Justicidin A

Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors.[Pubmed:37764441]

Molecules. 2023 Sep 16;28(18):6665.

The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy Justicidin A, and 6'-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of -7.526 kcal/mol, -7.438 kcal/mol, and -7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (-6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Development of a mesoporous silica based solid-phase extraction and ultra-performance liquid chromatography-MS/MS method for quantifying lignans in Justicia procumbens.[Pubmed:32040861]

Electrophoresis. 2020 Mar;41(5-6):379-385.

Justicia procumbens is a food and medicine homologous variety, popularly used for making vegetable soups. In this study, a novel mesoporous silica was synthesized and used as the sorbent of SPE for the purification of lignans from J. procumbens. A laboratory-made SPE cartridge was packed with 100 mg of mesoporous silica, which was washed with 10% methanol and eluted using 0.8 mL acetonitrile after sample loading. Afterward, the extract was analyzed by ultra-performance liquid chromatography (UPLC) and MS/MS. All the lignans were efficiently separated in 6 min with the noise level in the range of 50-150 cps. 6'-Hydroxy justicidin B, 6'-hydroxy Justicidin A, justicidin B, chinensinaphthol methyl ether, justicidin C, and neojusticdin A were identified to be the dominant molecular species in J. procumbens with contents of 0.065-0.37 mg/g in three tested sample batches from different geographic origins. In conclusion, the proposed mesoporous silica based SPE UPLC-MS/MS method is efficient in linearity (R(2) = 0.9989-0.9996), sensitivity (LOD

Justicidin A Reduces beta-Amyloid via Inhibiting Endocytosis of beta-Amyloid Precursor Protein.[Pubmed:30332887]

Biomol Ther (Seoul). 2019 May 1;27(3):276-282.

beta-amyloid precursor protein (APP) can be cleaved by alpha-, and gamma-secretase at plasma membrane producing soluble ectodomain fragment (sAPPalpha). Alternatively, following endocytosis, APP is cleaved by beta-, and gamma-secretase at early endosomes generating beta-amyloid (Abeta), the main culprit in Alzheimer's disease (AD). Thus, APP endocytosis is critical for Abeta production. Recently, we reported that Monsonia angustifolia, the indigenous vegetables consumed in Tanzania, improved cognitive function and decreased Abeta production. In this study, we examined the underlying mechanism of Justicidin A, the active compound of M. angustifolia, on Abeta production. We found that Justicidin A reduced endocytosis of APP, increasing sAPPalpha level, while decreasing Abeta level in HeLa cells overexpressing human APP with the Swedish mutation. The effect of Justicidin A on Abeta production was blocked by endocytosis inhibitors, indicating that the decreased APP endocytosis by Justicidin A is the underlying mechanism. Thus, Justicidin A, the active compound of M. angustifolia, may be a novel agent for AD treatment.

DW2008S and its major constituents from Justicia procumbens exert anti-asthmatic effect via multitargeting activity.[Pubmed:29512870]

J Cell Mol Med. 2018 May;22(5):2680-2691.

Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, Justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A(3) (A(3) AR), which mediates mast cell-dependent inflammation and bronchoconstriction. DW2008S and JB inhibited human phosphodiesterase 4 (PDE4), which is known to cause bronchoconstriction; however, the required concentrations were higher than those needed to affect TIGIT . These findings suggest that DW2008S can potentially ameliorate Th2-driven airway inflammation and bronchoconstriction through negative regulation of TIGIT and blockade of A(3) AR and PDE4 activities.

A Strategy for Preparative Separation of 10 Lignans from Justicia procumbens L. by High-Speed Counter-Current Chromatography.[Pubmed:29168751]

Molecules. 2017 Nov 23;22(12):2024.

Ten compounds, including three lignan glycosides and seven lignans, were purified from Justicia procumbens L. in 8 h using an efficient strategy based on high-speed counter-current chromatography (HSCCC). The two-phase solvent system composed of petroleum-ethyl acetate-methanol-H(2)O (1:0.7:1:0.7, v/v) was firstly employed to separate the crude extract (320 mg), from which 19.3 mg of justicidin B (f), 10.8 mg of Justicidin A (g), 13.9 mg of 6'-hydroxyjusticidin C (h), 7.7 mg of justicidin E (i), 6.3 mg of lignan J(1) (j) were obtained with 91.3 mg of enriched mixture of compounds a-e. The enriched mixture (91.3 mg) was further separated using the solvent system consisting of petroleum-ethyl acetate-methanol-H(2)O (3:3.8:3:3.8, v/v), yielding 12.1 mg of procumbenoside E (a); 7.6 mg of diphyllin-1-O-beta-d-apiofuranoside (b); 7.4 mg of diphyllin (c); 8.3 mg of 6'-hydroxy justicidin B (d); and 7.9 mg of diphyllin acetyl apioside (e). The purities of the 10 components were all above 94%, and their structures were identified by NMR and ESI-MS spectra. The results demonstrated that the strategy based on HSCCC for the separation of lignans and their glycosides was efficient and rapid.

Justicia procumbens Extract (DW2008) Selectively Suppresses Th2 Cytokines in Splenocytes and Ameliorates Ovalbumin-Induced Airway Inflammation in a Mouse Model of Asthma.[Pubmed:28867724]

Biol Pharm Bull. 2017;40(9):1416-1422.

DW2008 is an anhydrous ethanol extract of Justicia procumbens produced by Dong-Wha Pharmaceutical, Inc., Co. as a candidate anti-asthmatic drug. In this study, DW2008 selectively reduced T helper 2 (Th2) cytokines in mouse splenocytes and ameliorated ovalbumin-induced airway inflammation by downregulating pulmonary infiltration of differential inflammatory cells and Th2 cytokines more than a decoction or ethanol extract of J. procumbens did in a mouse asthma model. DW2008 also significantly inhibited airway hyperresponsiveness and reduced the thickness of the airway epithelium. HPLC analysis showed that the major peaks (Justicidin A and B) of DW2008 were higher than those of the other extracts. Justicidin A and B significantly suppressed Th2 cytokine levels in mouse spleen cells and exhibited a protective effect in ovalbumin-induced airway inflammation. Our findings indicate that DW2008 effectively inhibits allergic airway inflammatory reactions and airway hyperresponsiveness in a mouse model of asthma, suggesting its potential as an anti-asthmatic agent.

Protective Roles of Monsonia angustifolia and Its Active Compounds in Experimental Models of Alzheimer's Disease.[Pubmed:28378593]

J Agric Food Chem. 2017 Apr 19;65(15):3133-3140.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the accumulation of neurotoxic beta-amyloid (Abeta) peptides, which consequently affects cognitive decline and memory impairment. Current research on AD treatment is actively focusing on the prevention of neurotoxic Abeta peptide accumulation. Monsonia angustifolia is reported to be consumed as an indigenous vegetable in Tanzania. In this study, we investigated the effect of the ethanol (EtOH) extract of M. angustifolia dried ground material on Abeta production and spatial learning ability as protection against AD. The formation of Abeta peptides was significantly reduced in HeLa cells stably transfected with the Swedish mutant form of beta-amyloid precursor protein (APPsw) after treatment with a 60% EtOH extract of M. angustifolia. We next examined the cognitive-improving effects of the EtOH extract in vivo. Tg2576 mice were treated with extract for 6 months and subjected to Morris water maze and novel object recognition tests. The results showed that the 60% EtOH extract of M. angustifolia significantly ameliorated behavioral deficits of the AD transgenic mice and reduced the level of insoluble Abeta42 in the cerebral cortex and hippocampus. We further found that the 60% EtOH extract was effective for memory function recovery after shorter treatment (4 months). In addition, we isolated and identified several single compounds, Justicidin A, 5-methoxyJusticidin A, chinensinaphthol, retrochinensinaphthol methyl ether, and suchilactone, from M. angustifolia and tested these compounds. Among them, Justicidin A potently decreased the formation of Abeta in APPsw-transfected cells. These data suggest that the 60% EtOH extract of M. angustifolia has the potential to be developed as a treatment of AD. Furthermore, Justicidin A may contribute, at least partially, to the Abeta alteration observed with the extract treatment.