HPLC-HRMS/MS and anti-inflammatory effects of bunya pine resin through multifaceted pathway modulation: NUMB/NOTCH1/HES1/mTOR/ PI3K/HMGB1 signaling cascades.

The oleoresins of the Araucaria bidwillii Hook. (A.B.) are commonly used for the treatment of several conditions. However, the full phytochemical profile of its active compounds and its mechanism of action to protect the liver from toxicity remain unclear. The purpose of this research was to investigate the complete set of data relating to the A.B. active metabolites and explore the hepatoprotective properties of AB ethanolic extract on MTX-induced liver injury mainly due to its anti-inflammatory role. Hepatic markers, oxidative stress, inflammatory mediators, the NOTCH/NICD signaling cascade, HES1 expression, HMGB1/TLR4, and the PI3K/mTOR axis were assessed. HPLC-HRMS/MS analysis of A.B. led to the annotation of fifteen compounds from different classes, where diterpenes are the dominant class. Additionally, A.B. (100 and 200 mg/kg) significantly decreased hepatic markers, oxidative stress, and inflammatory mediators. Moreover, the extract significantly increased NOTCH pathway stimulation and HES1 expression, accompanied by a significant decline in the NUMB and HMGB1/TLR4 axes. In addition, it significantly inhibited the PI3K/mTOR pathway, with a prominent effect at the higher dose. This study presents A.B. as a promising hepatoprotective agent through stimulation of the NOTCH pathway and inhibition of the HMGB1/TLR4 pathway, as well as the PI3K/mTOR/NF-κB axis, besides its antioxidant and anti-inflammatory effects.

• Publication year

  2025

• Venue

  InflammoPharmacology

• Publication date

  2025-03-31

• Fields of study

  Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1007/s10787-025-01660-xPMID 40163273
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Genome‐wide Association Study of Methotrexate‐Induced Liver Injury in Rheumatoid Arthritis Patients

  2023cited by this paper
• Vanillic acid alleviates liver fibrosis through inhibiting autophagy in hepatic stellate cells via the MIF/CD74 signaling pathway.

  2023cited by this paper
• Methotrexate and Triptolide regulate Notch signaling pathway by targeting the Nedd4-Numb axis.

  2023cited by this paper
• Drug induced liver injury: causative agents and predictors for the outcome - a retrospective study at Tanta University Hospital, Egypt.

  2023cited by this paper
• A low dose of naloxone mitigates autoimmune hepatitis by regulating TLR4/NF-κB and Nrf2/HO-1 signaling pathways

  2023cited by this paper
• Erythropoietin Suppresses the Hepatic Fibrosis Caused by Thioacetamide: Role of the PI3K/Akt and TLR4 Signaling Pathways

  2023cited by this paper
• Vinpocetine mitigates methotrexate-induced duodenal intoxication by modulating NF-κB, JAK1/STAT-3, and RIPK1/RIPK3/MLKL signals

  2023cited by this paper
• Gallic acid and metformin co-administration reduce oxidative stress, apoptosis and inflammation via Fas/caspase-3 and NF-κB signaling pathways in thioacetamide-induced acute hepatic encephalopathy in rats

  2023cited by this paper
• Anti-Cancer Agent: The Labdane Diterpenoid-Andrographolide

  2023cited by this paper
• HR LC-MS/MS metabolomic profiling of Yucca aloifolia fruit and the potential neuroprotective effect on rotenone-induced Parkinson’s disease in rats

  2023cited by this paper
• Ferritinophagy‐mediated ferroptosis facilitates methotrexate‐induced hepatotoxicity by high‐mobility group box 1 (HMGB1)

  2023cited by this paper
• Protective Effects of Crocin Against Methotrexate-Induced Hepatotoxicity in Adult Male Albino Rats: Histological, Immunohistochemical, and Biochemical Study

  2023cited by this paper
• Integrated multiomics analysis to infer COVID-19 biological insights

  2023cited by this paper
• Evaluation of Hepatoprotective Potential of Polyherbal Preparations in CCl4-Induced Hepatotoxicity in Mice

  2022cited by this paper
• Hepatoprotective activity of the ethanolic extract of Morus indica roots from Indian Bodo tribes

  2022cited by this paper
• Gastroprotective and anti-Helicobacter pylori potentials of essential oils from the oleoresins of Araucaria bidwillii and Araucaria heterophylla

  2022cited by this paper
• Methotrexate-Induced Liver Injury Is Associated with Oxidative Stress, Impaired Mitochondrial Respiration, and Endoplasmic Reticulum Stress In Vitro

  2022cited by this paper
• Enhancement of the Protective Activity of Vanillic Acid against Tetrachloro-Carbon (CCl4) Hepatotoxicity in Male Rats by the Synthesis of Silver Nanoparticles (AgNPs)

  2022cited by this paper
• Hepatoprotective effects of carvedilol and crocin against leflunomide-induced liver injury.

  2022cited by this paper
• Inhibition of inflammatory liver injury by the HMGB1-A box through HMGB1/TLR-4/NF-κB signaling in an acute liver failure mouse model

  2022cited by this paper
• Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the ‎TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis.

  2022cited by this paper
• New Diterpenes with Potential Antitumoral Activity Isolated from Plants in the Years 2017–2022

  2022cited by this paper
• Mechanistic Insights into the Pharmacological Significance of Silymarin

  2022cited by this paper
• Multiple functions of MLKL in liver fibrosis, from necroptosis to hepatic stellate cell activation

  2022cited by this paper
• Evaluation of hepatoprotective activity of ethanolic extract of Pterocarpus marsupium Roxb. leaves against paracetamol-induced liver damage via reduction of oxidative stress

  2022cited by this paper
• TNF in the liver: targeting a central player in inflammation

  2022cited by this paper
• Toll-like receptor 4-mediated necroptosis in the development of necrotizing enterocolitis

  2021cited by this paper
• Inhibition of Notch1 signaling reduces hepatocyte injury in nonalcoholic fatty liver disease via autophagy.

  2021cited by this paper
• Modulation of the PI3K/Akt/mTOR signaling pathway by probiotics as a fruitful target for orchestrating the immune response

  2021cited by this paper
• Biological and chemical evaluation of some African plants belonging to Kalanchoe species: Antitrypanosomal, cytotoxic, antitopoisomerase I activities and chemical profiling using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometer

  2021cited by this paper
• Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms.

  2021cited by this paper
• Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?

  2021cited by this paper
• Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling

  2021cited by this paper
• The role of resveratrol in hepatatoxicity caused by methotrexate

  2021cited by this paper
• Targeting inflammation and redox aberrations by perindopril attenuates methotrexate-induced intestinal injury in rats: Role of TLR4/NF-κB and c-Fos/c-Jun pro-inflammatory pathways and PPAR-γ/SIRT1 cytoprotective signals.

  2021cited by this paper
• Medicinal plants with hepatoprotective potentials against carbon tetrachloride-induced toxicity: a review

  2021cited by this paper
• Bisflavonoids fraction from Araucaria bidwilli Hook., reverses hyperlipidemia induced atherosclerosis in high-fat diet induced hyperlipidemia

  2020cited by this paper
• Evaluation of the Anti-inflammatory and Antioxidant Activities of Selected Resin Exudates

  2020cited by this paper
• HMGB1/PI3K/Akt/mTOR Signaling Participates in the Pathological Process of Acute Lung Injury by Regulating the Maturation and Function of Dendritic Cells

  2020cited by this paper
• Expression of Notch–Hif-1α signaling pathway in liver regeneration of rats

  2020cited by this paper
• Anti-inflammatory and antioxidant effects of Apium graveolens L. extracts mitigate against fatal acetaminophen-induced acute liver toxicity.

  2020cited by this paper
• Phytochemistry, Chemotaxonomy, and Biological Activities of the Araucariaceae Family—A Review

  2020cited by this paper
• Alleviation of Liver Dysfunction, Oxidative Stress and Inflammation Underlies the Protective Effect of Ferulic Acid in Methotrexate-Induced Hepatotoxicity

  2020cited by this paper
• Methotrexate and its mechanisms of action in inflammatory arthritis

  2020cited by this paper
• Curcumin Protects against White Matter Injury through NF-κB and Nrf2 Cross Talk

  2020cited by this paper
• Localization of DLL1- and NICD-positive osteoblasts in cortical bone during postnatal growth in rats.

  2020cited by this paper
• Generation of Retinaldehyde for Retinoic Acid Biosynthesis

  2019cited by this paper
• The Roles of Notch Signaling in Liver Development and Disease

  2019cited by this paper
• Hepatoprotective Activity of Some Medicinal Plants in Sudan

  2019cited by this paper
• Plant Sterol Ester of α-Linolenic Acid Attenuates Nonalcoholic Fatty Liver Disease by Rescuing the Adaption to Endoplasmic Reticulum Stress and Enhancing Mitochondrial Biogenesis

  2019cited by this paper
• Leflunomide-induced liver injury in mice: Involvement of TLR4 mediated activation of PI3K/mTOR/NFκB pathway.

  2019cited by this paper
• Oleic Acid Protects against Hepatic Ischemia and Reperfusion Injury in Mice by Inhibiting AKT/mTOR Pathways

  2019cited by this paper
• Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats

  2019cited by this paper
• Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats.

  2018cited by this paper
• Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years

  2017cited by this paper
• Blockade of Notch signaling promotes acetaminophen-induced liver injury

  2017cited by this paper
• Propolis Diterpenes as a Remarkable Bio-Source for Drug Discovery Development: A Review

  2017cited by this paper
• Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats.

  2017cited by this paper
• Drug-induced liver injury: recent advances in diagnosis and risk assessment

  2017cited by this paper
• Risk of liver disease in methotrexate treated patients

  2017cited by this paper
• Selected hepatoprotective herbal medicines: Evidence from ethnomedicinal applications, animal models, and possible mechanism of actions

  2017cited by this paper
• Berberine ameliorates methotrexate-induced liver injury by activating Nrf2/HO-1 pathway and PPARγ, and suppressing oxidative stress and apoptosis in rats.

  2017cited by this paper
• Methotrexate in the Treatment of Psoriasis and Rheumatoid Arthritis: Mechanistic Insights, Current Issues and Novel Delivery Approaches.

  2017cited by this paper
• Drug-induced liver injury.

  2016cited by this paper
• Preventing and Managing Toxicities of High-Dose Methotrexate

  2016cited by this paper
• New Labdane-Type Diterpenoids and Anti-Inflammatory Constituents from Hedychium coronarium

  2013cited by this paper
• Risk factors for idiosyncratic drug-induced liver injury.

  2010cited by this paper
• Apoptosis: A Review of Programmed Cell Death

  2007cited by this paper
• Protective effect of biflavones from Araucaria bidwillii Hook in rat cerebral ischemia/reperfusion induced oxidative stress.

  2007cited by this paper
• PHARMACOLOGICAL STUDIES OF ARAUCARIA BIDWILLI HOOK

  1993cited by this paper

• Balancing efficacy and hepatotoxicity: a comprehensive review of oral medications in psoriasis management

  2025cites this paper
• Identification of Novel Triazole-Pyrazole Conjugates as Potential Anticonvulsant Agents: Synthesis and Biological Evaluations.

  2025cites this paper
• Protective effects of melatonin and naringenin against acitretin induced hepatotoxicity via modulation of oxidative stress and inflammatory signaling

  2025cites this paper
• Molecular hybrids integrated with Benzofuran, 1,2,3-Triazole and Pyrazole structural motifs: Design, synthesis, biological evaluation, and in vivo studies.

  2025cites this paper
• Effects of Low-Dose Silver Nanoparticles on Odontoblastic Mineralization and Inflammatory Responses under an Inflammatory Microenvironment Subtitle: Involvement of the PI3K/Akt-NF-κB Signaling Pathway in MDPC-23 Cells.

  2025cites this paper