Evaluating larvicidal, ovicidal and growth inhibiting activity of five medicinal plant extracts on Culex pipiens (Diptera: Culicidae), the West Nile virus vector.

Mosquitoes, one of the deadliest animals on the planet, cause millions of fatalities each year by transmitting several human illnesses. Synthetic pesticides were previously used to prevent the spread of diseases by mosquitoes, which was effective in protecting humans but caused serious human health problems, environmental damage, and developed mosquito pesticide resistance. This research focuses on exploring new, more effective, safer, and environmentally friendly compounds to improve mosquito vector management. Phytochemicals are possible biological agents for controlling pests and many are target-specific, rapidly biodegradable, and eco-friendly. The potential of extracts of Lantana camara, Melia azedarach, Nerium oleander, Ricinus communis, and Withania somnifera against 3rd instar Culex pipiens (Common house mosquito) larvae was evaluated. Methanol extracts had more toxic effects against Cx. pipiens larvae (95-100%, 24 h post-treatment) than aqueous extracts (63-91%, 24 h post-treatment). The methanol extracts of Nerium oleander (LC50 = 158.92 ppm) and Ricinus communis (LC50 = 175.04 ppm) were very effective at killing mosquito larvae, 24 h after treatment. N. oleander (LC50 = 373.29 ppm) showed high efficacy in aqueous plant extracts. Among the different extracts of the five plants screened, the methanol extract of R. communis recorded the highest ovicidal activity of 5% at 800 ppm concentration. Total developmental duration and growth index were highly affected by R. communis and M. azedarach methanol extracts. In field tests it was clear that plant extracts decreased mosquito larval density, especially when mixed with mosquito Bti briquette, with stability up to seven days for N. oleander. GC-MS results showed that the methanol extract had a higher number of chemical compounds, particularly with more terpene compounds. A high-performance liquid chromatography (HPLC) technique was used to detect the existence of non-volatile polyphenols and flavonoids. All five methanol extracts showed high concentrations of active ingredients such as gallic acid, chlorogenic acid (more than 100 µg/ml) and the rosmarinic acid was also found in all the five extracts in addition to 17 active polyphenols and flavonoids presented at moderate to low concentrations. Molecular modeling of 18 active ingredients detected by the HPLC were performed to the vicinity of one of the fatty acid binding proteins of lm-FABP (PDB code: 2FLJ). Rutin, Caffeic acid, coumaric acid and rosmarinic acid which presented densely in R. communis and N. oleander showed multiple and stable intermolecular hydrogen bonding and π-π stacking interactions. The inhibition ability of the fatty acid binding protein, FABP4, was evaluated with remarkable receptor inhibition evident, especially with R. communis and N. oleander having inhibitory concentrations of IC50 = 0.425 and 0.599 µg/mL, respectively. The active phytochemical compounds in the plants suggest promising larvicidal and ovicidal activity, and have potential as a safe and effective alternative to synthetic insecticides.

Effects of Melia azedarach extract on demographic and biochemical characteristics of the cabbage aphid, Brevicoryne brassicae.

The cabbage aphid, Brevicoryne brassicae L. (Aphididae: Hemiptera) a destructive aphid, is native to Europe and is now found in many other parts of the world. Currently, one of the main problems of Iranian cabbage growers is the significant damage caused by this pest. Also, due to the fresh eating of cabbage, it is necessary to use non-chemical methods to control the pests. Our bioassay tests showed that Melia azedarach L. (Meliaceae) fruit extract showed high toxicity to cabbage aphid. In this study, sublethal effects of M. azedarach extract was investigated on some demographic and biochemical properties of B. brassicae. The results showed that the sublethal concentrations (LC10 and LC20) and LC50 values were 0.68, 1.16, and 3.42 µg/ml, respectively. Compared to the control, sublethal concentrations of insecticide significantly decreased the gross reproductive rate (GRR), net reproductive rate (R0), intrinsic rate of increase (rm), finite rate of increase (λ), intrinsic rate of birth (b), intrinsic rate of death (d), weekly growth rate (rw), reproductive rate and adult longevity of the pest. Meanwhile, the mean generation time (T) and population doubling time (DT) of this aphid increased significantly. Additionally, sublethal doses of insecticide reduced the energy reserves of the pest such as carbohydrate, protein and lipid content compared to the controls. In addition to modify the pH, this extract also changed the distribution and concentration of sodium and potassium ions in haemolymph. Therefore, sublethal concentrations of M. Azedarach fruit extract can be used in the management program of B. brassicae.

Improvement and prediction of the extraction parameters of lupeol and stigmasterol metabolites of Melia azedarach with response surface methodology.

BACKGROUND: Melia azedarach is known as a medicinal plant that has wide biological activities such as analgesic, antibacterial, and antifungal effects and is used to treat a wide range of diseases such as diarrhea, malaria, and various skin diseases. However, optimizing the extraction of valuable secondary metabolites of M. azedarach using alternative extraction methods has not been investigated. This research aims to develop an effective, fast, and environmentally friendly extraction method using Ultrasound-assisted extraction, methanol and temperature to optimize the extraction of two secondary metabolites, lupeol and stigmasterol, from young roots of M. azedarach using the response surface methodology. METHODS: Box-behnken design was applied to optimize different factors (solvent, temperature, and ultrasonication time). The amounts of lupeol and stigmasterol in the root of M. azedarach were detected by the HPLC-DAD. The required time for the analysis of each sample by the HPLC-DAD system was considered to be 8 min. RESULTS: The results indicated that the highest amount of lupeol (7.82 mg/g DW) and stigmasterol (6.76 mg/g DW) was obtained using 50% methanol at 45 °C and ultrasonication for 30 min, and 50% methanol in 35 °C, and ultrasonication for 30 min, respectively. Using the response surface methodology, the predicted conditions for lupeol and stigmasterol from root of M. azedarach were as follows; lupeol: 100% methanol, temperature 45 °C and ultrasonication time 40 min (14.540 mg/g DW) and stigmasterol 43.75% methanol, temperature 34.4 °C and ultrasonication time 25.3 min (5.832 mg/g DW). CONCLUSIONS: The results showed that the amount of secondary metabolites lupeol and stigmasterol in the root of M. azedarach could be improved by optimizing the extraction process utilizing response surface methodology.

Limonoids from the roots of Melia azedarach and their anti-inflammatory activity.

Twelve undescribed limonoids, meliazedarines J-U (1-12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1-8 were identified as ring intact limonoids, while compounds 9-12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1-4, 6, 8, 9, and 11-13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 µΜ. Furthermore, compound 3 effectively reduced interleukin-1ß secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.

Phytochemical and Antioxidant Profile of the Medicinal Plant Melia azedarach Subjected to Water Deficit Conditions.

Environmental stress triggered by climate change can alter the plant's metabolite profile, which affects its physiology and performance. This is particularly important in medicinal species because their economic value depends on the richness of their phytocompounds. We aimed to characterize how water deficit modulated the medicinal species Melia azedarach's lipophilic profile and antioxidant status. Young plants were exposed to water deficit for 20 days, and lipophilic metabolite profile and the antioxidant capacity were evaluated. Leaves of M. azedarach are rich in important fatty acids and oleamide. Water deficit increased the radical scavenging capacity, total phenol, flavonoids, and catechol pools, and the accumulation of ß-sitosterol, myo-inositol, succinic acid, sucrose, d-glucose and derivatives, d-psicofuranose, d-(+)-fructofuranose, and the fatty acids stearic, α-linolenic, linoleic and palmitic acids. These responses are relevant to protecting the plant against climate change-related stress and also increase the nutritional and antioxidant quality of M. azedarach leaves.

Triterpenoids from the fruits of Melia azedarach L. and their cytotoxic activities.

Eleven undescribed tetracyclic triterpenoids, meliazedarachins A-K, along with twenty-six known compounds were isolated from the fruits of Melia azedarach L.. Their structures were determined by HRESIMS, UV, IR, NMR, X-ray diffraction, electronic circular dichroism (ECD) spectra, and the modified Mosher's method. The cytotoxic activities of all the isolates were measured. Meliazedarachin K and mesendanin N showed cytotoxicity against five human cancer cell lines with IC50 values ranging from 9.02 to 31.31 µM. Meliazedarachin K showed significant cytotoxicity against HCT116 cell line with IC50 value of 9.02 ± 0.84 µM. 21α-methylmelianodiol showed significant cytotoxicity against HCT116 and RKO cell lines with IC50 values of 10.16 ± 1.22 and 8.57 ± 0.80 µM, respectively.

The Development of a Green Innovative Bioactive Film for Industrial Application as a New Emerging Technology to Protect the Quality of Fruits.

Today, the most significant challenge encountered by food manufacturers is degradation in the food quality during storage, which is countered by expensive packing, which causes enormous monetary and environmental costs. Edible packaging is a potential alternative for protecting food quality and improving shelf life by delaying microbial growth and providing moisture and gas barrier properties. For the first time, the current article reports the preparation of the new films from Ditriterpenoids and Secomeliacins isolated from Melia azedarach (Dharek) Azadirachta indica plants to protect the quality of fruits. After evaluating these films, their mechanical, specific respirational, coating crystal elongation, elastic, water vapor transmission rate (WVTR), film thickness, and nanoindentation test properties are applied to apple fruit for several storage periods: 0, 3, 6, 9 days. The fruits were evaluated for postharvest quality by screening several essential phytochemical, physiological responses under film coating and storage conditions. It was observed that prepared films were highly active during storage periods. Coated fruits showed improved quality due to the protection of the film, which lowered the transmission rate and enhanced the diffusion rate, followed by an increase in the shelf life. The coating crystals were higher in Film-5 and lower activity in untreated films. It was observed that the application of films through dipping was a simple technique at a laboratory scale, whereas extrusion and spraying were preferred on a commercial scale. The phytochemicals screening of treated fruits during the storage period showed that a maximum of eight important bioactive compounds were present in fruits after the treatment of films. It was resolved that new active films (1-5) were helpful in the effective maintenance of fruit quality and all essential compounds during storage periods. It was concluded that these films could be helpful for fruits growers and the processing industry to maintain fruit quality during the storage period as a new emerging technology.

Phytochemical composition of almond oil from Melia azedarach L. and its larvicidal, ovicidal, repellent and enzyme activities in Culex pipiens L.

Melia azedarach L. (Meliaceae) is a botanical species with focal point of global research for its biological properties. The Melia azedarach tree is distinguished by its rapid growth, its adaptation to different temperate zones, as well as its insecticidal properties. All this made us think of exploiting it in biological control against different stages of mosquitoes. To this end, we aim, through the present work, to evaluate the effectiveness of Melia azedarach extracts against Culex pipiens mosquito. More specifically, our study focuses on determining the chemical composition of Melia almond oil, as well as the larvicidal, ovicidal and repellent activities on Culex pipiens L. mosquito as well as the activities of acetylcholinesterase (AChE) and glutathione-S-transferase (GST). Almond oil was extracted by a Soxhlet and subjected to gas chromatography-mass spectrometry (GC/MS). The yield was found to be 35.17%. The chemical composition revealed the presence of various phytoconstituents. A total of 7 compounds were identified, the main ones being 9,11-Octadecadienoic acid, methyl ester, (E,E)- (79.32%), 9-octadecenoic acid (Z)-, methyl ester (13.24%), hexadecanoic acid and methyl ester (3.69%). The larvicidal bioassays were performed according to the protocol recommended by the World Health Organization with concentrations varying from 20 to 80 mg/L depending on the exposure time (24, 48 and 72 hours). The almond oil exhibited remarkable larvicidal activity against fourth instar larvae and the lethal concentrations were determined (LC25= 23.70 mg/L, LC50=35.49 mg/L, LC90=79.61 mg/L). The results also showed that the oil caused an ovicidal activity with a significant effect on egg hatch. The recorded hatching percentages were respectively 88.79% and 72.40% for the LC25 and LC50, and this compared to the control series. Moreover, this oil exhibited significant repellency against adult mosquitoes. Furthermore, the enzymatic measurements performed on LC50 and LC90 treated larvae revealed a neurotoxic activity and a stimulation of the detoxification system as evidenced, respectively, by an inhibition of AChE and induction in GST activity. Overall, our data proved that Melia azedarach almond oil could be considered as a potent biorational alternative to synthetic insecticides for mosquito control.

Pregnane Steroids from the Leaves of Melia Azedarach and Apoptotic Activity against T47D Cells.

OBJECTIVE: Nature has provided us with many pharmaceutical resources so far. Breast cancer shows an increasing trend in the world for the last decade and becomes one of five leading causes of death. Among the plants, Melia azedarach L. has been used widely in traditional medicine for many ailments including breast cancer. Following our previous findings that the ethyl acetate fraction was the most active cytotoxic fraction against T47D cells, we aimed to isolate the cytotoxic compounds and further elucidate their apoptotic mechanisms. METHODS: The compounds were isolated through a series of chromatography with cytotoxicity evaluations. Identification of the isolated compounds was achieved by intensive spectroscopic analysis such as NMR, MS, and IR spectra. Cytotoxicity was evaluated by MTT method using doxorubicin as a reference compound. The expression of apoptosis-related factors was quantified by flow cytometry and immunocytochemistry. RESULTS: Two isomers of pregnane steroids with molecular weight 330.2087 (C21H30O3) were isolated from the EtOAc extract. Spectroscopic analysis revealed the structures as 17-ethylene-3,4-dihydroxy-14-methyl-18-norandrostene-16-one (1) and 17-ethylene-3,4-dihydroxy-5-pregnene-16-one (2), respectively. These compounds showed moderate cytotoxicity (IC50 172.9 and 62.2 µg/mL, respectively) comparable to doxorubicin (IC50 3.08 µg/mL). The execution of apoptosis may be related to the increase of the ratio of BAX/bcl-2 of the cells.  Conclusion: The EtOAc fraction of Melia azedarach L. leaves and the isolated 5-pregnene-16-one steroids are promising reagents for breast cancer treatment by introducing apoptosis to tumor cells. However, further researches are required to highlight its safety and usage in vivo.
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Phytochemical Investigations and In Vitro Bioactivity Screening on Melia azedarach L. Leaves Extract from Nepal.

Melia azedarach is a common tree used in the traditional medicine of Nepal. In this work, leaves were considered as source of bioactive constituents and composition of methanol extract was evaluated and compared with starting plant material. Flavonoid glycosides and limonoids were identified and quantified by HPLC-DAD-MSn approaches in dried leaves and methanolic extract, while HPLC-APCI-MSn and GC/MS analysis were used to study phytosterol and lipid compositions. ß-Sitosterol and rutin were the most abundant constituents. HPLC-APCI-MSn and HPLC-DAD-MSn analysis revealed high levels of phytosterols and flavonoids in methanolic extract accounting 9.6 and 7.5 % on the dried weight, respectively. On the other hand, HPLC/MSn data revealed that limonoid constituents were in minor amount in the extract <0.1 %, compared with leaves (0.7 %) indicating that degradation occurred during extraction or concentration procedures. The methanol extract was subjected to different bioassays, and antioxidant activity was evaluated. Limited inhibitory activity on acetyl and butyryl cholinesterase, as well as on amylase were detected. Moreover, tyrosinase inhibition was significant resulting in 131.57±0.51 mg kojic acid equivalents/g of dried methanol extract, suggesting possible use of this M. azedarach extract in skin hyperpigmentation conditions. Moderate cytotoxic activity, with IC50 of 26.4 µg/mL was observed against human ovarian cancer cell lines (2008 cells). Our findings indicate that the Nepalese M. azedarach leaves can be considered as valuable starting material for the extraction of phenolics and phytosterols, yielding extracts with possible cosmetic and pharmaceutical applications.

Chemical Components of Aqueous Extracts of Melia azedarach Fruits and Their Effects on The Transcriptome of Staphylococcus aureus.

Staphylococcus aureus is the causative agent of numerous and varied clinical infections. Crude aqueous extracts of Melia azedarach fruits inhibit the planktonic growth and initial biofilm formation of S. aureus in a dose-dependent manner. Moreover, the biofilm topologies became sparse and decreased as the concentration of the aqueous extracts increased. RNA-Seq analyses revealed 532 differentially expressed genes (DEGs) after S. aureus exposure to 0.25 g/ml extracts; 319 of them were upregulated, and 213 were downregulated. The majority of DEGs were categorized into abundant sub-groups in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, untargeted UHPLC-MS/MS analyses of the aqueous extracts of M. azedarach fruits demonstrated a highly complex profile in positive and negative electrospray ionization modes. The extracts primarily consisted of lipids and lipid-like molecules, organic acids and their derivatives, phenylpropanoids, polyketides, organoheterocyclic compounds, and benzenoids annotated by abundant lipid maps and KEGG pathways. Overall, this study provides evidences that the aqueous extracts of M. azedarach fruits can control S. aureus infections and sought to understand the mode of action of these extracts on S. aureus.

Bioactive Limonoids and Triterpenoids from the Fruits of Melia azedarach.

Nine new limonoids, meliazedarines A-I (1-9), seven known analogues (10-16), and five known triterpenoids (17-21) were isolated from the fruits of Melia azedarach. Their structures were determined by analysis of 1D and 2D NMR, HRESIMS, X-ray diffraction, and electronic circular dichroism (ECD) data. Compound 7 showed significant cytotoxicity against the HCT116 cell line with IC50 values of 0.3 ± 0.1 µM.

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.

Phosphoric Acid Activated Carbon from Melia azedarach Waste Sawdust for Adsorptive Removal of Reactive Orange 16: Equilibrium Modelling and Thermodynamic Analysis.

Waste wood biomass as precursor for manufacturing activated carbon (AC) can provide a solution to ever increasing global water quality concerns. In our current work, Melia azedarach derived phosphoric acid-treated AC (MA-AC400) was manufactured at a laboratory scale. This novel MA-AC400 was tested for RO16 dye removal performance as a function of contact time, adsorbent dosage, pH, temperature and initial dye concentration in a batch scale arrangement. MA-AC400 was characterized via scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, dynamic light scattering (DLS) and fluorescence spectroscopy. MA-AC400 is characterized as mesoporous with BET surface area of 293.13 m2 g-1 and average pore width of 20.33 Å. pHPZC and Boehm titration confirm the acidic surface charges with dominance of phenolic functional groups. The average DLS particle size of MA-AC400 was found in the narrow range of 0.12 to 0.30 µm and this polydispersity was confirmed with multiple excitation fluorescence wavelengths. MA-AC400 showed equilibrium adsorption efficiency of 97.8% for RO16 dye at its initial concentration of 30 mg L-1 and adsorbent dose of 1 g L-1. Thermodynamic study endorsed the spontaneous, favorable, irreversible and exothermic process for RO16 adsorption onto MA-AC400. Equilibrium adsorption data was better explained by Langmuir with high goodness of fit (R2, 0.9964) and this fitness was endorsed with lower error functions. The kinetics data was found well fitted to pseudo-second order (PSO), and intra-particle diffusion kinetic models. Increasing diffusion constant values confirm the intraparticle diffusion at higher RO16 initial concentration and reverse was true for PSO chemisorption kinetics. MA-AC400 exhibited low desorption with studied eluents and its cost was calculated to be $8.36/kg.

Determination of toosendanin and trans-anethole in Fructus Meliae Toosendan and Fructus Foeniculi by HPLC-MS/MS and GC-MS/MS in rat plasma and their potential herb-herb interactions.

ETHNOPHARMACOLOGICAL RELEVANCE: The objective of traditional Chinese medicine (TCM) combination theory is to "reduce toxicity and increase efficiency", especially to solve the liver toxicity of many TCMs. Fructus Meliae Toosendan (CLZ)-Fructus Foeniculi (XHX) is a typical traditional Chinese herb pair that decreases the toxicity and increases the efficiency of the herbs. Fructus Meliae Toosendan (CLZ, cold-natured) has significant liver toxicity. However, it has been widely used in combination with Fructus Foeniculi (XHX, hot-natured) for thousands of years in TCM, in which form it shows no hepatotoxicity, indicating that the combined use of XHX and CLZ can reduce the hepatotoxicity of CLZ. Herb-herb interactions could affect herb pharmacokinetics and in vivo efficacy. The herb-herb interactions between CLZ and XHX are still unknown. MATERIALS AND METHODS: This study used liquid chromatography tandem mass spectrometry (LC-MS) and gas chromatography tandem mass spectrometry (GC-MS) to establish methods for detecting toosendanin and trans-anethole, the main active substances of CLZ and XHX, respectively. Additionally, we investigated their herb-herb interactions via pharmacokinetic and pharmacodynamic studies. RESULTS: The results indicate that the established analytical methods are suitable for detecting toosendanin and trans-anethole, and the methodology meets the requirements of biological sample testing methods. Compared with the CLZ group, the pharmacokinetic parameters Cmax , AUC(0-t) , AUC(0-∞) , MRT(0-t) and MRT(0-∞) of toosendanin in the CLZ-XHX group notably decreased and the values of Vz/F remarkably increased. Compared with the XHX group, the pharmacokinetic parameters Cmax , AUC0-t , AUC0-∞, Tmax and t1/2z of trans-anethole notably increased in the CLZ-XHX group, and the values of CLz/F and Vz/F obviously decreased. CONCLUSION: The pharmacokinetic results indicate that XHX can significantly decrease the absorption and bioavailability and accelerate the elimination process of toosendanin in CLZ. XHX could decrease the risk of in vivo accumulation of the toxic constituent of CLZ, toosendanin, thus decreasing its toxicity. It has also been shown that CLZ can significantly increase absorption and bioavailability and attenuate the elimination process of trans-anethole in XHX, thus enhancing its efficacy. Hepatotoxicity studies indicate that CLZ has significant hepatotoxicity, and its combined use with XHX can decrease its liver-damaging properties.

Biosynthesis of Silver Nanoparticles from Melia azedarach: Enhancement of Antibacterial, Wound Healing, Antidiabetic and Antioxidant Activities.

PURPOSE: Global demand for novel, biocompatible, eco-friendly resources to fight diseases inspired this study. We investigated plants used in traditional medicine systems and utilized nanotechnology to synthesize, evaluate, and enhance potential applications in nanomedicine. METHODS: Aqueous leaf extract from Melia azedarach (MA) was utilized for bio-synthesis of silver nanoparticles (MA-AgNPs). Reaction conditions were optimized for high yield and colloidal stability was evaluated using UV-Vis spectroscopy. MA-AgNPs were characterized by scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Standard methods were used to analyze the antibacterial, wound healing, antidiabetic, antioxidant, and cytotoxic activities. RESULTS: The formation of MA-AgNPs at room temperature was confirmed by stable brown colloidal solution with maximum absorbance at 420 nm (UV-Vis Spectroscopy). MA-AgNPs were spherical (SEM), uniformly dispersed, 14-20 nm in diameter (TEM), and crystalline in nature (XRD). Presence of elemental silver was confirmed by peak at 3 KeV (EDX). FTIR data revealed the presence of functional groups which indicate phyto-constituents (polyphenols, flavonoids, and terpenoids) may have acted as the reducing and capping agents. MA-AgNPs (1000 µg/mL) showed larger zone of inhibition than MA-extract in the disk diffusion assay for human pathogenic gram positive bacteria, Bacillus cereus (34 mm) and gram negative, Escherichia coli (37 mm), thus confirming their higher antibacterial activity. The cell scratch assay on human dermal fibroblast cells revealed potential wound healing activity. The MA-AgNPs (400 µg/mL) demonstrated high antidiabetic efficacy as measured by α-amylase (85.75%) and α-glucosidase (80.33%) inhibition assays and antioxidant activity as analyzed by DPPH (63.83%) and ABTS (63.61%) radical scavenging assays. Toxic effect of MA-AgNPs against human chang liver cells (CCL-13) as determined by MTS assay, optical microscopic and CMFDA dye methods was insignificant. CONCLUSION: This sustainable, green synthesis of AgNPs is a competitive alternative to conventional methods and will play a significant role in biomedical applications of Melia azedarach.

Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity.

BACKGROUND: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS: Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.

Two new nimbolinin- and trichilin-class limonoids isolated from the fruits of Melia azedarach.

Two new furan fragment isomerized limonoids, meliazedalides A and B (compounds 1 and 2), were isolated from the fruits of Melia azedarach Linn.. Their chemical structures were elucidated on the basis of HR-ESI-MS and 1D and 2D NMR data, which belonged to nimbolinin- and trichilin-class, respectively. Compound 2 exhibited weak inhibitory effect on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages with IC50 being 37.41 µmol·L-1.

Chemical constituents from the leaves of Melia azedarach.

Six compounds, benzyl 3-O-ß-D-glucopyranosyl-7-hydroxybenzoate (1), spathulenol (2), 1,7,8-trihydroxy-2-naphtaldehyde (3), quercetin (4), astragalin (5) and 2-methoxy-4-(2-propenyl)phenyl ß-D-glucoside (6), were isolated from the leaves of Melia azedarach L. The structure elucidation of compound 1 was discussed in detail based on its 2D-NMR data. Compound 1 showed weak cytotoxicity against the cell lines of T-24, NCI-H460, HepG2, SMMC-7721, CNE, MDA-MB-231 and B16F10 with the inhibition rates from 10.01% to 34.05% at the concentration of 80 µM.

Functional growth inhibition of influenza A and B viruses by liquid and powder components of leaves from the subtropical plant Melia azedarach L.

We evaluated the anti-influenza-virus effects of Melia components and discuss the utility of these components. The effects of leaf components of Melia azedarach L. on viruses were examined, and plaque inhibition tests were performed. The in vivo efficacy of M. azedarach L. was tested in a mouse model. Leaf components of Melia azedarach L. markedly inhibited the growth of various influenza viruses. In an initial screening, multiplication and haemagglutination (HA) activities of H1N1, H3N2, H5, and B influenza viruses were inactivated by the liquid extract of leaves of M. azedarach L. (MLE). Furthermore, plaque inhibition titres of H1N1, H3N2, and B influenza viruses treated with MLE ranged from 103.7 to 104.2. MLE possessed high plaque-inhibitory activity against pandemic avian H5N1, H7N9, and H9N2 vaccine candidate strains, with a plaque inhibition titre of more than 104.2. Notably, the buoyant density decreased from 1.175 to 1.137 g/cm3, and spikeless particles appeared. We identified four anti-influenza virus substances: pheophorbide b, pheophorbide a, pyropheophorbide a, and pheophytin a. Photomorphogenesis inside the envelope may lead to removal of HA and neuraminidase spikes from viruses. Thus, MLE could efficiently remove floating influenza virus in the air space without toxicity. Consistent with this finding, intranasal administration of MLE in mice significantly decreased the occurrence of pneumonia. Additionally, leaf powder of Melia (MLP) inactivated influenza viruses and viruses in the intestines of chickens. MLE and MLP may have applications as novel, safe biological disinfectants for use in humans and poultry.