LC-QToF chemical profiling of Euphorbia grantii Oliv. and its potential to inhibit LPS-induced lung inflammation in rats via the NF-κB, CY450P2E1, and P38 MAPK14 pathways

Inflammopharmacology https://doi.org/10.1007/s10787-023-01298-7 Inflammopharmacology ORIGINAL ARTICLE LC‑QToF chemical profiling of Euphorbia grantii Oliv. and its potential to inhibit LPS‑induced lung inflammation in rats via the NF‑κB, CY450P2E1, and P38 MAPK14 pathways Mai Hussin Radi1 · Riham A. El‑Shiekh2 · Amany Mohammed Hegab3 · Shirley Ragae Henry4 · Bharathi Avula5 · Kumar Katragunta5 · Ikhlas A. Khan5,6 · Ali M. El‑Halawany2 · Essam Abdel‑Sattar2 Received: 18 May 2023 / Accepted: 12 July 2023 © The Author(s) 2023 Abstract Acute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. The aerial parts of Euphorbia grantii Oliv. were extracted with methanol to give a total methanolic extract (TME), which was further fractionated into dichloromethane (DCMF) and the remaining mother liquor (MLF) fractions. Biological guided anti-inflammatory assays in vitro revealed that the DCMF showed the highest activity (IC50 6.9 ± 0.2 μg/mL and 0.29 ± 0.01 μg/mL) compared to. celecoxib ( IC50 of 88.0 ± 1 μg/mL and 0.30 ± 0.01 μg/mL) on COX-1 and COX-2, respectively. Additionally, anti-LOX activity was I C50 = 24.0 ± 2.5 μg/mL vs. zileuton with IC50 of 40.0 ± 0.5 μg/mL. LC-DAD-QToF analysis of TME and the active DCMF resulted in the tentative identification and characterization of 56 phytochemical compounds, where the diterpenes were the dominated metabolites. An LPS-induced inflammatory model of ALI (10 mg/kg i.p) was used to assess the anti-inflammatory potential of DCMF in vivo at dose of 200 mg/kg and 300 mg/kg compared to dexamethasone (5 mg/kg i.p). Our treatments significantly reduced the pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and MPO), increased the activity of antioxidant enzymes (SOD, CAT, and GSH), decreased the activity of oxidative stress enzyme (MDA), and reduced the expression of inflammatory genes (p38.MAPK14 and CY450P2E1). The western blotting of NF-κB p65 in lung tissues was inhibited after orally administration of the DCMF. Histopathological study of the lung tissues, scoring, and immunohistochemistry of transforming growth factor-beta 1 (TGF-β1) were also assessed. In both dose regimens, DCMF of E. grantii prevented further lung damage and reduced the side effects of LPS on acute lung tissue injury. Keywords Euphorbia grantii · Lipopolysaccharide · Anti-inflammatory · Acute lung injury · LC-DAD-QToF chemical profiling · In vitro and in vivo * Essam Abdel‑Sattar 1 Herbal Department, Egyptian Drug Authority (EDA), Giza, Egypt 2 Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt 3 Developmental Pharmacology Department, Egyptian Drug Authority (EDA), Giza, Egypt 4 Histopathology Department, Egyptian Drug Authority (EDA), Giza, Egypt 5 School of Pharmacy, National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA 6 Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA Abbreviations ALI Acute lung injury APCS Antigen-presenting cells ARDS Acute respiratory distress syndrome CAT Catalase COX-1 Cyclooxygenase 1 COX-2 Cyclooxygenase 2 CY450P2E1 Cytochrome P450 family 2 subfamily E member 1 ELISA Enzyme linked immunosorbent assay GSH Reduce glutathione IL-1 Interleukin-1 IL-6 Interleukin-6 LC-DAD-QToF Liquid chromatography diode array detector-quadrupole time-of-flight mass spectrometry 13 Vol.:(0123456789) M. H. Radi et al. LOX Lipoxygenase LPS Lipopolysaccharide MDA Malondialdehyde MPO Myeloperoxidase NF-κB p65 Nuclear factor Kappa B p38.MAPK14 Mitogen-activated protein kinase 14 SOD Superoxide dismutase TGF-β1 Transforming growth factor-beta 1 TLR4 Toll-like receptor 4 TNF-α Tumor necrosis factor-α Introduction Inflammation is a complex reaction that involves interactions between antigen-presenting cells (i.e., APCs), monocytes, and activated lymphocytes, which then differentiate into macrophages. During this process, a large number of cytokines are released (Latruffe 2017). Inflammation is also an early response of vascular tissues to infection, injuries, and harmful stimuli such as pathogens and irritants. Furthermore, inflammation is involved in non-specific immune responses that aim to neutralize invaders, repair damaged cells, and initiate the healing processes (Ferrero-Miliani et al. 2007). Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute respiratory failure syndromes characterized by severe pulmonary edema, neutrophil accumulation, and hypoxemia in the lungs (Luh and Chiang 2007). The incidence of ALI/ARDS is high and is associated with marked mortality and morbidity (Zhang et al. 2009). ALI/ARDS is the most common reason of severe respiratory failure caused by damage to the alveoli and capillary barrier (Lee et al. 2021). ARDS occurs with 75% of cases categorized as moderate or severe conditions (Matthay et al. 2019). The fatality rates from mild to severe ARDS remain of about 27–45%, which is considerably higher than for other acute/chronic diseases as pneumonia, asthma, and myocardial infarction (Diamond et al. 2020). SARS-CoV-2 at the heart of the COVID-19 pandemic has worsened the threat of ARDS from a major healthcare alarm to a global crisis worldwide (Li and Ma 2020). Severe inflammation of the airway caused by inhalation of infectious substances into the bronchi is very important in the pathogenesis of ARDS (Han and Mallampalli 2015). ARDS is an acute lung disease with numerous causes that involves various cellular factors alongside the pathogenic growth and results in multiple types of destruction to the tissues (Matthay and Zemans 2011; Sharp et al. 2015). Only symptomatic relief drugs are currently available, as inhaled nitric oxide or steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs) (Gebistorf et al. 2016; Khilnani and Hadda 2011). Numerous side effects are reported for their uses as hypertension, gastrointestinal perforation, peptic ulcers, hemorrhage, gastrointestinal distress, and inflammation (Ho et al. 2020). Though, 13 the efficacy and safety of these therapies remain inadequate and there is a high medical need for a ultimate treatment for ARDS (Patel et al. 2018). Lipopolysaccharide (LPS), commonly observed in the cell wall of gram-negative bacteria, is known to induce inflammation. LPS-induced acute lung injury (ALI), an animal model of severe pulmonary inflammation, is widely used to study ARDS (Rittirsch et al. 2008; Qi et al. 2017). Injection of LPS stimulates macrophages to produce the proinflammatory cytokines such as TNF-α, IL-6, IL-10, and IL-1β, which induce the infiltration and activation of neutrophils (Rittirsch et al. 2008; Chen et al. 2020; de Souza et al. 2017). Stimulated neutrophils next produce a large amount of reactive oxygen species (ROS) and cytokines, further worsen severe lung damage through damaging inflammatory res (...truncated)