Codelivery of ivermectin and methyl dihydrojasmonate in nanostructured lipid carrier for synergistic antileukemia therapy.

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.

Alliaxylines A-E: five new mexicanolides from the stem barks of Dysoxylum alliaceum (Blume) Blume ex A.Juss.

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.

Ceramicines U-Z from Chisocheton ceramicus and structure-antimalarial activity relationship study.

Ceramicines are a series of limonoids which were isolated from the barks of Malaysian Chisocheton ceramicus (Meliaceae), and were known to show various biological activity. Six new limonoids, ceramicines U-Z (1-6), with a cyclopentanone[α]phenanthrene ring system with a ß-furyl ring at C-17 were isolated from the barks of C. ceramicus. Their structures were determined on the basis of the 1D and 2D NMR analyses, and their absolute configurations were investigated by CD spectroscopy. Ceramicine W (3) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC50 value of 1.2 µM. In addition, the structure-antimalarial activity relationship (SAR) of the ceramicines was investigated to identify substituent patterns that may enhance activity. It appears that ring B and the functional groups in the vicinity of rings B and C are critical for the antimalarial activity of the ceramicines. In particular, bulky ester substituents with equatorial orientation at C-7 and C-12 greatly increase the antimalarial activity.

Erythrocarpines IN, new limonoids from the barks of Chisocheton erythrocarpus and their neuroprotective effects against hydrogen peroxide in NG108-15 cells.

A phytochemical study on the bark of Chisocheton erythrocarpus Hiern (Meliaceae) has led to the isolation of six new phragmalin-type limonoids named erythrocarpines I - N (1-6) along with one known limonoid, erythrocarpine F (7). Their structures were fully characterized by spectroscopic methods. The pre-treatment of NG108-15 cells with 1-5, 7 (2 h) demonstrated low to good protective effects against H2O2 exposure; 1 (83.77% ± 1.84 at 12.5 µM), 2 (69.07 ± 2.01 at 12.5 µM), 3 (80.38 ± 2.1 at 12.5 µM), 4 (62.33 ± 1.95 at 25 µM),5 (58.67 ± 1.85 at 50 µM) and 7 (66.07 ± 2.03 at 12.5 µM). Interestingly, 1 and 3 demonstrated comparable protective effects to positive control epigallocatechin gallate (EGCG) with similar cell viability capacity (≈ 80%), having achieved that at lower concentration (12.5 µM) than EGCG (50 µM). Collectively, the results suggested the promising use of 1 and 3 as potential neuroprotective agents against hydrogen peroxide-induced cytotoxicity in neuronal model.

Limonoids and alkaloids from Tetradium austrosinense (Hand.-Mazz.) T.G.Hartley.

A pair of new enantiomeric indolopyridoquinazoline-type alkaloids, (+)-1,7S,8R- and (-)-1,7R,8S-trihydroxyrutaecarpine (3a and 3b), and a new limonoid-tyrosamine hybrid, austrosinin (8), along with six known alkaloids and limonoids, were isolated from the stems with leaves of Tetradium austrosinense. Their structures were elucidated on the basis of analysis of MS, NMR, ECD and time-dependent density functional theory-based electronic circular dichroism (TDDFT-ECD) calculations, as well as proposed biosynthetic pathway. An anti-inflammatory bioassay in vitro showed 8 had significant immunosuppressive effect against the production of pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.

B-seco Limonoids with anti-inflammatory activity from Tetradium fraxinifolium (Hook.) T.G.Hartley.

Fraxinifolines A-F (1-6), six new B-seco limonoids, together with four known A,D-di-seco ones, were isolated from the twigs with leaves of Tetradium fraxinifolium. Their structures with absolute configurations were elucidated on the basis of analysis of MS, NMR, single-crystal X-ray diffraction and biogenetic pathway. An anti-inflammatory bioassay in vitro showed limonoids 1-3 had significant immunosuppressive effect against the production of pro-inflammatory cytokines (IL-1ß and/or TNF-α) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.

Xylomolins O-X: New limonoids from the Thai mangrove Xylocarpus moluccensis.

Ten new limonoids, named xylomolins O-X, were isolated from seeds of the mangrove Xylocarpus moluccensis, collected in the mangrove swamp of Trang Province, Thailand. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis. The absolute configurations of five compounds (1, 3, 8-10) were unequivocally determined by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation. Xylomolins OU (1-7) are structurally intriguing mexicanolides, and xylomolin V (8) is a derivative of azadirone. Xylomolin W (9) is the first phragmalin 1,8,9-orthoester with report on X-ray crystallography from the genus Xylocarpus. In addition, xylomolin X (10) is the fifth member of the khayalactone class of limonoids with a hexahydro-2H-2,5-propanocyclopenta[b]furan motif. Compounds 1-10 inhibited NO production in LPS-activated RAW 264.7 macrophages in the range of 10.45-95.47% at the concentration of 100.0 µM. Xylomolin X (10) and xylomolin V (8), exhibited the most potent activity with IC50 values of 9.90 ± 1.84 µM and 14.66 ± 2.33 µM, respectively.

Antimalarial ceramicines Q-T from Chisocheton ceramicus.

Ceramicines are a series of limonoids that were isolated from the bark of Malaysian Chisocheton ceramicus (Meliaceae) and were known to show various biological activity. Four new limonoids, ceramicines Q-T (1-4) were isolated from the barks of C. ceramicus, and their structures were determined on the basis of the 1D and 2D NMR analyses in combination with calculated 13C chemical shift data. Ceramicines Q-T (1-4) were established to be new limonoids with a cyclopentanone[α]phenanthren ring system with a ß-furyl ring at C-17, and without a tetrahydrofuran ring like ceramicine B, which is characteristic of known ceramicines. Ceramicine R (2) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC50 value of 2.8 µM.

Munronin V with 7/7/6 tricarbocyclic framework from Munronia henryi harms inhibits tau pathology by activating autophagy.

Munronin V (1), isolated from Munronia henryi Harms, is the first example, to the best of our knowledge, of an unprecedented 7/7/6 tricarbocyclic framework featuring an unusual A,B-seco-limonoid ring. The structures of munronin V were established from extensive spectroscopic and electronic circular dichroism (ECD) analyses. The novel A,B-seco with two seven-membered lactones was formed as a result of Baeyer-Villiger oxidation. Compound 1 activated autophagy and inhibited Tau pathology as revealed by flow cytometric analyses, confocal imaging analysis and western blotting, and this effect was mediated by transcription factor EB (TFEB). These findings suggested that 1 might have potential as a compound for combating Alzheimer's disease.

Identification of limonoids from Walsura yunnanensis and evaluation of their cytotoxicity against cancer cell lines.

Three new limonoids, walsurauias A-C (1-3), along with four known ones, were isolated from the leaves and twigs of Walsura yunnanensis C. Y. Wu. Their structures were determined on the basis of comprehensive spectroscopic data analysis. The new limonoids were screened for their cytotoxic activity (IC50 0.81-5.73 µM) against four human cancer cell lines, including A549, HepG2, HCT116 p21KO and CNE-2. And α,ß-unsaturated ketone moieties in rings A and B are essential for their cytotoxic activity. Selected compounds were further investigated. Compounds 1-3 effectively induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner in cancer cells. In addition, compounds 1-3 inhibited the colony formation and compounds 2 and 3 suppressed the migration of cancer cells.

Bioassay-guided isolation of vilasinin-type limonoids and phenyl alkene from the leaves of Trichilia gilgiana and their antiplasmodial activities.

Bioassay-guided fractionation of the CH2Cl2-MeOH (1:1) leaves extract of Trichilia gilgiana, yielded two new vilasinin-type limonoids named gilgianin A (1) and gilgianin B (2), one new phenyl alkene derivative designated as gilgialkene A (3), along with six known compounds: rubescin H (4), TS3 (5), trichirubine A (6), sitosteryl-6'-O-undecanoate-ß-D-glucoside (7), scopoletin (8), and octadecane-2-one (9). Their structures were elucidated based on spectroscopic analysis and comparison with literature data. Compounds 5 and 6 exhibited the highest antiplasmodial activity with IC50 values of 1.14 and 1.32 µM respectively. Moreover, compound 5 was very cytotoxic with CC50 value of 0.88 µM, compared to compound 6, which was not cytotoxic (CC50 > 10 µg/mL). Compounds 1 (IC50 = 9.84 µM), 2 (IC50 = 11.04 µM) and 4 (IC50 = 10.71 µM) presented good antiplasmodial activity while also exhibiting significant cytotoxicity, with CC50 values ranging from of 14.45 to 29.7 µM.[Formula: see text].

Insecticidal Triterpenes in Meliaceae: Plant Species, Molecules and Activities: Part â (Aphanamixis-Chukrasia).

Plant-originated triterpenes are important insecticidal molecules. The research on insecticidal activity of molecules from Meliaceae plants has always received attention due to the molecules from this family showing a variety of insecticidal activities with diverse mechanisms of action. In this paper, we discuss 102 triterpenoid molecules with insecticidal activity of plants of eight genera (Aglaia, Aphanamixis, Azadirachta, Cabralea, Carapa, Cedrela, Chisocheton, and Chukrasia) in Meliaceae. In total, 19 insecticidal plant species are presented. Among these species, Azadirachta indica A. Juss is the most well-known insecticidal plant and azadirachtin is the active molecule most widely recognized and highly effective botanical insecticide. However, it is noteworthy that six species from Cedrela were reported to show insecticidal activity and deserve future study. In this paper, a total of 102 insecticidal molecules are summarized, including 96 nortriterpenes, 4 tetracyclic triterpenes, and 2 pentacyclic triterpenes. Results showed antifeedant activity, growth inhibition activity, poisonous activity, or other activities. Among them, 43 molecules from 15 plant species showed antifeedant activity against 16 insect species, 49 molecules from 14 plant species exhibited poisonous activity on 10 insect species, and 19 molecules from 11 plant species possessed growth regulatory activity on 12 insect species. Among these molecules, azadirachtins were found to be the most successful botanical insecticides. Still, other molecules possessed more than one type of obvious activity, including 7-deacetylgedunin, salannin, gedunin, azadirone, salannol, azadiradione, and methyl angolensate. Most of these molecules are only in the primary stage of study activity; their mechanism of action and structure-activity relationship warrant further study.

Trichilones A-E: New Limonoids from Trichilia adolfi.

In addition to the trichilianones A-D recently reported from Trichilia adolfi, a continuing investigation of the chemical constituents of the ethanol extract of the bark of this medicinal plant yielded the five new limonoids 1-5. They are characterized by having four fused rings and are new examples of prieurianin-type limonoids, having a ε-lactone which in 4 and 5 is α, ß- unsaturated. The structures of the isolated metabolites were determined by high field NMR spectroscopy and HR mass spectrometry. The new metabolites were shown to have the ε-lactone fused with a tetrahydrofuran ring which is connected to an oxidized hexane ring joined with a cyclo-pentanone having a 3-furanyl substituent. As the crude extract possesses antileishmanial activity, the compounds were assayed for cytotoxic and antiparasitic activities in vitro in murine macrophage cells (raw 264.7 cells) and in Leishmania amazoniensis as well as L. braziliensis promastigotes. Metabolites 1-3 and 5 showed moderate cytotoxicity (between 30-94 µg/mL) but are not responsible for the antileishmanial effect of the extract.

iRGD conjugated nimbolide liposomes protect against endotoxin induced acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a deadly respiratory illness associated with refractory hypoxemia and pulmonary edema. The recent pandemic outbreak of COVID-19 is associated with severe pneumonia and inflammatory cytokine storm in the lungs. The anti-inflammatory phytomedicine nimbolide (NIM) may not be feasible for clinical translation due to poor pharmacokinetic properties and lack of suitable delivery systems. To overcome these barriers, we have developed nimbolide liposomes conjugated with iRGD peptide (iRGD-NIMLip) for targeting lung inflammation. It was observed that iRGD-NIMLip treatment significantly inhibited oxidative stress and cytokine storm compared to nimbolide free-drug (f-NIM), nimbolide liposomes (NIMLip), and exhibited superior activity compared to dexamethasone (DEX). iRGD-NIMLip abrogated the LPS induced p65 NF-κB, Akt, MAPK, Integrin ß3 and ß5, STAT3, and DNMT1 expression. Collectively, our results demonstrate that iRGD-NIMLip could be a promising novel drug delivery system to target severe pathological consequences observed in ARDS and COVID-19 associated cytokine storm.

Toonaolides A-X, limonoids from Toona ciliata: Isolation, structural elucidation, and bioactivity against NLRP3 inflammasome.

Twenty-four new limonoids, toonaolides A-X (1-24), characterized with an α,ß-unsaturated-γ-lactone A-ring were isolated from the twigs of Toona ciliata. Their structures and absolute configurations were elucidated by spectroscopic data, X-ray diffraction crystallography, and quantum chemistry calculations. Most of the isolated compounds (except 9, 18, and 24 which possessed the maleimide ring) featured the rare 21-hydroxybutenolide or 23-hydroxybutenolide moieties. In particular, compound 1 has an unprecedented limonoid architecture with 6/6 cis-fused A/B ring system and 2 has an unusual tetrahydrofuran ring B skeleton, featuring a 7/5/6/5 ring system. The biological evaluation showed that compounds 9, 11, 12, 14, and 18 exhibited significantly anti-NLRP3 inflammasome activity with IC50 values ranging from 3.2 to 9.7 µM. Analysis of IL-1ß and caspase-1 expression revealed that compounds 11 and 12 are selective inhibitors of NLRP3 inflammasome, which could ameliorate cell pyroptosis by blocking NLRP3 inflammasome activation.

1-Cinnamoyltrichilinin from Melia azedarach Causes Apoptosis through the p38 MAPK Pathway in HL-60 Human Leukemia Cells.

Acute myeloid leukemia (AML) is an aggressive type of human leukemia with a low survival rate, and its complete remission remains challenging. Although chemotherapy is the first-line treatment of AML, it exerts toxicity in noncancerous cells when used in high doses, thus necessitating the development of novel compounds with a high therapeutic window. This study aimed to investigate the anticancer effects of several compounds derived from the fruits of Melia azedarach (a tree with medicinal properties). Among them, 1-cinnamoyltrichilinin (CT) was found to strongly suppress the viability of HL-60 human leukemia cells. CT treatment induced apoptosis and increased nuclear fragmentation and fractional DNA content in HL-60 cells in a dose-dependent manner. CT induced phosphorylation of p38 mitogen-activated protein kinases (p38), though not of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and activated Bcl-2 family proteins towards the proapoptosis and cleavage of caspase-3 and poly (ADP-ribose) polymerase. Both CT-mediated apoptosis and apoptotic protein expression were reversed by treatment with the p38 inhibitor, thereby indicating the p38 pathway to be critical in CT-stimulated apoptosis. The results collectively indicated CT to suppress HL-60 survival by activating the p38 pathway and inducing apoptosis, hence being a novel potential therapeutic agent for AML.

Limonoids from the Fresh Young Leaves and Buds of Toona sinensis and Their Potential Neuroprotective Effects.

Toona sinensis, popularly known as Chinese toon or Chinese mahogany, is a perennial deciduous arbor belonging to the genus Toona in the Meliaceae family, which is widely distributed and cultivated in eastern and southeastern Asia. Its fresh young leaves and buds have been consumed as a very popular nutritious vegetable in China and confirmed to display a wide variety of biological activities. To investigate the chemical constituents and their potential health benefits from the fresh young leaves and buds of T. sinensis, a phytochemical study on its fresh young leaves and buds was therefore undertaken. In our current investigation, 16 limonoids (1-16), including four new limonoids, toonasinenoids A-D (1-4), and a new naturally occurring limonoid, toonasinenoid E (5), were isolated and characterized from the fresh young leaves and buds of T. sinensis. The chemical structures and absolute configurations of limonoids 1-5 were elucidated by comprehensive spectroscopic data analyses. All known limonoids (6-16) were identified via comparing their experimental spectral data containing mass spectrometry data, 1H and 13C nuclear magnetic resonance data, and optical rotation values to the data reported in the literature. All known limonoids (6-16) were isolated from T. sinensis for the first time. Furthermore, the neuroprotective effects of all isolated limonoids 1-16 against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells were assessed in vitro. Limonoids 1-16 exhibited notable neuroprotective activities, with EC50 values in the range from 0.27 ± 0.03 to 17.28 ± 0.16 µM. These results suggest that regular consumption of the fresh young leaves and buds of T. sinensis might prevent the occurrence and development of Parkinson's disease (PD). Moreover, the isolation and characterization of these limonoids that exhibit notable neuroprotective activities from the fresh young leaves and buds of T. sinensis could be very significant for researching and developing new neuroprotective drugs used for the prevention and treatment of PD.

Chemical Constituents from Citrus changshan-huyou and Their Anti-Inflammatory Activities.

A systematically chemical investigation of Citrus changshan-huyou Y.B.Chang resulted in the isolation and structure determination of twelve known natural products, including limonoid, nootkatone, scoparone, ß-sitosterol, 3,3',4',5,6,7,8,-heptamethoxyflavone, nobiletin, tangeretin, naringin, hesperidin, neohesperidin, 3,5-dihydroxyphenyl ß-D-glucoside, ß-sitosterol-D-glucoside. The structure modification of the most abundant compound limonin further led to eight limonoid derivatives, including epi-limonol, epi-limonyl acetate, and six new compounds epi-limonol A, limonol A, limonol B, epi-limonol B, epi-limonol C, epi-limonol D, which enlarged the chemical diversity of limonin related limonoids. The structures of the new limonoid derivatives were identified by extensive spectroscopic analysis. In bioassay, all the isolates, the semi-synthetic derivatives and the previously isolated limonoids in our natural product library were subjected for anti-inflammatory activities evaluation, and several limonoids exhibited the inhibition of TNF-α release.

Angiogenic and anti-inflammatory properties of azadirachtin A improve random skin flap survival in rats.

Random skin flaps are widely used to repair tissue defects. However, the distal flap regions are prone to ischemic necrosis, limiting clinical applications. Azadirachtin A, a fruit extract from the neem, improves tissue blood supply and metabolism, reduces cell swelling, promotes tissue healing, and prevents venous thrombosis. We explored whether it enhances random skin flap survival. Fifty-four Sprague-Dawley rats were divided into control, low-dose, and high-dose Azadirachtin A-treated groups using a random number table. We used an improved version of the McFarlane technique to create flaps. On day 2, superoxide dismutase and malondialdehyde levels were measured. Tissue slices prepared on day 7 were stained with hematoxylin and eosin. The expression levels of vascular endothelial growth factor (VEGF), toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-kB), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were immunohistochemically assayed. Microcirculatory blood flow was measured via laser Doppler blood flowmetry. Flap angiography was performed using the lead-oxide gelatin injection technique. And the azadirachtin A groups exhibited a greater mean flap survival area, an improved mean blood vessel density, a greater blood flow, and higher superoxide dismutase and VEGF levels, especially at the high dose. Azadirachtin A markedly reduced the levels of TNF-α, IL-6, IL-1ß, TLR4, and NF-kB. These findings suggest that azadirachtin A promotes random skin flap survival by improving the blood supply, reducing tissue inflammation, and inhibiting flap ischemia reperfusion injury.

Eco-Friendly Castor Oil-Based Delivery System with Sustained Pesticide Release and Enhanced Retention.

The deposition of pesticides and their retention on plant surfaces are critical challenges for modern precision agriculture, which directly affect phytosanitary treatment, bioavailability, efficacy, and the loss of pesticides. Herein, a novel and eco-friendly waterborne polyurethane delivery system was developed to enhance the spray deposition and pesticide retention on plant surfaces. More specifically, biobased cationic and anionic waterborne polyurethane dispersions were synthesized from castor oil. Both cationic and anionic polyurethane dispersions exhibited remarkable microstructural, amphiphilic, and nanoparticle morphologies with a core-shell structure that served to encapsulate a biopesticide (azadirachtin) in their hydrophobic cores (WPU-ACT). The results indicated that the cationic WPU-ACT carriers exhibited a better sustained release behavior and a better protective effect from light and heat for azadirachtin. In addition, the simultaneous spray of anionic and cationic WPU-ACT significantly enhanced the spray deposition and prolonged the retention of pesticides due to the reduced surface tension and surface precipitation induced by the electrostatic interaction when two droplets with opposite charges come into contact with each other. A field efficacy assessment also indicated that the simultaneous spray of anionic and cationic WPU-ACT could control the infestation of brown planthopper in rice crops. Castor oil-based waterborne polyurethanes in this study work as an efficient pesticide delivery system by exhibiting enhanced deposition, rainfastness, retention ability, protection, and sustained release behavior, holding great promise for spraying pesticide formulations in modern and environmentally friendly agricultural applications.