β-Caryophyllene as a Novel Modulator of the Renin–Angiotensin System: A Path to Reduce Inflammation and Restore Taste Function
Abstract
1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Experimental Design and Drug Administration
2.3. Monitoring of Health Status
2.4. Open Field Test
2.5. Two-Bottle Preference Test
2.6. Collection of Serum and Lingual Samples
2.7. Determination of the Enzymatic Activity of ACE2 and Renin Concentration
2.8. Quantification of Pro and Anti-Inflammatory Cytokines
2.9. Serum Corticosterone Determination
2.10. Apoptosis Determination
2.11. Quantification of CB2 Expression
2.12. Statistical Analysis
3. Results
3.1. β-Caryophyllene Reduces the Deterioration of Health Status
3.2. Dysgeusia Improved with β-Caryophyllene Treatment
3.3. β-Caryophyllene Attenuates Inflammation and Corticosterone Levels While Modulating the Renin–Angiotensin System
3.4. β-Caryophyllene Reduces Apoptosis in the Tongue While Preserving CB2 Expression Levels
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
6-CFDA | 6-carboxyfluorescein diacetate |
(P)RR | (Pro)Renin Receptor |
Ang-(1-7) | Angiotensin-(1-7) |
Ang I | Angiotensin I |
Ang II | Angiotensin I |
AT1R | Angiotensin II type 1 Receptor |
AT2R | Angiotensin II type 2 Receptor |
ACE | Angiotensin-Converting Enzyme |
ACE2 | Angiotensin-Converting Enzyme 2 |
ACE2KO | Angiotensin-Converting Enzyme 2 Knockout |
AUC | Area Under the Curve |
BCP | β-Caryophyllene control group |
BCP+LPS | Treatment group |
CB2 | Cannabinoid Receptor type 2 |
CIBO | Centro de Investigación Biomédica de Occidente |
COX-2 | Cyclooxygenase-2 |
CT | Control group |
CT+ | Positive control group |
Cy3 | Cyanine 3 |
DAB | Diaminobenzidine |
HPA | Hypothalamic–Pituitary–Adrenal axis |
IL-1β | Interleukin-1β |
IL-6 | Interleukin-6 |
IL-10 | Interleukin-10 |
IL-13 | Interleukin-13 |
IMSS | Instituto Mexicano del Seguro Social |
IQR | Interquartile Range |
LPS | Lipopolysaccharide group |
MasR | Mas Receptor 1 |
MAPK | Mitogen-Activated Protein Kinases |
NCD | Noncommunicable Chronic Diseases |
NF-κB | Nuclear Factor-kappa B |
OD | Optical Density |
RAS | Renin–Angiotensin System |
SD | Standard Deviation |
TLR | Toll-Like Receptors |
TNF-α | Tumor Necrosis Factor-α |
ZnSO4 | Zinc Sulphate |
References
- The Population Division of the Department of Economic and Social Affairs. World Population Ageing 2015; United Nations: New York, NY, USA, 2015. [Google Scholar]
- Murray, C.J.L. Findings from the Global Burden of Disease Study 2021. Lancet 2024, 403, 2259–2262. [Google Scholar] [CrossRef]
- Tsalamandris, S.; Antonopoulos, A.S.; Oikonomou, E.; Papamikroulis, G.-A.; Vogiatzi, G.; Papaioannou, S.; Deftereos, S.; Tousoulis, D. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur. Cardiol. Rev. 2019, 14, 50–59. [Google Scholar] [CrossRef] [PubMed]
- Sorriento, D.; Iaccarino, G. Inflammation and Cardiovascular Diseases: The Most Recent Findings. Int. J. Mol. Sci. 2019, 20, 3879. [Google Scholar] [CrossRef]
- Rohm, T.V.; Meier, D.T.; Olefsky, J.M.; Donath, M.Y. Inflammation in Obesity, Diabetes, and Related Disorders. Immunity 2022, 55, 31–55. [Google Scholar] [CrossRef]
- Zhao, H.; Wu, L.; Yan, G.; Chen, Y.; Zhou, M.; Wu, Y.; Li, Y. Inflammation and Tumor Progression: Signaling Pathways and Targeted Intervention. Signal Transduct. Target. Ther. 2021, 6, 263. [Google Scholar] [CrossRef]
- Mutiawati, E.; Fahriani, M.; Mamada, S.; Fajar, J.; Frediansyah, A.; Maliga, H.; Ilmawan, M.; Emran, T.; Ophinni, Y.; Ichsan, I.; et al. Anosmia and Dysgeusia in SARS-CoV-2 Infection: Incidence and Effects on COVID-19 Severity and Mortality, and the Possible Pathobiology Mechanisms—A Systematic Review and Meta-Analysis. F1000Research 2021, 10. [Google Scholar] [CrossRef]
- Antolín Amérigo, D.; Cubero, J.L.; Colás, C.; Alobid, I.; Mullol, J.; Valero, A. High Frequency of Smell and Taste Dysfunction in Health Care Professionals with COVID-19 Working in Allergy Departments. J. Investig. Allergol. Clin. Immunol. 2021, 31, 151–161. [Google Scholar] [CrossRef] [PubMed]
- Sato, H.; Wada, H.; Matsumoto, H.; Takagiwa, M.; Goto, T.K. Differences in Dynamic Perception of Salty Taste Intensity between Young and Older Adults. Sci. Rep. 2022, 12, 7558. [Google Scholar] [CrossRef] [PubMed]
- Takeuchi, K.; Yoshii, K.; Ohtubo, Y. Age-Related Electrophysiological Changes in Mouse Taste Receptor Cells. Exp. Physiol. 2021, 106, 519–531. [Google Scholar] [CrossRef]
- Lozada-Nur, F.; Chainani-Wu, N.; Fortuna, G.; Sroussi, H. Dysgeusia in COVID-19: Possible Mechanisms and Implications. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2020, 130, 344–346. [Google Scholar] [CrossRef]
- Xu, H.; Zhong, L.; Deng, J.; Peng, J.; Dan, H.; Zeng, X.; Li, T.; Chen, Q. High Expression of ACE2 Receptor of 2019-nCoV on the Epithelial Cells of Oral Mucosa. Int. J. Oral Sci. 2020, 12, 8. [Google Scholar] [CrossRef]
- Park, G.C.; Bang, S.-Y.; Lee, H.W.; Choi, K.U.; Kim, J.M.; Shin, S.-C.; Cheon, Y.; Sung, E.-S.; Lee, M.; Lee, J.-C.; et al. ACE2 and TMPRSS2 Immunolocalization and Oral Manifestations of COVID-19. Oral Dis. 2022, 28, 2456–2464. [Google Scholar] [CrossRef] [PubMed]
- Chatindiara, I.; Sheridan, N.; Kruger, M.; Wham, C. Eating Less the Logical Thing to Do? Vulnerability to Malnutrition with Advancing Age: A Qualitative Study. Appetite 2020, 146, 104502. [Google Scholar] [CrossRef] [PubMed]
- Silva, L.A.d.; Jaluul, O.; Teixeira, M.J.; Siqueira, J.T.T.d.; Jacob Filho, W.; Siqueira, S.R.D.T.d. Quantitative Sensory Testing in Elderly: Longitudinal Study. Arq. Neuropsiquiatr. 2018, 76, 743–750. [Google Scholar] [CrossRef]
- Annane, D.; Bellissant, E.; Bollaert, P.; Briegel, J.; Keh, D.; Kupfer, Y.; Pirracchio, R.; Rochwerg, B. Corticosteroids for Treating Sepsis in Children and Adults. Cochrane Database Syst. Rev. 2019, 6, CD002243. [Google Scholar] [CrossRef] [PubMed]
- Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J.-Z.; Xie, X.-Q.; Altmann, K.-H.; Karsak, M.; Zimmer, A. Beta-Caryophyllene Is a Dietary Cannabinoid. Proc. Natl. Acad. Sci. USA 2008, 105, 9099. [Google Scholar] [CrossRef]
- Shigemura, N.; Takai, S.; Hirose, F.; Yoshida, R.; Sanematsu, K.; Ninomiya, Y. Expression of Renin-Angiotensin System Components in the Taste Organ of Mice. Nutrients 2019, 11, 2251. [Google Scholar] [CrossRef]
- Capece, D.; Verzella, D.; Flati, I.; Arboretto, P.; Cornice, J.; Franzoso, G. NF-κB: Blending Metabolism, Immunity, and Inflammation. Trends Immunol. 2022, 43, 757–775. [Google Scholar] [CrossRef]
- Espinoza-Gutiérrez, H.A.; López-Salido, S.C.; Flores-Soto, M.E.; Tejeda-Martínez, A.R.; Chaparro-Huerta, V.; Viveros-Paredes, J.M. Angiotensinergic Effect of β-Caryophyllene on Lipopolysaccharide- Induced Systemic Inflammation. Biochem. Biophys. Res. Commun. 2024, 719, 150081. [Google Scholar] [CrossRef]
- Francomano, F.; Caruso, A.; Barbarossa, A.; Fazio, A.; La Torre, C.; Ceramella, J.; Mallamaci, R.; Saturnino, C.; Iacopetta, D.; Sinicropi, M.S. β-Caryophyllene: A Sesquiterpene with Countless Biological Properties. Appl. Sci. 2019, 9, 5420. [Google Scholar] [CrossRef]
- Food and Drug Administration. Summary of Data for Chemical Selection: β-Caryophyllene; Food and Drug Administration: Silver Spring, MD, USA, 1997.
- Li, T.; Zhao, M.; Raza, A.; Guo, J.; He, T.; Zou, T.; Song, H. The Effect of Taste and Taste Perception on Satiation/Satiety: A Review. Food Funct. 2020, 11, 2838–2847. [Google Scholar] [CrossRef]
- Atwood, B.K.; Straiker, A.; Mackie, K. CB2: Therapeutic Target-in-Waiting. Progress. Neuropsychopharmacol. Biol. Psychiatry 2012, 38, 16–20. [Google Scholar] [CrossRef]
- Musaelyan, K.; Aldridge, S.; Du Preez, A.; Egeland, M.; Zunszain, P.A.; Pariante, C.M.; Thuret, S.; Fernandes, C. Repeated Lipopolysaccharide Exposure Modifies Immune and Sickness Behaviour Response in an Animal Model of Chronic Inflammation. J. Psychopharmacol. 2018, 32, 236–247. [Google Scholar] [CrossRef]
- Flores-Soto, M.E.; Corona-Angeles, J.A.; Tejeda-Martinez, A.R.; Flores-Guzman, P.A.; Luna-Mujica, I.; Chaparro-Huerta, V.; Viveros-Paredes, J.M. β-Caryophyllene Exerts Protective Antioxidant Effects through the Activation of NQO1 in the MPTP Model of Parkinson’s Disease. Neurosci. Lett. 2021, 742, 135534. [Google Scholar] [CrossRef]
- Espinoza-Gutiérrez, H.A.; López-Salido, S.C.; Flores-Soto, M.E.; Tejeda-Martínez, A.R.; Bañuelos-Pineda, J.; Viveros-Paredes, J.M. β-Caryophyllene’s Potential Modulation of the Renin-Angiotensin System: Implications for Anosmia and Neuroinflammation in the Olfactory Circuitry. Int. Immunopharmacol. 2025, 164, 115373. [Google Scholar] [CrossRef] [PubMed]
- Viveros-Paredes, J.M.; González-Castañeda, R.E.; Gertsch, J.; Chaparro-Huerta, V.; López-Roa, R.I.; Vázquez-Valls, E.; Beas-Zarate, C.; Camins-Espuny, A.; Flores-Soto, M.E. Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP. Pharmaceuticals 2017, 10, 60. [Google Scholar] [CrossRef] [PubMed]
- Meyer, C.W.; Ootsuka, Y.; Romanovsky, A.A. Body Temperature Measurements for Metabolic Phenotyping in Mice. Front. Physiol. 2017, 8, 520. [Google Scholar] [CrossRef]
- Gould, T.D. Mood and Anxiety Related Phenotypes in Mice: Characterization Using Behavioral Tests; Humana Press: New York, NY, USA, 2009; ISBN 978-1-60761-302-2. [Google Scholar]
- Sinclair, M.S.; Perea-Martinez, I.; Abouyared, M.; St. John, S.J.; Chaudhari, N. Oxytocin Decreases Sweet Taste Sensitivity in Mice. Physiol. Behav. 2015, 141, 103–110. [Google Scholar] [CrossRef] [PubMed]
- Waterborg, J.H. The Lowry Method for Protein Quantitation. In The Protein Protocols Handbook; Walker, J.M., Ed.; Humana Press: Totowa, NJ, USA, 2009; pp. 7–10. ISBN 978-1-59745-198-7. [Google Scholar]
- Gómez-Gálvez, Y.; Palomo-Garo, C.; Fernández-Ruiz, J.; García, C. Potential of the Cannabinoid CB2 Receptor as a Pharmacological Target against Inflammation in Parkinson’s Disease. Progress. Neuropsychopharmacol. Biol. Psychiatry 2016, 64, 200–208. [Google Scholar] [CrossRef]
- Poeze, M.; Bruins, M.J.; Luiking, Y.C.; Deutz, N.E. Reduced Caloric Intake during Endotoxemia Reduces Arginine Availability and Metabolism. Am. J. Clin. Nutr. 2010, 91, 992–1001. [Google Scholar] [CrossRef]
- Das, U.N.; Ramos, E.J.B.; Meguid, M.M. Metabolic Alterations during Inflammation and Its Modulation by Central Actions of Omega-3 Fatty Acids. Curr. Opin. Clin. Nutr. Metab. Care 2003, 6, 413–419. [Google Scholar] [CrossRef]
- Stofkova, A. Cachexia—The Interplay Between the Immune System, Brain Control and Metabolism. In Inflammatory Diseases: Immunopathology, Clinical and Pharmacological Bases; Khatami, M., Ed.; IntechOpen: Rijeka, Croatia, 2012. [Google Scholar]
- Figueiredo Cerqueira, M.M.d.; Castro, M.M.L.; Vieira, A.A.; Kurosawa, J.A.A.; Amaral Junior, F.L.d.; Siqueira Mendes, F.d.C.C.d.; Sosthenes, M.C.K. Comparative Analysis between Open Field and Elevated Plus Maze Tests as a Method for Evaluating Anxiety-like Behavior in Mice. Heliyon 2023, 9, e14522. [Google Scholar] [CrossRef] [PubMed]
- Hennessy, M.B.; Deak, T.; Schiml, P.A. Sociality and Sickness: Have Cytokines Evolved to Serve Social Functions beyond Times of Pathogen Exposure? Brain Behav. Immun. 2014, 37, 15–20. [Google Scholar] [CrossRef] [PubMed]
- Lillo, J.; Lillo, A.; Zafra, D.A.; Miralpeix, C.; Rivas-Santisteban, R.; Casals, N.; Navarro, G.; Franco, R. Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet. Int. J. Mol. Sci. 2021, 22, 8928. [Google Scholar] [CrossRef] [PubMed]
- Bahi, A.; Al Mansouri, S.; Al Memari, E.; Al Ameri, M.; Nurulain, S.M.; Ojha, S. β-Caryophyllene, a CB2 Receptor Agonist Produces Multiple Behavioral Changes Relevant to Anxiety and Depression in Mice. Physiol. Behav. 2014, 135, 119–124. [Google Scholar] [CrossRef]
- Tordoff, M.G.; Bachmanov, A.A. Mouse Taste Preference Tests: Why Only Two Bottles? Chem. Senses 2003, 28, 315–324. [Google Scholar] [CrossRef]
- Murata, Y.; Beauchamp, G.K.; Bachmanov, A.A. Taste Perception of Monosodium Glutamate and Inosine Monophosphate by129P3/J and C57BL/6ByJ Mice. Physiol. Behav. 2009, 98, 481–488. [Google Scholar] [CrossRef]
- Gaillard, D.; Stratford, J.M. Measurement of Behavioral Taste Responses in Mice: Two-Bottle Preference, Lickometer, and Conditioned Taste-Aversion Tests. Curr. Protoc. Mouse Biol. 2016, 6, 380–407. [Google Scholar] [CrossRef]
- Wang, H.; Zhou, M.; Brand, J.; Huang, L. Inflammation and Taste Disorders. Ann. N. Y. Acad. Sci. 2009, 1170, 596–603. [Google Scholar] [CrossRef]
- Ichihara, A.; Yatabe, M.S. The (pro)Renin Receptor in Health and Disease. Nat. Rev. Nephrol. 2019, 15, 693–712. [Google Scholar] [CrossRef]
- de Carvalho Santuchi, M.; Dutra, M.F.; Vago, J.P.; Lima, K.M.; Galvão, I.; de Souza-Neto, F.P.; Morais e Silva, M.; Oliveira, A.C.; de Oliveira, F.C.B.; Gonçalves, R.; et al. Angiotensin-(1-7) and Alamandine Promote Anti-Inflammatory Response in Macrophages In Vitro and In Vivo. Mediat. Inflamm. 2019, 2019, 2401081. [Google Scholar] [CrossRef]
- Freitas, R.A.; Junior, R.R.P.; Justina, V.D.; Bressan, A.F.M.; Bomfim, G.F.; Carneiro, F.S.; Giachini, F.R.; Lima, V.V. Angiotensin (1-7)-Attenuated Vasoconstriction Is Associated with the Interleukin-10 Signaling Pathway. Life Sci. 2020, 262, 118552. [Google Scholar] [CrossRef]
- Niri, P.; Saha, A.; Polopalli, S.; Kumar, M.; Das, S.; Saha, B.; Goyary, D.; Bhutia, Y.D.; Karmakar, S.; Kishor, S.; et al. β-Caryophyllene Attenuates Oxidative Stress and Inflammatory Response in LPS Induced Acute Lung Injury by Targeting ACE2/MasR and Nrf2/HO-1/NF-κB Axis. Biochem. Biophys. Res. Commun. 2025, 746, 151286. [Google Scholar] [CrossRef] [PubMed]
- Costa-Pereira, A.P. Regulation of IL-6-Type Cytokine Responses by MAPKs. Biochem. Soc. Trans. 2014, 42, 59–62. [Google Scholar] [CrossRef]
- Rex, J.; Lutz, A.; Faletti, L.E.; Albrecht, U.; Thomas, M.; Bode, J.G.; Borner, C.; Sawodny, O.; Merfort, I. IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation. Front. Physiol. 2019, 10, 117. [Google Scholar] [CrossRef] [PubMed]
- Shaji, C.S.; Saraswathy, R. Taste Receptors Influencing Effective Modalities in Human Health—A Cutting Edge Update on TAS1R and TAS2R Receptor Polymorphisms in Taste Perception and Disease Risk. Nutr. Health 2023, 02601060231186865. [Google Scholar] [CrossRef] [PubMed]
- Narukawa, M.; Kamiyoshihara, A.; Kawae, M.; Kohta, R.; Misaka, T. Analysis of Aging-Dependent Changes in Taste Sensitivities of the Senescence-Accelerated Mouse SAMP1. Exp. Gerontol. 2018, 113, 64–73. [Google Scholar] [CrossRef]
- Miura, H.; Nakayama, A.; Shindo, Y.; Kusakabe, Y.; Tomonari, H.; Harada, S. Expression of Gustducin Overlaps with That of Type III IP3 Receptor in Taste Buds of the Rat Soft Palate. Chem. Senses 2007, 32, 689–696. [Google Scholar] [CrossRef]
- Herman, J.P.; McKlveen, J.M.; Ghosal, S.; Kopp, B.; Wulsin, A.; Makinson, R.; Scheimann, J.; Myers, B. Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr. Physiol. 2016, 6, 603–621. [Google Scholar] [CrossRef]
- Gądek-Michalska, A.; Bugajski, J. Interleukin-1 (IL-1) in Stress-Induced Activation of Limbic-Hypothalamic-Pituitary Adrenal Axis. Pharmacol. Rep. 2010, 62, 969–982. [Google Scholar] [CrossRef]
- Zoppi, S.; Madrigal, J.L.; Caso, J.R.; García-Gutiérrez, M.S.; Manzanares, J.; Leza, J.C.; García-Bueno, B. Regulatory Role of the Cannabinoid CB2 Receptor in Stress-Induced Neuroinflammation in Mice. Br. J. Pharmacol. 2014, 171, 2814–2826. [Google Scholar] [CrossRef] [PubMed]
- Alberti, T.B.; Barbosa, W.L.; Vieira, J.L.; Raposo, N.R.; Dutra, R.C. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. Int. J. Mol. Sci. 2017, 18, 691. [Google Scholar] [CrossRef]
- Horváth, B.; Mukhopadhyay, P.; Kechrid, M.; Patel, V.; Tanchian, G.; Wink, D.A.; Gertsch, J.; Pacher, P. β-Caryophyllene Ameliorates Cisplatin-Induced Nephrotoxicity in a Cannabinoid 2 Receptor-Dependent Manner. Free. Radic. Biol. Med. 2012, 52, 1325–1333. [Google Scholar] [CrossRef] [PubMed]
- McCoy, K.L. Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation. Mediat. Inflamm. 2016, 2016, 5831315. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
López-Salido, S.C.; Espinoza-Gutiérrez, H.A.; Flores-Soto, M.E.; Martínez-Preciado, A.H.; Viveros-Paredes, J.M. β-Caryophyllene as a Novel Modulator of the Renin–Angiotensin System: A Path to Reduce Inflammation and Restore Taste Function. Biomedicines 2025, 13, 2514. https://doi.org/10.3390/biomedicines13102514
López-Salido SC, Espinoza-Gutiérrez HA, Flores-Soto ME, Martínez-Preciado AH, Viveros-Paredes JM. β-Caryophyllene as a Novel Modulator of the Renin–Angiotensin System: A Path to Reduce Inflammation and Restore Taste Function. Biomedicines. 2025; 13(10):2514. https://doi.org/10.3390/biomedicines13102514
Chicago/Turabian StyleLópez-Salido, Sofía Cecilia, Hugo Alejandro Espinoza-Gutiérrez, Mario Eduardo Flores-Soto, Alma Hortensia Martínez-Preciado, and Juan Manuel Viveros-Paredes. 2025. "β-Caryophyllene as a Novel Modulator of the Renin–Angiotensin System: A Path to Reduce Inflammation and Restore Taste Function" Biomedicines 13, no. 10: 2514. https://doi.org/10.3390/biomedicines13102514
APA StyleLópez-Salido, S. C., Espinoza-Gutiérrez, H. A., Flores-Soto, M. E., Martínez-Preciado, A. H., & Viveros-Paredes, J. M. (2025). β-Caryophyllene as a Novel Modulator of the Renin–Angiotensin System: A Path to Reduce Inflammation and Restore Taste Function. Biomedicines, 13(10), 2514. https://doi.org/10.3390/biomedicines13102514