D-carvone attenuates LPS-induced acute lung injury via TLR4/NF-��B and Nrf2/HO-1 signaling pathways in rats.

Advanced Search

Nergis Ula��, Hilal ��st��nda��, Se��kin ��zkanlar, Elif Erba��, Adem Kara, Yunusemre ��zkanlar

Author Information

Nergis Ula��: Department of Internal Medicine, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey. ORCID
Hilal ��st��nda��: Department of Physiology, Faculty of Medicine, Erzincan Binali Y��ld��r��m University, Erzincan, Turkey. hurcar@gmail.com. ORCID
Se��kin ��zkanlar: Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey. ORCID
Elif Erba��: Department of Histology and Embryology, Faculty of Veterinary Medicine, Atat��rk University, Erzurum, Turkey. ORCID
Adem Kara: Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey. ORCID
Yunusemre ��zkanlar: Department of Internal Medicine, Faculty of Veterinary, Ondokuz Mayis University, Samsun, Turkey. ORCID

PMID: 40116872 DOI: 10.1007/s00210-025-04024-y

Acute lung injury (ALI) is a severe respiratory disorder associated with high morbidity and mortality. Lipopolysaccharide (LPS) is widely used to induce ALI in animal models. D-carvone, a natural monoterpene, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effects of D-carvone on LPS-induced ALI in rats. Thirty-six male rats were randomly divided into six groups (n��=��6): control, D-carvone (10 mg/kg and 20 mg/kg p.o.), LPS (10 mg/kg E. coli lipopolysaccharide i.p.), and LPS��+��D-carvone (LPS with either 10 or 20 mg/kg D-carvone). D-carvone was administered orally once daily for 10 days. On day 10, sepsis was induced with LPS administration, and samples were collected after 6 h under deep anesthesia. LPS administration caused significant lung injury, as evidenced by increased histopathological scores, upregulation of pro-inflammatory markers (TLR4, IL-1��, TNF-��), and oxidative stress (increased MDA, decreased GSH and SOD). Treatment with D-carvone at both doses significantly attenuated these changes. D-carvone downregulated pro-inflammatory markers, upregulated anti-inflammatory (NRF2) and anti-apoptotic (Bcl-2) proteins, and reduced the levels of pro-inflammatory cytokines (IL-1��, TNF-��, IL-8) in lung tissues. In conclusion, D-carvone protects against LPS-induced ALI in rats, possibly through its anti-inflammatory and antioxidant properties. These findings suggest that D-carvone could be a potential therapeutic candidate for preventing and treating ALI.

Apoptosis Cytokines D-carvone Inflammation Lung injury Oxidative stress Sepsis

Aboushanab SA, Ali H, Narala VR, Ragab RF, Kovaleva EG (2021) Potential therapeutic interventions of plant��derived isoflavones against acute lung injury. Int Immunopharmacol 101:108204 [PMID: 34619497]
Albertine KH, Soulier MF, Wang Z, Ishizaka A, Hashimoto S, Zimmerman GA, Matthay MA, Ware LB (2002) Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol 161:1783��1796 [PMID: 12414525]
Asle-Rousta M, Amini R, Aghazadeh S (2023) Carvone suppresses oxidative stress and inflammation in the liver of immobilised rats. Arch Physiol Biochem 129:597��602 [PMID: 33270467]
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, Van Haren F, Larsson A, McAuley DF (2016) Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315:788��800 [PMID: 26903337]
Bhatia M, He M, Zhang H, Moochhala S (2009) Sepsis as a model of SIRS. Front Biosci 14:4703��4711
Celep NA, ��zkanlar S, Erba�� E, Kara A, Ula�� N (2023) Protective effects of the purinergic receptor antagonist A438079 on lipopolysaccharide-induced kidney injury in rats. Laboratuvar Hayvanlar�� Bilimi ve Uygulamalar�� Derg 3:6��11
Celep NA, Erba�� E, Kara H, Kara A (2024) Silymarin reduces paclitaxel-induced lung damage via down-regulating P2X7R expression and inhibiting inflammation and apoptosis in the rats. Pak Vet J 44(1):169��175
Chen G, Song Y, Ma F, Ma Y (2020) Anti-arthritic activity of D-carvone against complete Freund��s adjuvant-induced arthritis in rats through modulation of inflammatory cytokines. Korean J Physiol Pharmacol 24:453��462 [PMID: 33093267]
Cho H-Y, Kleeberger SR (2014) Noblesse oblige: NRF2 functions in the airways. Am J Respir Cell Mol Biol 50:844��847 [PMID: 24783956]
Dai M, Wu L, Yu K, Xu R, Wei Y, Chinnathambi A, Alahmadi TA, Zhou M (2020) D-carvone inhibit cerebral ischemia/reperfusion induced inflammatory response TLR4/NLRP3 signaling pathway. Biomed Pharmacother 132:110870 [PMID: 33080468]
De Carvalho CC, Da Fonseca MMR (2006) Carvone: why and how should one bother to produce this terpene. Food Chem 95:413��422
Erba�� E, Celep NA, Tekiner D, Gen�� A, Gedikli S (2024a) Assessment of toxicological effects of favipiravir (T-705) on the lung tissue of rats: an experimental study. J Biochem Mol Toxicol 38:e23536 [PMID: 37942797]
Erba�� E, Gelen V, ��zt��rk E (2024b) Therapeutic effect of D-carvone on inflammation, apoptosis, and cell damage in lithium-induced liver injury model in rats. Turk J Vet Res 8:95��101
Fan E, Brodie D, Slutsky AS (2018) Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA 319:698��710 [PMID: 29466596]
Galani V, Tatsaki E, Bai M, Kitsoulis P, Lekka M, Nakos G, Kanavaros P (2010) The role of apoptosis in the pathophysiology of acute respiratory distress syndrome (ARDS): an up-to-date cell-specific review. Pathol-Res Pract 206:145��150 [PMID: 20097014]
Gao H, Ren Y, Liu C (2022) Aloe-emodin suppresses oxidative stress and inflammation via a PI3K-dependent mechanism in a murine model of sepsis. Evid-Based Complement Alternat Med 2022:9697887 [PMID: 35978995]
Gopalakrishnan T, Ganapathy S, Veeran V, Namasivayam N (2019) Preventive effect of D-carvone during DMBA induced mouse skin tumorigenesis by modulating xenobiotic metabolism and induction of apoptotic events. Biomed Pharmacother 111:178��187 [PMID: 30583225]
Guo F-F, Meng F-G, Zhang X-N, Zeng T (2022) Spermidine inhibits LPS-induced pro-inflammatory activation of macrophages by acting on Nrf2 signaling but not autophagy. J Funct Foods 94:105115
Iyappan P, Bala MD, Sureshkumar M, Veeraraghavan VP, Palanisamy A (2021) D-carvone induced ROS mediated apoptotic cell death in human leukemic cell lines (Molt-4). Bioinformation 17:171 [PMID: 34393434]
J��ger W, Mayer M, Platzer P, Reznicek G, Dietrich H, Buchbauer G (2000) Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes. J Pharm Pharmacol 52:191��197 [PMID: 10714949]
Jiang K, Guo S, Yang C, Yang J, Chen Y, Shaukat A, Zhao G, Wu H, Deng G (2018) Barbaloin protects against lipopolysaccharide (LPS)-induced acute lung injury by inhibiting the ROS-mediated PI3K/AKT/NF-��B pathway. Int Immunopharmacol 64:140��150 [PMID: 30173054]
Kara A, Ozkanlar S (2023) Blockade of P2X7 receptor-mediated purinergic signaling with A438079 protects against LPS-induced liver injury in rats. J Biochem Mol Toxicol 37:e23443 [PMID: 37365769]
Keddissi JI, Youness HA, Jones KR, Kinasewitz GT (2018) Fluid management in acute respiratory distress syndrome: a narrative review. Can J Respir Ther 55:1 [PMID: 31297439]
Kellner M, Noonepalle S, Lu Q, Srivastava A, Zemskov E, Black SM (2017) ROS signaling in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pulmonary vasculature redox signaling in health and disease: 105��137. https://doi.org/10.1007/978-3-319-63245-2_8
Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73:3221��3247 [PMID: 27100828]
Lu Y-C, Yeh W-C, Ohashi PS (2008) LPS/TLR4 signal transduction pathway. Cytokine 42:145��151 [PMID: 18304834]
Lv L, Yang N, Cao Y, Dang J, Cheng L, El-Sheikh MA, Zhang Y (2021) D-carvone inhibits the JAK/STAT3 signaling pathway and induced the apoptotic cell death in the human gastric cancer AGS cells. J Biochem Mol Toxicol 35:e22746 [PMID: 33661530]
Mahde S, Kathem SH (2023) Anti-inflammatory effect of L-carvone on lipopolysaccharide-induced acute lung injury. Iraqi J Pharm Sci 32:125��132
Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, Herridge M, Randolph AG, Calfee CS (2019) Acute respiratory distress syndrome. Nat Rev Dis Primers 5:18 [PMID: 30872586]
Matute-Bello G, Frevert CW, Martin TR (2008) Animal models of acute lung injury. Am J Physiol-Lung Cell Mol Physiol 295:L379��L399 [PMID: 18621912]
Mo��o G, Sousa C, Capit��o A, MacKinnon SS, Leit��o AJ, Mendes AF (2023) Synthesis of carvone derivatives and in silico and in vitro screening of anti-inflammatory activity in murine macrophages. Int J Mol Sci 24:2263 [PMID: 36768590]
Mohamed ME, Younis NS (2022) Ameliorative effect of D-carvone against hepatic ischemia-reperfusion-induced injury in rats. Life 12:1502 [PMID: 36294936]
Ogaly HA, Aldulmani SA, Al-Zahrani FA, Abd-Elsalam RM (2022) D-carvone attenuates CCl4-induced liver fibrosis in rats by inhibiting oxidative stress and TGF-ss 1/SMAD3 signaling pathway. Biology 11:739 [PMID: 35625467]
Ozkanlar S, Ulas N, Kaynar O, Satici E (2023) P2X7 receptor antagonist A-438079 alleviates oxidative stress of lung in LPS-induced septic rats. Purinergic Signal 19:699��707 [PMID: 36959434]
Passmore MR, Byrne L, Obonyo NG, See Hoe LE, Boon A-C, Diab SD, Dunster KR, Bisht K, Tung J-P, Fauzi MH (2018) Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock. Respir Res 19:1��10
Rajeshwari T, Raja B (2015b) D-carvone, a monoterpene reverses alterations in heart rate, nitric oxide, aortic lipids and enzymatic antioxidant status in nitric oxide deficient hypertensive rats. Int Lett Nat Sci 5. https://doi.org/10.56431/p-7g9a7y
Rajeshwari T, Raja B (2015) Antioxidant and free radical scavenging effect of D-carvone in hypertensive rats. In vivo and in vitro study. Int Lett Nat Sci 35:6��12
Sousa C, Neves BM, Leit��o AJ, Mendes AF (2023) Molecular mechanisms underlying the anti-inflammatory properties of (R)-(-)-Carvone: potential roles of JNK1, Nrf2 and NF-��B. Pharmaceutics 15:249 [PMID: 36678878]
Thompson BT, Chambers RC, Liu KD (2017) Acute respiratory distress syndrome. N Engl J Med 377:562��572 [PMID: 28792873]
Ulas N, Ozkanlar Y, Ozkanlar S, Timurkan MO, Aydin H (2023) Clinical and inflammatory response to antiviral treatments in dogs with parvoviral enteritis. J Vet Sci 25:e11 [>PMCID: ]

��st��nda�� H (2023) The role of antioxidants in sepsis management: a review of therapeutic applications. Eurasian J Mol Biochem Sci 2:38��48

��st��nda�� H, Demir ��, ��i��ek B, Huyut MT, Y��ce N, Tavac�� T (2023a) Protective effect of melatonin and ascorbic acid combination on sepsis-induced lung injury: an experimental study. Clin Exp Pharmacol Physiol 50:634��646 [PMID: 37199082]
��st��nda�� H, Do��anay S, Kal��ndemirta�� FD, Demir ��, Huyut MT, Kurt N, ��zgeri�� FB, Akbaba �� (2023b) A new treatment approach: melatonin and ascorbic acid synergy shields against sepsis-induced heart and kidney damage in male rats. Life Sci 329:121875 [PMID: 37355223]
Vellingiri V, Thirusangu P, Din I (2020) Acute respiratory distress syndrome: therapeutics, pathobiology, and prognosis. Chronic Lung Diseases: Pathophysiology and Therapeutics: 143��156. https://doi.org/10.1007/978-981-15-3734-9_7
Xie K, Yu Y, Huang Y, Zheng L, Li J, Chen H, Han H, Hou L, Gong G, Wang G (2012) Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock 37:548��555 [PMID: 22508291]
Ye J, Hua S, Liu S, Tian F, Ji X, Li Y, Hou M, Xu W, Meng L, Sun L (2022) Enantioselective effects of chiral fragrance carvone (L-and D-carvone) on the physiology, oxidative damage, synthesis, and release of microcystin-LR in Microcystis aeruginosa. Sci Total Environ 853:158631 [PMID: 36084777]
Zeng F, Li Y, Zhang X, Shen L, Zhao X, Beta T, Li B, Chen R, Huang W (2024) Immune regulation and inflammation inhibition of Arctium lappa L. polysaccharides by TLR4/NF-��B signaling pathway in cells. Int J Biol Macromol 254:127700 [PMID: 37918584]
Zhao M, Du J (2020) Anti-inflammatory and protective effects of D-carvone on lipopolysaccharide (LPS)-induced acute lung injury in mice. J King Saud Univ-Sci 32:1592��1596
Zhu X, Wang G, Wu S, Li C (2020) Protective effect of D-carvone against dextran sulfate sodium induced ulcerative colitis in Balb/c mice and LPS induced RAW cells via the inhibition of COX-2 and TNF-��. J Environ Pathol Toxicol Oncol 39:235 [PMID: 32865915]

Journal Article

No available data.

OpenLB
Open Library of Bioscience