injection of streptozotocin (STZ) and then the diabetic rats were administered nimbolide (5 mg/kg and 20 mg/kg) or dimethyl sulfoxide daily for 12 weeks. H9c2 cardiomyocytes were exposed to high glucose (25 mM glucose) to mimic DCM in vitro. The protective effects of nimbolide against DCM were evaluated in vivo and in vitro. The potential molecular mechanism of nimbolide in DCM was further explored. We found that nimbolide dose-dependently decreased blood glucose and improved body weight of diabetic rats. Additionally, nimbolide dose-dependently improved cardiac function, alleviated myocardial injury/fibrosis, and inhibited endoplasmic reticulum (ER) stress and apoptosis in diabetic rats. Moreover, nimbolide dose-dependently improved mitochondrial function and activated the Akt/mTOR signaling. We consistently demonstrated the cardioprotective effects of nimbolide in an in vitro model of DCM. The involvement of ER stress and mitochondrial pathways were further confirmed by using inhibitors of ER stress and mitochondrial division. By applying a specific Akt inhibitor SC66, the cardioprotective effects of nimbolide were partially blocked. Our study indicated that nimbolide alleviated DCM by activating Akt/mTOR pathway. Nimbolide may be a novel therapeutic agent for DCM treatment.

Asunto(s)

Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Estrés del Retículo Endoplásmico , Limoninas , Mitocondrias , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Limoninas/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Sprague-Dawley , Línea Celular , Apoptosis/efectos de los fármacos , Cardiotónicos/farmacología

RESUMEN

Plants of the Meliaceae family have long attracted researchers' interest due to their various insecticidal activities, with triterpenes being the main active ingredients. In this paper, we discuss 93 triterpenoids with insecticidal activity from 37 insecticidal plant species of 15 genera (Munronia, Neobeguea, Pseudocedrela, Nymania, Quivisia, Ruagea, Dysoxylum, Soymida, Lansium, Sandoricum, Walsura, Trichilia, Swietenia, Turraea, and Xylocarpus) in the family Meliaceae. Among these genera, Trichilia deserves further research, with twelve species possessing insecticidal activity. The 93 insecticidal molecules included 27 ring-seco limonoids (comprising 1 ring A-seco group chemical, 1 ring B-seco group chemical, 5 ring D-seco group chemicals, 14 rings A,B-seco group chemicals, 5 rings B,D-seco group chemicals, and 1 rings A,B,D-seco group chemical), 22 ring-intact limonoids (comprising 5 cedrelone-class chemicals, 6 trichilin-class chemicals, 7 havanensin-class chemicals, 2 azadirone-class chemicals, 1 vilasinin-class chemical, and 1 other chemical), 33 2,30-linkage chemicals (comprising 25 mexicanolide-class chemicals and 8 phragmalin-class chemicals), 3 1,n-linkage-group chemicals, 3 onoceranoid-type triterpenoids, 2 apotirucallane-type terpenoids, 2 kokosanolide-type tetranortriterpenoids, and 1 cycloartane triterpene. In particular, 59 molecules showed antifeedant activity, 30 molecules exhibited poisonous effects, and 9 molecules possessed growth regulatory activity. Particularly, khayasin, beddomei lactone, 3ß,24,25-trihydroxycycloartane, humilinolides A-E and methyl-2-hydroxy-3ß-isobutyroxy-1-oxomeliac-8(30)-enate showed excellent insecticidal activities, which were comparable to that of azadirachtin and thus deserved more attention. Moreover, it was noteworthy that various chemicals (such as 12α-diacetoxywalsuranolide, 11ß,12α-diacetoxycedrelone, 1α,7α,12α-triacetoxy-4α-carbomethoxy-11ß-hydroxy-14ß,15ß-epoxyhavanensin, and 11-epi-21-hydroxytoonacilide, etc.) from Turraea showed excellent insecticidal activity. Specially, the insecticidal activity of khayasin from Neobeguea against the coconut leaf beetle were similar to that of rotenone. Therefore, it was a promising candidate insecticide for the control of the coconut leaf beetle.

Asunto(s)

Insecticidas , Meliaceae , Triterpenos , Meliaceae/química , Triterpenos/farmacología , Triterpenos/química , Insecticidas/farmacología , Insecticidas/química , Animales , Limoninas/farmacología , Limoninas/química , Extractos Vegetales/química , Extractos Vegetales/farmacología

RESUMEN

The isolation, structure determination, and biological evaluation of constituents from the organic extract of Turraea delphinensis Wahlert (Meliaceae) resulted in the isolation of 51 secondary metabolites, including 14 new terpenoids (six cycloartanes, four tirucallanes/euphanes, three limonoids, and a 7-keto sterol). Among the new compounds, 1 is the first triterpenoid with a trioxaspiro[4.4]nonane side chain, while 11-13 are the first 17-γ-lactone tetranortriterpenoids with four oxygenated functional groups at C-1, -3, -6, and -7. The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a vinblastine-resistant cell line.

Asunto(s)

Antineoplásicos Fitogénicos , Ensayos de Selección de Medicamentos Antitumorales , Meliaceae , Terpenos , Triterpenos , Humanos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Terpenos/farmacología , Terpenos/química , Terpenos/aislamiento & purificación , Estructura Molecular , Meliaceae/química , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Línea Celular Tumoral , Limoninas/farmacología , Limoninas/química , Limoninas/aislamiento & purificación , Proliferación Celular/efectos de los fármacos

RESUMEN

Acquired resistance represents a critical clinical challenge to molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) treatment in hepatocellular carcinoma (HCC). Therefore, it is urgent to explore new mechanisms and therapeutics that can overcome or delay resistance. Here, a US Food and Drug Administration (FDA)-approved pleuromutilin antibiotic is identified that overcomes sorafenib resistance in HCC cell lines, cell line-derived xenograft (CDX) and hydrodynamic injection mouse models. It is demonstrated that lefamulin targets interleukin enhancer-binding factor 3 (ILF3) to increase the sorafenib susceptibility of HCC via impairing mitochondrial function. Mechanistically, lefamulin directly binds to the Alanine-99 site of ILF3 protein and interferes with acetyltransferase general control non-depressible 5 (GCN5) and CREB binding protein (CBP) mediated acetylation of Lysine-100 site, which disrupts the ILF3-mediated transcription of mitochondrial ribosomal protein L12 (MRPL12) and subsequent mitochondrial biogenesis. Clinical data further confirm that high ILF3 or MRPL12 expression is associated with poor survival and targeted therapy efficacy in HCC. Conclusively, this findings suggest that ILF3 is a potential therapeutic target for overcoming resistance to TKIs, and lefamulin may be a novel combination therapy strategy for HCC treatment with sorafenib and regorafenib.

Asunto(s)

Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Mitocondrias , Proteínas del Factor Nuclear 90 , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Animales , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proteínas del Factor Nuclear 90/metabolismo , Proteínas del Factor Nuclear 90/genética , Línea Celular Tumoral , Diterpenos/farmacología , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Homeostasis/efectos de los fármacos , Sorafenib/farmacología , Modelos Animales de Enfermedad , Limoninas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Benzofuranos , Naftoquinonas

RESUMEN

Cell membrane coating strategies have been increasingly researched in new drug discovery from complex herb extracts. However, these systems failed to maintain the functionality of the coated cells because cell membranes, not whole cells were used. Original source cells can be used as a vector for active compound screening in a manner that mimics in vivo processes. In this study, we established a novel approach to fabricate high-density fibroblast growth factor receptor 4 (FGFR4)-HEK293 cells on microcarriers covered with collagen through cell culture and covalent immobilization between proteins. This method enables the efficient screening of active compounds from herbs. Two compounds, evodiamine and limonin, were obtained from Fructus evodiae, which were proven to inhibit the FGFR4 target. Enhanced immobilization effects and negligible damage to FGFR4-HEK293 cells treated with paraformaldehyde were successfully confirmed by immunofluorescence assays and transmission electron microscopy. A column was prepared and used to analyze different compounds. The results showed that the method was selective, specific, and reproducible. Overall, the high density of cells immobilized on microcarriers achieved through cell culture and covalent immobilization represents a promising strategy for affinity screening. This approach highlights the potential of the affinity screening method to identify active compounds from an herbal matrix against designed targets and its prospects for use in drug discovery from herbs.

Asunto(s)

Células Inmovilizadas , Quinazolinas , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos , Humanos , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Células HEK293 , Quinazolinas/farmacología , Quinazolinas/química , Células Inmovilizadas/metabolismo , Evodia/química , Limoninas/farmacología , Limoninas/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Biomimética/métodos , Frutas/química , Colágeno , Evaluación Preclínica de Medicamentos/métodos

RESUMEN

Nimbolide, one of the main ingredients constituent of Azadirachta indica (neem) leaf extract, has garnered attention for its potential as an anticancer agent. Its efficacy against various cancers and chemopreventive action has been demonstrated through numerous in vivo and in vitro studies. This updated review aims to comprehensively explore the chemopreventive and anticancer properties of nimbolide, emphasizing its molecular mechanisms of action and potential therapeutic applications in oncology. The review synthesizes evidence from various studies that examine nimbolide's roles in apoptosis induction, anti-proliferation, cell death, metastasis inhibition, angiogenesis suppression, and modulation of carcinogen-metabolizing enzymes. Nimbolide exhibits multifaceted anticancer activities, including the modulation of multiple cell signaling pathways related to inflammation, invasion, survival, growth, metastasis, and angiogenesis. However, its pharmacological development is still in the early stages, mainly due to limited pharmacokinetic and comprehensive long-term toxicological studies. Nimbolide shows promising anticancer and chemopreventive properties, but there is need for systematic preclinical pharmacokinetic and toxicological research. Such studies are essential for establishing safe dosage ranges for first-in-human clinical trials and further advancing nimbolide's development as a therapeutic agent against various cancers. The review highlights the potential of nimbolide in cancer treatment and underscores the importance of rigorous preclinical evaluation to realize its full therapeutic potential.

Asunto(s)

Limoninas , Neoplasias , Humanos , Limoninas/farmacología , Limoninas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Azadirachta/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos

RESUMEN

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

Asunto(s)

Portadores de Fármacos , Ivermectina , Lípidos , Nanoestructuras , Humanos , Ivermectina/administración & dosificación , Ivermectina/química , Ivermectina/farmacocinética , Ivermectina/farmacología , Animales , Portadores de Fármacos/química , Lípidos/química , Células K562 , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Sinergismo Farmacológico , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacos , Masculino , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Limoninas/administración & dosificación , Limoninas/farmacología , Limoninas/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Ratas

RESUMEN

Phytochemical study of the fruits of Chisocheton erythrocarpus (Hiern) allowed the identification of eight undescribed limonoids, namely erythrocarpines O - V (1-6, 7a and 7b), along with seven known compounds. The structures of these compounds were elucidated based on spectroscopic and HRMS data, along with electronic circular dichroism to configure the absolute configuration. Erythrocarpines O and P are γ-hydroxybutenolide analogs of mexicanolide-type limonoids while erythrocarpine Q - V are phragmalin-type limonoids possessing a 1,29-oxymethylene bridge with either benzoyl or cinnamoyl moiety in their structures. Mosquito larvicidal activity revealed that crude DCM extract of C. erythrocarpus possessed a good larvicidal effect against Aedes aegypti larvae in 48 h (LC50 = 153.0 ppm). Subsequent larvicidal activity of isolated compounds indicated that erythrocarpine G (10) and 14-deoxyxyloccensin K (11) were responsible for the enhanced larvicidal effect of the extract, reporting LC50 values of 18.55 ppm and 41.16 ppm, respectively. Moreover, residual activity testing of the crude DCM extract revealed that the duration of its larvicidal effects is up to 14 days, where it maintained a 98 % larval mortality throughout the test period, under laboratory conditions.

Asunto(s)

Aedes , Frutas , Insecticidas , Larva , Limoninas , Meliaceae , Animales , Larva/efectos de los fármacos , Limoninas/farmacología , Limoninas/aislamiento & purificación , Limoninas/química , Insecticidas/farmacología , Insecticidas/química , Insecticidas/aislamiento & purificación , Frutas/química , Aedes/efectos de los fármacos , Meliaceae/química , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga

RESUMEN

Different types of limonoids have been isolated from plants of the Chisocheton genus, notably from the species Chisocheton ceramicus Miq. which is largely distributed in the Indonesian archipelago and Malaysia region. A variety of natural products have been found in the bark of the tree and characterized as antimicrobial and/or antiproliferative agents. The isolated limonoids include chisomicines A-E, proceranolide, and a few other compounds. A focus is made on a large series of limonoids designated ceramicines A to Z including derivatives with antiparasitic activities, antioxidant, antimelanogenic, and antiproliferative effects and/or acting as regulators of lipogenesis. The lead compound in the series is ceramicine B functioning as a potent inhibitor of lipid droplet accumulation (LDA). Extracts from Chisocheton ceramicus and ceramicines have shown anti-LDA effects, with little or no cytotoxic effects. Ceramicine B is the most active compound functioning as a regulator of lipid storage in cells and tissues. Ceramicine B is a transcriptional repressor of peroxisome proliferator-activated receptor γ (PPARγ) and an inhibitor of phosphorylation of the transcription factor FoxO1, acting via an upstream molecular target. Targeting of glycogen synthase kinase-3ß is proposed, based on the analogy with structurally related limonoids known to target this enzyme, and supported by a molecular docking analysis. The target and pathway implicated in ceramicine B activity are discussed. The analysis shed light on ceramicine B as a natural product precursor for the design of novel compounds capable of reducing LDA in cells and of potential interest for the treatment of obesity, liver diseases, and other pathologies.

Asunto(s)

Limoninas , Limoninas/farmacología , Limoninas/aislamiento & purificación , Limoninas/química , Animales , Humanos , Meliaceae/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Adipogénesis/efectos de los fármacos , Estructura Molecular

RESUMEN

Five new B-seco-limonoids, namely toonanoronoids A-E (1-5), in conjunction with three previously reported compounds, were isolated from the EtOAc extract of the twigs and leaves of Toona ciliata var. yunnanensis. Their structures were elucidated through comprehensive spectroscopic and X-ray crystallographic analysis. The cytotoxic activities of new compounds against five human tumor cell lines (HL-60, SMMC-7721, A549, MCF-7, and SW480) were screened, Compounds 4 and 5 exerted inhibition toward two tumor cell lines (HL-60, SW-480) with IC50 values between 1.7 and 5.9 µM.

Asunto(s)

Antineoplásicos Fitogénicos , Limoninas , Fitoquímicos , Hojas de la Planta , Toona , Humanos , Estructura Molecular , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Hojas de la Planta/química , Limoninas/aislamiento & purificación , Limoninas/farmacología , Limoninas/química , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , China , Toona/química , Tallos de la Planta/química

RESUMEN

Limonoids are extremely diversified in plants, with many categories of products bearing an intact, rearranged or fragmented oxygenated scaffold. A specific subgroup of fragmented or degraded limonoids derives from the tetranortriterpenoid prieurianin, initially isolated from the tree Trichilia prieuriana but also found in other plants of the Meliaceae family, including the more abundant species Aphanamixis polystachya. Prieurianin-type limonoids include about seventy compounds, among which are dregeanin and rohitukin. Prieurianin and analogs exhibit insecticidal, antimicrobial, antiadipogenic and/or antiparasitic properties but their mechanism of action remains ill-defined at present. Previous studies have shown that prieurianin, initially known as endosidin 1, stabilizes the actin cytoskeleton in plant and mammalian cells via the modulation of the architecture and dynamic of the actin network, most likely via interference with actin-binding proteins. A new mechanistic hypothesis is advanced here based on the recent discovery of the targeting of the chaperone protein Hsp47 by the fragmented limonoid fraxinellone. Molecular modeling suggested that prieurianin and, to a lesser extent dregeanin, can form very stable complexes with Hsp47 at the protein-collagen interface. Hsp-binding may account for the insecticidal action of the product. The present review draws up a new mechanistic portrait of prieurianin and provides an overview of the pharmacological properties of this atypical limonoid and its chemical family.

Asunto(s)

Insecticidas , Limoninas , Meliaceae , Animales , Limoninas/farmacología , Citoesqueleto de Actina , Actinas , Antiparasitarios , Insecticidas/farmacología , Mamíferos

RESUMEN

The insecticidal property of ring C-seco limonoids has been discovered empirically and the target protein identified, but, to date, the molecular mechanism of action has not been described at the atomic scale. We elucidate on computational grounds whether nine C-seco limonoids present sufficiently high affinity to bind specifically with the putative target enzyme of the insects (ecdysone 20-monooxygenase). To this end, 3D models of ligands and the receptor target were generated and their interaction energies estimated by docking simulations. As a proof of concept, the tetrahydro-isoquinolinyl propenamide derivative QHC is the reference ligand bound to aldosterone synthase in the complex with PDB entry 4ZGX. It served as the 3D template for target modeling via homology. QHC was successfully docked back to its crystal pose in a one-digit nanomolar range. The reported experimental binding affinities span over the nanomolar to lower micromolar range. All nine limonoids were found with strong affinities in the range of -9 < ΔG < -13 kcal/mol. The molt hormone ecdysone showed a comparable ΔG energy of -12 kcal/mol, whereas -11 kcal/mol was the back docking result for the liganded crystal 4ZGX. In conclusion, the nine C-seco limonoids were strong binders on theoretical grounds in an activity range between a ten-fold lower to a ten-fold higher concentration level than insecticide ecdysone with its known target receptor. The comparable or even stronger binding hints at ecdysone 20-monooxygenase as their target biomolecule. Our assumption, however, is in need of future experimental confirmation before conclusions with certainty can be drawn about the true molecular mechanism of action for the C-seco limonoids under scrutiny.

Asunto(s)

Insecticidas , Limoninas , Oxigenasas , Insecticidas/farmacología , Ecdisona , Limoninas/farmacología , Muda

RESUMEN

Limonin is a natural tetracyclic triterpenoid compound in citrus seeds that presents hepatoprotective effects but is often discarded as agricultural waste because of its low content and low solubility. Herein, limonin with high purity (98.11%) from citrus seeds was obtained via purification by high-speed counter-current chromatography (HSCCC) and recrystallization. Limonin-loaded liposomes (Lip-LM) prepared by thin film hydration and high pressure homogenization method to enhance its solubility and hepatoprotective effect on APAP-induced liver injury (AILI). Lip-LM appeared as lipid nanoparticles under a transmission electron microscope, and showed well dispersed nano-scale size (69.04 ± 0.42 nm), high encapsulation efficiency (93.67% ± 2.51%), sustained release, fine stability. Lip-LM also exhibited significantly better hepatoprotective activity on AILI than free limonin in vivo. In summary, Lip-LM might be used as a potential hepatoprotective agent in the form of dietary supplement and provide an effective strategy to improve the potential value of citrus seeds.

Asunto(s)

Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Citrus , Limoninas , Liposomas , Sustancias Protectoras , Semillas , Limoninas/aislamiento & purificación , Limoninas/farmacología , Citrus/química , Semillas/química , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ratones , Sustancias Protectoras/farmacología , Sustancias Protectoras/aislamiento & purificación , Masculino , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología

RESUMEN

A total of five new mexicanolides (1-5), namely alliaxylines A-E, together with two known limonoids 6 and 7, were isolated and identified from Dysoxylum alliaceum (Blume) Blume ex. A.Juss. (Meliaceae). The structures of these compounds were elucidated based on extensive spectroscopic analyses, including HR-ESI-MS, UV, IR, 1D, and 2D NMR, as well as theoretical stimulation of NMR shifts with the DP4 + algorithm. Consequently, this study aimed to examine cytotoxic activities of these compounds against MCF-7 and A549 cell lines. The results implied that compound 2 was the most potent against the two tested cells, with IC50 values of 34.95 ± 0.21 and 44.39 ± 1.03 µM.

Asunto(s)

Limoninas , Meliaceae , Corteza de la Planta , Humanos , Meliaceae/química , Corteza de la Planta/química , Limoninas/química , Limoninas/farmacología , Limoninas/aislamiento & purificación , Estructura Molecular , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Células MCF-7 , Células A549 , Línea Celular Tumoral , Espectroscopía de Resonancia Magnética , Extractos Vegetales/química , Extractos Vegetales/farmacología , Tallos de la Planta/química