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A Report on Multi-Target Anti-Inflammatory Properties of Phytoconstituents from Monochoria hastata (Family: Pontederiaceae).

ABSTRACT: This study aims to investigate the potential analgesic properties of the crude extract of Monochoria hastata (MH) leaves using in vivo experiments and in silico analysis. The extract, in a dose-dependent manner, exhibited a moderate analgesic property (~54% pain inhibition in acetic acid-induced writhing test), which is significant (** p < 0.001) as compared to the control group. The complex inflammatory mechanism involves diverse pathways and they are inter-connected. Therefore, multiple inflammatory modulator proteins were selected as the target for in silico analysis. Computational analysis suggests that all the selected targets had different degrees of interaction with the phytochemicals from the extract. Rutin (RU), protocatechuic acid (PA), vanillic acid (VA), and ferulic acid (FA) could regulate multiple targets with a robust efficiency. None of the compounds showed selectivity to Cyclooxygenase-2 (COX-2). However, regulation of COX and lipoxygenase (LOX) cascade by PA can reduce non-steroidal analgesic drugs (NSAIDs)-related side effects, including asthma. RU showed robust regulation of cytokine-mediated pathways like RAS/MAPK and PI3K/NF-kB by inhibition of EGFR and IKBα (IKK), which may prevent multi-organ failure due to cytokine storm in several microbial infections, for example, SARS-CoV-2. Further investigation, using in vivo and in vitro experiments, can be conducted to develop multi-target anti-inflammatory drugs using the isolated compounds from the extract.

SUBMITTER: Haq MM

PROVIDER: S-EPMC8658818 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previous reports have illustrated that the incidence and mortality of cancer are increasing year by year worldwide. In addition, the occurrence, development, recurrence and metastasis of cancer are closely related to inflammation, which is a kind of defensive response of human body to various stimuli. As an important medicinal plant in Africa, Warburgia ugandensis has been reported to have certain anti-inflammatory and anti-proliferative activities, but its specific components and mechanisms of action remain elusive. To tackle this challenge, affinity ultrafiltration with drug targets of interest coupled to high-performance liquid chromatography-mass spectrometry (AUF-HPLC-MS/MS) could be utilized to quickly screen out bioactive constituents as ligands against target enzymes from complex extracts of this plant. AUF-HPLC-MS/MS with four drug targets, i.e., cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), topoisomerase I (Top I) and topoisomerase II (Top II) were used to rapidly screen and characterize the anti-inflammatory and anti-proliferative natural ligands from W. ugandensis, and the resulting potential active compounds as ligands with specific binding affinity to COX-2, 5-LOX, Top I and Top II, were isolated with modern separation and purification techniques and identified with spectroscopic method like NMR, and then their antiinflammatory and anti-proliferative activities were tested to verify the screening results from AUF-HPLC-MS/MS. Compounds 1 and 2, which screened out and identified from W. ugandensis showed remarkable binding affinity to COX-2, 5-LOX, Top I and Top II with AUF-HPLC-MS/MS. In addition, 1 new compound (compound 3), together with 5 known compounds were also isolated and identified from W. ugandensis. The structure of compound 3 was elucidated by extensive 1D, 2D NMR data and UPLC-QTOF-MS/MS. Furthermore, compounds 1 and 2 were further proved to possess both anti-inflammatory and anti-proliferative activities which are in good agreement with the screening results using AUF-HPLC-MS/MS. This work showcased an efficient method for quickly screening out bioactive components with anti-inflammatory and anti-proliferative activity from complex medicinal plant extracts using AUF-HPLC-MS/MS with target enzymes of interest, and also demonstrated that neolignanamides (compounds 1 and 2) from W. ugandensis would be the active components responsible for its anti-inflammatory and anti-proliferative activity with the potential to treat cancer and inflammation.

Project description:IntroductionGlucocorticoids are a mainstay of anti-inflammatory therapy, but significant adverse effects ultimately limit their utility. Previous efforts to design glucocorticoid structures with an increased therapeutic window have focused on dissociating anti-inflammatory transcriptional repression from adverse effects primarily driven by transcriptional activation. An alternative to this medicinal chemistry approach is a systems biology based strategy that seeks to amplify selectively the anti-inflammatory activity of very low dose glucocorticoid in immune cells without modulating alternative cellular networks that mediate glucocorticoid toxicity.MethodsThe combination of prednisolone and the antithrombotic drug dipyridamole was profiled using in vitro and in vivo models of anti-inflammatory activity and glucocorticoid-induced adverse effects to demonstrate a dissociated activity profile.ResultsThe combination synergistically suppresses release of proinflammatory mediators, including tumour necrosis factor-alpha, IL-6, chemokine (C-C motif) ligand 5 (RANTES), matrix metalloproteinase-9, and others, from human peripheral blood mononuclear cells and mouse macrophages. In rat models of acute lipopolysaccharide-induced endotoxemia and delayed-type hypersensitivity, and in chronic models of collagen-induced and adjuvant-induced arthritis, the combination produced anti-inflammatory activity that required only a subtherapeutic dose of prednisolone. The immune-specific amplification of prednisolone anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects, including corticosterone suppression or increased expression of tyrosine aminotransferase, in vivo after repeat dosing in rats. After 8 weeks of oral dosing in mice, treatment with the combination did not alter prednisolone-induced reduction in osteocalcin and mid-femur bone density, which are markers of steroid-induced osteoporosis. Additionally, amplification was not observed in the cellular network of corticotroph AtT-20/D16v-F2 cells in vitro, as measured by pro-opiomelanocortin expression and adrenocorticotropic hormone secretion.ConclusionsThese data suggest that the multi-target mechanism of low-dose prednisolone and dipyridamole creates a dissociated activity profile with an increased therapeutic window through cellular network selective amplification of glucocorticoid-mediated anti-inflammatory signaling.

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A Report on Multi-Target Anti-Inflammatory Properties of Phytoconstituents from Monochoria hastata (Family: Pontederiaceae).

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