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Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase

Shaari K, Suppaiah V, Wai LK, Stanslas J, Tejo BA, Israf DA, et al.

Bioorg Med Chem, 2011 Nov 1;19(21):6340-7.
PMID: 21958738 DOI: 10.1016/j.bmc.2011.09.001

A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC(50) value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC(4) with an IC(50) value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC(50) value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of -13.45 (electrostatic) and -5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.

Matched MeSH terms: Rutaceae/chemistry*
O-prenylated flavonoid, an antidiabetes constituent in Melicope lunu-ankenda

George S, Ajikumaran Nair S, Johnson AJ, Venkataraman R, Baby S

J Ethnopharmacol, 2015 Jun 20;168:158-63.
PMID: 25858510 DOI: 10.1016/j.jep.2015.03.060

Melicope lunu-ankenda leaves are used to treat diabetes in folklore medicinal practices in India and Malaysia. Here we report the isolation of an O-prenylated flavonoid (3,5,4'-trihydroxy-8,3'-dimethoxy-7-(3-methylbut-2-enoxy)flavone; OPF) from the leaves of M. lunu-ankenda and its antidiabetes activity against type-2 diabetes mellitus (T2DM).

Matched MeSH terms: Rutaceae*
Fulltext Biochemical characterization and 1H NMR based metabolomics revealed Melicope lunu-ankenda leaf extract a potent anti-diabetic agent in rats

Al-Zuaidy MH, Mumtaz MW, Hamid AA, Ismail A, Mohamed S, Razis AFA

BMC Complement Altern Med, 2017 Jul 10;17(1):359.
PMID: 28693595 DOI: 10.1186/s12906-017-1849-2

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by continuous hyperglycemia associated with insulin resistance and /or reduced insulin secretion. There is an emerging trend regarding the use of medicinal plants for the treatment of diabetes mellitus. Melicope lunu-ankenda (ML) is one of the Melicope species belonging to the family Rutaceae. In traditional medicines, its leaves and flowers are known to exhibit prodigious health benefits. The present study aimed at investigating anti-diabetic effect of Melicope lunu-ankenda (ML) leaves extract.
METHODS: In this study, anti-diabetic effect of ML extract is investigated in vivo to evaluate the biochemical changes, potential serum biomarkers and alterations in metabolic pathways pertaining to the treatment of HFD/STZ induced diabetic rats with ML extract using 1H NMR based metabolomics approach. Type 2 diabetic rats were treated with different doses (200 and 400 mg/kg BW) of Melicope lunu-ankenda leaf extract for 8 weeks, and serum samples were examined for clinical biochemistry. The metabolomics study of serum was also carried out using 1H NMR spectroscopy in combination with multivariate data analysis to explore differentiating serum metabolites and altered metabolic pathways.
RESULTS: The ML leaf extract (400 mg/kg BW) treatment significantly increased insulin level and insulin sensitivity of obese diabetic rats, with concomitant decrease in glucose level and insulin resistance. Significant reduction in total triglyceride, cholesterol and low density lipoprotein was also observed after treatment. Interestingly, there was a significant increase in high density lipoprotein of the treated rats. A decrease in renal injury markers and activities of liver enzymes was also observed. Moreover, metabolomics studies clearly demonstrated that, ML extract significantly ameliorated the disturbance in glucose metabolism, tricarboxylic acid cycle, lipid metabolism, and amino acid metabolism.
CONCLUSION: ML leaf extract exhibits potent antidiabetic properties, hence could be a useful and affordable alternative option for the management of T2DM.

Matched MeSH terms: Rutaceae/chemistry*
Fulltext Association between oxidative DNA damage, fruits and vegetables intake with breast cancer: a preliminary study in Klang Valley

Suzana Shahar, Kim, Tiu Teng, Nor Fadilah Rajab, Fatimah Arshad

Jurnal Sains Kesihatan Malaysia, 2008;6(1):61-77.
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A preliminary study was conducted to determine the level of oxidative DNA damage, fruits and vegetables intake among 50 breast cancer patients (cases) as compared to 50 healthy women (controls) with no known medical history of breast cancer in Klang Valley. Both groups were matched for age and ethnicity. Data on socio-demographic, health status and medical history, fruits and vegetables intake, and supplements intake were obtained through an interviewbased questionnaire. Anthropometry measurements included weight, height, and waist and hip circumference were also carried out on subjects. A total of 3mL fasting venous blood was drawn to assess lymphocytes oxidative DNA damage using Alkaline Comet Assay. Results indicated that the mean intake of fruits and vegetables was lower in cases (4.09 ± 1.17 servings/d) than controls (4.77 ± 0.90 servings/d)(p < 0.05) The intake of fruits and vegetables from family groups of solanaceae, myrtaceae, caricaceae, apiaceae, brinjal, rutaceae, broccoli, orange, carrot, watermelon were 0.5 - 1 servings/week significantly higher among controls as compared to cases (p < 0.05 for all parameters). However, the intake of fruits from rosaceae family and apple was higher among controls than cases (p < 0.05). The estimated intake of ß-carotene, carotenoids, vitamin A, vitamin C (p < 0.001), a-carotene and lycopene (p < 0.05) from fruits and vegetables were higher among controls than cases. Mean DNA damage level of cases (4.55 ± 1.78 % DNA in tail, %TD; 0.35 ± 0.21 tail moment, TM) were 3.5 and 3.9 times higher than the value of controls (1.3 ± 0.70% TD; 0.09 ± 0.09 TM) (p < 0.001) and the damage increased with higher values of waist hip ratio (% TD, r = 0.396, p < 0.05; TM, r = 0.349, p < 0.05) and waist circumference (% TD, r = 0.334, p < 0.05; TM, r = 0.360, p < 0.05). There was an inverse relationship between oxidative DNA damage with intake of total fruits and vegetables, cauliflowers and water convolvulus and also consumption from rutaceae and solanaceae families. Similar trend was noted for estimated intake of vitamin A, carotenoids, vitamin C, ß-carotene and lycopene. In conclusion, the intake of fruits and vegetables of five servings/d and the consumption of specific families and types of fruits and vegetables might protect against oxidative DNA damage and further reduce breast cancer risk.

Matched MeSH terms: Rutaceae
Syk/NF-κB-targeted anti-inflammatory activity of Melicope accedens (Blume) T.G. Hartley methanol extract

Kim JK, Choi E, Hong YH, Kim H, Jang YJ, Lee JS, et al.

J Ethnopharmacol, 2021 May 10;271:113887.
PMID: 33539951 DOI: 10.1016/j.jep.2021.113887

ETHNOPHARMACOLOGICAL RELEVANCE: Melicope accedens (Blume) Thomas G. Hartley is a plant included in the family Rutaceae and genus Melicope. It is a native plant from Vietnam that has been used for ethnopharmacology. In Indonesia and Malaysia, the leaves of M. accedens are applied externally to decrease fever.
AIM OF THE STUDY: The molecular mechanisms of the anti-inflammatory properties of M. accedens are not yet understood. Therefore, we examined those mechanisms using a methanol extract of M. accedens (Ma-ME) and determined the target molecule in macrophages.
MATERIALS AND METHODS: We evaluated the anti-inflammatory effects of Ma-ME in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and in an HCl/EtOH-triggered gastritis model in mice. To investigate the anti-inflammatory activity, we performed a nitric oxide (NO) production assay and ELISA assay for prostaglandin E2 (PGE2). RT-PCR, luciferase gene reporter assays, western blotting analyses, and a cellular thermal shift assay (CETSA) were conducted to identify the mechanism and target molecule of Ma-ME. The phytochemical composition of Ma-ME was analyzed by HPLC and LC-MS/MS.
RESULTS: Ma-ME suppressed the production of NO and PGE2 and the mRNA expression of proinflammatory genes (iNOS, IL-1β, and COX-2) in LPS-stimulated RAW264.7 cells without cytotoxicity. Ma-ME inhibited NF-κB activation by suppressing signaling molecules such as IκBα, Akt, Src, and Syk. Moreover, the CETSA assay revealed that Ma-ME binds to Syk, the most upstream molecule in the NF-κB signal pathway. Oral administration of Ma-ME not only alleviated inflammatory lesions, but also reduced the gene expression of IL-1β and p-Syk in mice with HCl/EtOH-induced gastritis. HPLC and LC-MS/MS analyses confirmed that Ma-ME contains various anti-inflammatory flavonoids, including quercetin, daidzein, and nevadensin.
CONCLUSIONS: Ma-ME exhibited anti-inflammatory activities in vitro and in vivo by targeting Syk in the NF-κB signaling pathway. Therefore, we propose that Ma-ME could be used to treat inflammatory diseases such as gastritis.

Matched MeSH terms: Rutaceae/chemistry*